NIEHS Spotlight Science Notebook

January 2014

Birnbaum presents plenary at meeting of Canadian toxicology groupNIEHS and NTP Director Linda Birnbaum, Ph.D., added an interesting twist on the famous quote from Paracelsus during her plenary talk Dec. 4 in Ottawa.

EPA releases chemical screening data and launches challengesResearchers gained access to more chemical screening data with the U.S. Environmental Protection Agency release of new information Dec. 17 on 1,800 chemicals.

NTP shares new toxicology approaches with international colleaguesAssociate Director John Bucher, Ph.D., delivered the keynote lecture at the Karolinska Institutet Nov. 20, on new approaches in toxicology research and testing.

Validating civic perspective, grassroots resources for environmental scienceResearch by members of the public can meet the rigors of science and help advance environmental health efforts, according to Sara Wylie, Ph.D., of Northeastern University.

Lewis Cantley discusses cancer metabolism in Rodbell LectureThe Dr. Martin Rodbell Lecture Series Seminar Dec. 10 featured Lewis Cantley, Ph.D., discussing the role of phosphoinositide 3-kinase signaling in cancer progression.

Seminar showcases Toxicogenetics Challenge winnersA panel of experts peer-reviewed the two most recent draft NTP Report on Carcinogens documents, known as monographs, at a public meeting Dec. 12-13 at NIEHS.

NTP panel peer reviews substances for potential listing as carcinogensA panel of experts peer-reviewed the two most recent draft NTP Report on Carcinogens documents, known as monographs, at a public meeting Dec. 12-13 at NIEHS.

Preterm birth linked with maternal phthalate exposure during pregnancyA new study by Superfund researchers found the women with the highest levels of phthalate exposure during pregnancy had up to five times the odds of preterm birth.

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2013 papers of the yearFrom the more than 2,800 NIEHS-funded studies published in 2013, leaders of the Institute’s three research divisions selected 30 for special recognition as Papers of the Year.

NIEHS Spotlight Science Notebook

Autism studies build on past investments and guide future researchCindy Lawler, Ph.D., discusses three new reports on autism illustrating the diverse nature of current research and its influence on future directions.

New study finds toenails help trace arsenic exposure from foodsDiet alone can be a significant source of arsenic exposure regardless of arsenic concentrations in drinking and cooking water, according to a new study.

NIEHS study identifies protein involved in DNA damage removalThe discovery may help uncover some of the genetic mishaps that contribute to neurodegenerative diseases, as well as point to new therapies for cancer patients.

Researchers find elevated flame retardant exposure among U.S. gymnastsGymnasts may be ingesting or inhaling dust created by foam blocks that contain hormone-disrupting flame retardant chemicals, according to a new study.

New evidence of gene–environment interaction in autismChildren possessing a specific genetic risk factor appear more likely to develop autism spectrum disorder when prenatal exposure to air pollution occurs.

Parents are right: autistic children experience more GI symptomsYoung children with autism spectrum disorder and developmental delays are at least three times more likely to experience frequent gastrointestinal problems.

Researchers’ work translated into positive results for public healthThe NIEHS-funded study of 6- to 8-year-old girls showed that the duration of being breast fed is associated with higher levels of certain polyfluoroalkyl chemicals.

Autism in Minneapolis higher among Somalis and whites than other groupsReport finds autism more prevalent among Somali and white children in Minneapolis.

Newly dedicated facility to house NIEHS-funded labsOfficials at the University of North Carolina, Wilmington cut the ribbon Nov. 18 for a new facility that will serve NIEHS-funded labs on the N.C. coast.

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LSB speaker discusses the role of mobile DNA elements in natureUnderstanding the significance of mobile DNA elements is important because half of human genome is derived from them, according to Phoebe Rice, Ph.D.

Extramural Research

Extramural papers of the month• Epigenetic changes associated with pancreatic

cancer might lead to early detection

• Phthalate exposure linked to preterm birth

• A 3-D map of chromatin interactions

• Girls are reaching puberty earlier

Intramural ResearchIntramural papers of the month

• tssRNAs associated with paused Poll II serve as scaffold for transcription factors

• Asthmatic reaction is dependent on dose and timing of endotoxins

• Modest changes in dNTP levels affect cell’s ability to repair mutations

• Distinct features of RNA binding protein make it unique among its family

NIEHS Spotlight

Students in NIEHS program WOW! supporters with interactive presentationsNIEHS scientists reaped the rewards of teaching and service as they participated in the Citizen Schools WOW! Event Dec. 12 at Lowe’s Grove Middle School in Durham, N.C.

Duke brings Superfund research to the Elizabeth River Learning BargeThe end of 2013 marks the first full semester of Duke University Superfund Research Program field work and outreach on the Elizabeth River Project Learning Barge.

Industry-academic collaboration streamlines decades of dataScientists from Pfizer and North Carolina State University culled more than 88,000 studies for information about toxicity for some 1,200 drugs.

Latoni tapped to head Scientific Review BranchNIEHS welcomed its new Scientific Review Branch chief Nov. 18, as Alfonso Latoni, Ph.D., joined the leadership of the Division of Extramural Research and Training.

Science Notebook

NTP seminar explores functional ecologyAn ongoing lecture series sponsored by NTP made an unexpected turn into animal ecology Dec. 10 with a talk at NIEHS by zoologist Vladimir Vershinin, D.Sc.

This month in EHPThe January issue of Environmental Health Perspectives highlights the role of environmental factors in myopia and the unique qualities of wind turbine noise.

NIEHS research helps unlock one of the secrets of stem cellsA new study by NIEHS researchers helps to explain the molecular basis of self-renewal and differentiation in embryonic stem cells.

Inside the Institute

Employees make the 2013 Giving Tree a successThis year’s Giving Tree allowed 160 area children to have a brighter holiday.

NIEHS scientists join other volunteers to teach children about nutritionThanks to volunteers from NIEHS and public service groups, six children in a Durham, N.C. program learned important lessons about healthy lifestyle and diet.

Calendar of Upcoming Events

• Jan. 7, in the Executive Conference Room, 12:00-1:00 p.m. — Receptor Mechanisms Discussion Group seminar on “The Role of Estrogen Receptor Signaling in Endometriosis,” by Katherine Burns, Ph.D.

• Jan. 10, in Rodbell B, 2:30-3:30 p.m. — Exposome Faculty Meeting

• Jan. 13, in Rodbell A, 9:00-10:00 a.m. — Keystone Science Lecture Seminar Series presentation on “Uncovering Early Life Exposure to Chemical Mixtures,” by Manish Arora, Ph.D.

• Jan. 17, in Rodbell A, 11:00 a.m.-12:00 p.m. — Laboratory of Reproductive and Developmental Toxicology Seminar Series, featuring David McClay, Ph.D., exploring “A Systems and Cellular Analysis of Primordial Germ Cell Homing to the Gonad”

• Jan. 24, in Rodbell Auditorium, 10:30 a.m.-12:00 p.m. — Distinguished Lecture Series with Joseph DeSimone, Ph.D., “Exploiting the Manufacturing Tools of the Microelectronics Industry to Make Precise Organic Particles for Therpeutics and Vaccines”

• Jan. 30, in Rodbell A, 11:00 a.m.-12:00 p.m. — Seminar featuring Sadis Matalon, Ph.D., exploring “Mechanisms and Modification of Halogen-induced Bronchial Hyperreactivity”

• View More Events: NIEHS Public Calendar

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NIEHS SpotlightBirnbaum presents plenary at meeting of Canadian toxicology group By Eddy Ball

NIEHSandNTPDirectorLindaBirnbaum,Ph.D.,addedaninterestingtwistonthefamousquotefromParacelsusduringherplenarytalkDec.4inOttawa,“Doesdosemakethepoison?Acurrentassessmentofnonmonotonicity.”

AddressingtheSocietyofToxicologyofCanada(STC)45thAnnualSymposiumon“MechanisticParadigmsforToxicologicalRegulation,”Birnbaum,whowasjoinedbyanNTPtoxicologistandtwoNIEHSgranteesatthemeeting,discussedanemergingparadigmofdoseresponse.

ThequotefromParacelsus(1493-1541),whoisacknowledgedasthefatheroftoxicology,pointstothetraditionalnotionofdoseresponse—thatincreasingdoseincreasestoxicityinamonotonicpattern.“Allthingsarepoison,”Paracelsusisquotedassaying,“andnothingiswithoutpoison;onlythedosepermitssomethingnottobepoisonous.”

Increasingly,toxicologistsinthefieldofenvironmentalhealthscience,suchasBirnbaum,arerecognizingthatforsomecompounds,especiallyhormonesandhormone-likechemicals,thereversemayholdtrue.Inthesecases,amuchsmallerdosemayhaveadisproportionateimpactontoxicity,whilegreaterdosesmayactuallyblunteffectsthroughseveralantagonisticmechanisms,includingthesaturationofreceptors.

“Thequestionisnolongerwhethernonmonotonicdoseresponsesare‘real’andoccurfrequentlyenoughtobeaconcern,”Birnbaumtoldheraudience.“Clearlythesearecommonphenomenawithwell-understoodmechanisms.Instead,thequestioniswhichdose–responseshapesshouldbeexpectedforspecificenvironmentalchemicalsandunderwhatspecificcircumstances.”

Does dose make the poison?Birnbaumbuiltthecaseforhercentralpremise,withexamplesofessentialnutrients,whichexercisetheirbeneficialeffectsatlowdoses,andhormones,specificallyprolactin,whichexertsbothstimulatoryandinhibitoryeffectsupontesticularsteroidogenesis.Shealsooutlined

Supporting the goals of our colleagues to the north

JoiningBirnbaumatthemeetingwereNTPtoxicologistScottAuerbach,Ph.D.,andNIEHSgranteesDeanJones,Ph.D.,ofEmoryUniversity,andTomGasiewicz,Ph.D.,oftheUniversityofRochester,whoisalsoamemberoftheNationalAdvisoryEnvironmentalHealthSciencesCouncil.Theirtalkswereprominent,amongthe11presentationsduringthesymposium’sthreethemedsessions:

• Auerbachexplored“Characterizationandapplicationoftoxicogenomicperturbationspace,”andJonesarguedfornewdirectionsintoxicologywithhistalk,“Sequencingthehumanexposome:acalltoaction.”Theirtalkswerepartofsessiontwo,“Genome,Epigenome,andExposome:FutureRolesinCarcinogenesisandToxicity.”

• Gasiewiczdiscussed“TheAhreceptorinhematopoieticstemcells(HSCs):regulationofsignalingpathwaysassociatedwithHSCfunction,”aspartofsessionthree,“MolecularToxicology:MappingthePathways.”

OnememberoftheSTCboardofdirectors,incomingpresidentDavidJosephy,Ph.D.,hadaspecialreasontoappreciatethecontributionsofNIEHSscientistsandgranteesatthesymposium.Anaward-winningmoleculartoxicologistattheUniversityofGuelphsince1983,JosephycompletedapostdoctoralfellowshipatNIEHSin1982.

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elevenmechanismsfornonmonotonicdoseresponse,includingtissue-specificshut-offresponse,biochemicalmodificationofreceptors,andendocrinefeedbackloops.

Thiscomplicatedandsomewhatcounter-intuitiveconcept,Birnbaumnoted,hasgainedincreasingacceptanceamongscientistsandregulators.Shepointedtoagrowingbodyofliteratureandstatementsin2012and2013byTheEndocrineSociety,U.S.EnvironmentalProtectionAgency(EPA),andEuropeanCommissionOfficeoftheChiefScientificAdvisor.ShealsoreferredtoanNTPreviewin2001ofliteratureonendocrinedisruptingcompounds(EDCs).

Acentralissueinenvironmentalhealthscience,Birnbaumcontinued,isthelow-doseeffectofexposuretoendocrinedisruptors,whichtheWorldHealthOrganizationdefinedin2002asexogenous,orexternal,substancesormixturesthatalterthefunctionoftheendocrinesystem.Disruptorsincludetheobviousplayers—naturalandsynthetichormones—butalsoplasticizingcompounds,fire-retardantchemicals,andsomepesticides.

A new conversation about endocrine disruptionEDCscanhaveimmediateeffects,buttheirmostharmfulimpactsareoftenmaskedordelayed—withexposuresduringsensitivedevelopmentalwindowstriggeringalterationsthatcausediseaseinlaterlife,especiallyinvulnerableindividualsandsensitivesubpopulations.“Low-doseexposuresthatseeminsignificantmayhavebiologicalmeaningifpersistent,bioaccumulative,and/orifexposureiscontinuousorrepetitive,”Birnbaumsaidinherconclusion.“Itisnotonlythedosethatmakesthepoison,butalsothetiming[oftheexposure].”

ReferringagaintotheEPAstatementonnonmonotonicdoseresponseearlierthisyear,Birnbaumreinforcedhercallforaction.“Itistimetostarttheconversationbetweenenvironmentalhealthscientists,toxicologists,andriskassessors,”shesaid,“todeterminehowourunderstandingoflow-doseeffectsandnonmonotonicdoseresponsesinfluencethewayriskassessmentsareperformedforchemicalswithendocrine-disruptingactivities.”

Duringthequestion-and-answerportionofherpresentation,Birnbaumfieldedarangeofquestionsabouthigh-throughputscreeningofpotentiallybadactors;replacementchemicals,suchasbisphenolS;andapplications,aswellasimplications,oftheprecautionaryprinciple.

Birnbaum, right, enjoyed an opportunity to talk with STC President Louise Winn, Ph.D., of Queen’s University, about environmental health concerns common to people in the U.S. and Canada. Birnbaum’s elegant argument for expanding perspective on dose response set the stage for the first session of the meeting, which examined future directions in the areas of carcinogenesis and toxicity. (Photo courtesy of David Josephy)

Symposium program chair Jayadev Raju, Ph.D., left, of Health Canada, and Jones shared ideas just before the proceedings commenced. (Photo courtesy of David Josephy)

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EPA releases chemical screening data and launches challengesResearchersgainedaccesstomorechemicalscreeningdatawiththeU.S.EnvironmentalProtectionAgency(EPA)releaseofnewinformationDec.17on1,800chemicalsfoundinindustrialandconsumerproducts,foodadditives,anddrugs.

Thedataweregatheredthroughadvancedtechniques,includingroboticsandhigh-throughputscreening,aspartofanongoingfederalcollaborationtoimprovechemicalscreening.Thecollaboration,Tox21,includesEPA,NTP,theNationalCenterforAdvancingTranslationalSciences,andtheU.S.FoodandDrugAdministration.

“Makingthesedatapubliclyavailablewillhelpresearchersacrossdisciplinestobetteridentifyhazardouschemicals,”saidRaymondTice,Ph.D.,whoheadstheNTPBiomolecularScreeningBranch,intheEPApressrelease.“WearepleasedtobeapartnerinthesecollaborativeeffortsandlookforwardtofurtherenhancingtheamountofTox21dataavailabletothepublic.”

ThechemicalscreeningdataisaccessibleonEPA’snewinteractiveChemicalSafetyforSustainabilityoriCSSDashboard.

Thatsameday,EPAannouncedaseriesofchallengesinvitingthescienceandtechnologycommunitytoworkwiththedataandprovidesolutionsforhowthenewchemicalscreeningdatacanbeusedtopredictthelowestdosethatshowsadverseeffectsinanimals.Challengewinnerswillreceiveawardsfortheirinnovativeresearchideas.

“Today’sreleasemarksanimportantmilestoneincommunicatingandimprovingourunderstandingoftheimpactchemicalshaveonhumanhealthandtheenvironment,”saidLekKadeli,actingassistantadministratorforEPA’sOfficeofResearchandDevelopment.

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Auerbach is a molecular toxicologist in the NTP Biomolecular Screening Branch. His primary role is the analysis and interpretation of multivariate data sets. (Photo courtesy of David Josephy)

Gasiewicz discussed a transcription factor that has a critical role in the body’s response to toxic exposures. (Photo courtesy of David Josephy)

Josephy described the question-and-answer session following Birnbaum’s talk as lively and stimulating. “We need to consider risk-benefit issues,” Birnbaum said, in response to one question. “Do we really need particular compounds [that may pose a risk to health] for particular purposes?” (Photo courtesy of the University of Guelph)

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NTP shares new toxicology approaches with international colleagues By Robin Mackar

It’snoteverydayscientistsgetinvitedtogiveapresentationinthesameplacewheretheNobelPrizeinPhysiologyorMedicinehasbeenchosensince1901,butthreeNTPmembersdidexactlythatthisfallattheAdvancingRiskAssessmentofEnvironmentalAgentsConference.

AttherequestoftheKarolinskaInstitutetinSweden,NTPAssociateDirectorJohnBucher,Ph.D.,deliveredthekeynotelectureNov.20onnewapproachesintoxicologyresearchandtestingandhowtheyarebeingappliedtoadvancethehealthriskassessmentprocessintheU.S.

Bucher’stalknicelysetthetoneforthenextsessionledbytwootherNTPinvitedguests,KristinaThayer,Ph.D.,directoroftheNTPOfficeofHealthAssessmentandTranslation(OHAT),andAndrewRooney,Ph.D.,OHATdeputydirector,whodiscussedtheNTPframeworkforsystematicreview.

Allofthetalksweregiveninthenewstate-of-the-artlecturehall,AulaMedica,which,asofDec.7,becamethevenueforscientificpresentationsbyallNobellaureatesinphysiologyormedicine,beforereceivingtheirmedalsfromtheKingofSweden.“Averyimpressive,ifnotintimidating,environmenttogiveasciencetalkin,”Buchernoteduponhisreturn.

Advancing risk assessmentThetwodayconference,“AdvancingRiskAssessmentofEnvironmentalAgents,”washostedbytheInstituteofEnvironmentalMedicine(InstitutetförMiljömedicinorIMM),aninterdisciplinaryresearchdepartmentattheKarolinskaInstitutet.TheIMMinvitedleadingresearchersfromtheU.S.,Italy,Holland,andSweden,todiscusshowtotakeresearchfindingsandmoderntechnologiesandapplythemtoadvancethehealthriskassessmentprocess.

AndersAhlbom,Ph.D.,directorandchairofIMM,kickedoffthemeetingbywelcomingtheinternationalspeakers,presentingthemwithabriefoverviewofhealthriskassessmentatIMM,andlayingoutsomeofthemajorchallengesthatallgovernmentagenciesfacewhenconductingenvironmentalhealthriskassessments.

Linked video:Take a self-paced virtual tour of the new Hall of Medicine at the Karolinska Institutet.

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Under Bucher’s leadership, NTP has forged several new partnerships, internationally and domestically, including the Tox21 interagency consortium. (Photo courtesy of Steve McCaw)

Thayer leads OHAT efforts to examine emerging issues in toxicology, such as obesity and diabetes, that may be triggered by exposures to endocrine-disrupting chemicals (see story). She also contributes to the NTP and NIEHS green chemistry initiative, which evaluates and compares the relative toxicity of chemicals proposed as safer replacements for other toxic chemicals. (Photo courtesy of Steve McCaw)

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Oneofthemajorgoalsoftheconferencewastofigureouthowtomoveforwardwiththeintegrationoftoxicological,epidemiological,andmechanisticresearchstudiesintotheriskassessmentprocess.

Bucher’stalkfocusedontheproactiveapproachbyNTPtoaddresschallengesinenvironmentalhealth.HediscussedtheprogressmadesincethereleaseoftheNTPRoadmapin2005,alongwithrecentadvancesintoxicologytestingandanalysisapproaches.

HisdiscussionsetthestageforThayerandRooneytoillustratehowRoadmapprogresshashelpedNTPestablishasystematicreviewprocessforhealthassessmentsthatfocusesontheintegrationofdata.OHATdevelopsliterature-basedevaluationstoframeitsinvestigationsofpotentialhumanhealthhazardsandexaminethestateofthescience.

Learning from one anotherThayertalkedaboutsteps1-4oftheOHATframeworkforsystematicreview,whichfocusesonthecriticalaspectsofdevelopingtheprotocol,managingdata,andassessingstudyquality.Thayeralsodazzledthe200attendeeswiththedataentryandanalysistoolsthatNTPisusingtoconducttheevaluations.Allthetoolswilleventuallybemadeavailabletothepublicfreeofcharge.

Rooneyfocusedonsteps5-7,whichguidetheintegrationofepidemiological,toxicological,andotherrelevantdata.“Therewasalotofinterestinthemethodswe’resharing,”Rooneysaid.“Theylikedtheclear,step-by-stepprocessofhowweareintegratingdifferentlinesofevidencetodevelopconclusions.”

Attendeeswereespeciallyinterestedinthedataentrytoolsandthepossibilityofholdingtrainingsessions,sootherscanusetheNTPprocess,andeveryonecanbeginenteringandstoringinformationinthesameway,Thayernoted.

“Noonehastheresourcestokeepreinventingthewheel,”Thayersaid.“Otheragencies,nationallyandinternationally,arelookingtotheNTPtotakeanactiveroleindevelopingandevaluatingapproachesforbringingsystematicreviewmethodsintoenvironmentalhealthscience.”

(RobinMackarisnewsdirectorintheNIEHSOfficeofCommunicationsandPublicLiaison,andafrequentcontributortotheEnvironmentalFactor.)

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In addition to his work on the theoretical framework of systematic review, Rooney was instrumental in the OHAT evaluation of literature on the potential health effects of low-level exposures to lead (see story) in 2011. (Photo courtesy of Steve McCaw)

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Validating civic perspective, grassroots resources for environmental science By Joe Balintfy

Researchbymembersofthepubliccanmeettherigorsofscienceandhelpadvanceenvironmentalhealthefforts,accordingtoSaraWylie,Ph.D.,assistantprofessorofanthropologyatNortheasternUniversity.WylievisitedNIEHSDec.9andpresented“TowardaCivicScience:PuttingToolsforRigorousResearchintoPublicHands.”

“[I’m]reallytryingtoshowhowchangingthetoolsthatweuseforscience,howbuildingonlinedatabasesforgatheringcommunityexperiences,andthenhowexpertanalysisofdatacouldproducearesponsivenetworkforcommunity-basedenvironmentalmonitoring,”Wyliesaid.

Wylieoutlinedwhatshecalledacivicapproachtoenvironmentalhealthresearch,withpeopleonthefrontlinesbecomingdirectlyinvolvedindoingrigorousscience.Usingsuchdevicesasballoons,modifiedconsumercameras,andfree-sourcesoftware,theendresultsofagrassrootsapproachcanincludebetterimagesofoilspills,moreepidemiologicaldataonendocrine-disruptingchemicals,andmorethoroughmonitoringofwellwater.

Tools in the hands of those closest to the sourcesWhatstartedasdevelopmentofaninexpensivewaytomakesatellite-likemaps,usingheliumballoonsanddigitalcameras,evolvedintoaresourceplatformcalledPublicLab,whichcommunitiesusedduringtheGulfoilspilltocreate,archive,andimprovedocumentationofthedisaster’senvironmentalimpact.

SymmaFinn,Ph.D.,oftheNIEHSPopulationHealthBranch,hostedthepresentation.Assheexplained,balloonmappingvalidatedlocalconcernsthatthingswerenotascleanedupas

Presentation demonstrates how efforts parallel NIEHS strategic planThroughoutWylie’spresentation,shemadeparallelstoNIEHSstrategicgoals,inparticulargoals5-8,whichincludeidentifyingemergingenvironmentalhealththreats,conductingcommunity-basedparticipatoryresearch,creatingcollaborations,andteachingenvironmentalhealthscience.

Forexample,shepointedoutthatthetoolsofPublicLabhelpidentifyemergingthreats,fostercommunity-basedresearch,andencouragescientificliteracy.Onetool,adaptedbyFEMAtocrowdsourcehurricanedamageimages,resultedinmorethan6,000individuals,makingmorethan130,000assessments,showinghowahealththreatcanbemonitored,andhowthepubliccanbeinvolvedandeducated.TheEndocrineDisruptionExchange,shesaid,alsomeetsthegoalofmonitoringhealththreats,aswellasenhancingcollaboration,whilethepublicuseofdo-it-yourselftoolsandcontributingtoaccessibledatabasesfostersscientificliteracy.

Wylie pointed out how her research projects connect to NIEHS strategic goals 5-8. (Photo by Steve McCaw)

Listen as Wylie describes her concept of civic science and the ways today’s tools can be modified to encourage popular, grassroots research (01:45)

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seeninsatelliteimages.“Peopleonthegroundunderstandtheircommunitiesandtheirecosystemawholelotbetterthanscientistsgivethemcreditfor,”Finnsaid,addingthatscientistsgroundedinthegrassrootscanachievewhatNativeAmericanstermlocalecologicalknowledge.

Balloonmapping,whichusesfree-sourcemappingsoftwaresuchasMapKnitter,hassincebeenusedtohelpdetectinflowsattheGowanusCanal,aSuperfundcleanupsiteinNewYork.WyliesaidtherearemanymoreresourcesPublicLaboffers.“OneofthetoolsthatPublicLabhasdevelopedisfordoinglow-costthermalinspectionsofyourhome.”

Wylieemphasizedthatthesetools,alongwithothersindevelopment,canhelpbothcommunitiesandgovernmentagencies.ShepointedtoacollaborationthatinvolvedFederalEmergencyManagementAgency(FEMA)useofaPublicLabtoolshortlyafterHurricaneSandy.“[It]enabled6,000peopletogetonlineandparticipate.”PeoplesearchedimagesoftheNewJerseycoasttoidentifytheoneswiththemostdamage,tohelpFEMAtargetitsresponse.

A balloon map of the Gulf oil spill in Wilkinson Bay, La., shows broken booms better than satellite images can. This kind of mapping can also be integrated with satellite images and Google maps. (Photo courtesy of Public Lab)

The WellWatch website is an extrAct tool that maps complaints and tracks issues, including health outcomes, near oil and gas wells. Wylie said it is a platform for rigorous grassroots mapping and epidemiology that creates support networks across communities. (Photo courtesy of MIT Comparative Media Studies)

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Community-based data collection and analysisWyliealsodescribedcivicsciencedataresources,andpointedtoTheEndocrineDisruptionExchange,whichhascompiledadatabaseofchemicalsandseveralmetalsusedinnaturalgasdevelopment.FinnechoedWylie’sargumentaboutthepotentialfordatacollectedbycommunitiestoguideresearch.“Itmaybringupquestionsorhypothesesthatwewouldnothavethoughtof[otherwise],”shesaid.

AnotherexampleWyliesharedisextrAct,asuiteofpubliclyaccessibledatabasesandmapsthathelpaggregategrassrootsefforts.ShesaidthegoalofextrActistopromotecommunication.“Forinstance,[extrActcanhelp]communitiesdealingwithoilandgasextractionfindeachotherandbuildacommunityofconcernaroundthatindustry—particularlyforlandowners,whotendtoexperienceissuesinrealisolation—tryingtocreateaninfrastructureforpeopletosharetheirproblemsandtostartattractingresearcherstolookattheircases.”

(JoeBalintfyisapublicaffairsspecialistintheNIEHSOfficeofCommunicationsandPublicLiaison.)

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Newly dedicated facility to house NIEHS-funded labs By Eddy Ball

OfficialsattheUniversityofNorthCarolinaWilmington(UNCW)cuttheribbonNov.18foranewfacilitythatwillserveNIEHS-fundedlabsontheN.C.coastparticipatinginaninnovativepublic-privatepartnershipinitiativetoadvancehealthresearchandtranslation.

Theceremonyatthenew69,000square-footMarineBiotechnologyinNorthCarolina(MARBIONC)buildingfeaturedcommentsbyUNCWChancellorGaryMiller,Ph.D.,theUNCWBoardofTrustees,andCongressmanMikeMcIntyre,D-N.C.InattendancewereNIEHSProgramDirectorFrederickTyson,Ph.D.,granteeDanielBaden,Ph.D.,representativesfromtheNationalInstituteofStandardsandTechnology(NIST),NationalOceanographicandAtmosphericAdministration,andMARBIONC,aswellaspublic-privatepartnersandthegeneralpublic.

UNCWused30-yearbondstopayforhalfofthe$30millionbuilding.TheotherhalfcamefromfederalstimulusmoneyprovidedbyNIST.ThegreenbuildingisLEED(LeadershipinEnergyandEnvironmentalDesign)silvercertifiedandoffersflexiblemodularlabspaceforlease.

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Baden stands beside samples in the red tide study culture room. (Photo courtesy of UNCW and Jamie Moncrief)

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Scientistsintheuniversity-relatedMARBIONCprogramhavebeenworkingtowardthegoalofturningmaterialsinthemarineenvironmentintonewproducts,drugs,andtechnologies,aswellascreatingpotentialspin-offcompaniesandjobs.AsitsUNCWwebsiteproclaims,“MARBIONCisinthebusinessoftransformingthemysteriesofthedeepintothemiraclesofthemarketplace.”

The NIEHS connectionAtthehuboftheNIEHSconnectionwiththeMARBIONCfacilityisBaden,anexpertinthefieldofmarinebiologyandanNIEHSgranteesince1991,whenhewasonthefacultyatMiamiUniversity.Currently,BadenisdirectoroftheCenterforMarineScience(CMS),whichistheUNCWpartnerinMARBIONC,andadministersthenon-profitMARBIONCDevelopmentGroup.

ResearchunderwayatCMSisemblematicofthewayMARBIONCplanstotranslatebasicresearch.Baden’sworkwithextremelytoxicmicroorganismbloomsthatflourishinwarmAtlanticwatersledtothesurprisediscoveryofanaturalantitoxin,brevenal,whichisalsoproducedbytheorganism.Itturnsoutthatbrevenalhaspotentialfortreatingpatientswithcysticfibrosis,chronicobstructivepulmonarydisease,andotherrelatedlungdiseases(seestory).

“Theantitoxinitself,knownasbrevenal,promotesaseriesofphysiologiceffectsknownasmucociliaryclearance,”BadenexplainedinaninterviewwithSteveCurwoodoftheradioprogramLivingonEarth.“Andtheeasywayofsayingthatisitmakesyourmucusthinneranditmakesitcapableofbeingexpulsedfromthelungmuchmorereadily.”

“Putthetwotogether,anditshouldbeatherapyforanythingthathasthick,ropeymucusthatcan’tbeclearedfromthelung.”

AccordingtoTyson,theopeningoftheMARBIONCmarksamajorsuccesscomingfromtheharmfulalgalbloomresearchthatNIEHShassupportedforseveraldecades.“Characterizationofthemechanismsoftoxicityassociatedwithbrevetoxins,andtheultimateidentificationofbrevenalanditstherapeuticpotential,wasthekeyresearchdriverthatledtotheestablishmentofMARBIONCDevelopmentGroupandthestate-of-the-artmarineresearchfacility,”hesaid.

Crest Research Park at UNCW is a place for university researchers, private firms, and government agencies to work together to create biotechnology products and solutions. (Aerial photo courtesy of UNCW)

The MARBIONC building’s labs are well-lit, spacious, easily adaptable for tenants, and filled with state-of-the-art equipment. (Photo courtesy of Dan Baden)

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Autism studies build on past investments and guide future research By Kelly Lenox

ThreenewNIEHS-fundedstudiesonautismspectrumdisorder(ASD)illustratethebroadscopeofcurrentresearchintothissignificanthealthconcern.CindyLawler,Ph.D.,chiefoftheNIEHSGenes,Environment,andHealthBranch,whichmanagestheInstitute’sgrantsforautismresearch,discussedtheseexcitingnewadvancesinthequesttobetterunderstandandhelppreventandtreatthesedisorders.

Results of long-term investmentAstudyteamledbyresearchersattheUniversityofSouthernCalifornia(seestory)foundthatthecombinationofprenatalexposuretoairpollutants,combinedwithageneticpredispositiontoASD,ledtoahigherriskofthedisorder.Theseresultsprovideanimportantadvanceinthefield,andalsoillustrate,asLawlerpointedout,thevalueoflong-terminvestment.“Thisstoryhasbeenawhileinthemaking,butNIEHShasbeeninvolvedalongthetrajectory,fundingnotonlythisstudy,butsomeofthoseonwhichitbuilds.”

ForLawler,theCenterforChildren’sEnvironmentalHealthattheUniversityofCalifornia(UC),Davis,illustrateshowconsistentfundingandinterdisciplinarycollaborationaremovingthefieldforward.ThecentergaverisetotheCHARGE(ChildhoodAutismRisksfromGeneticsandtheEnvironment)studyattheUCDavisMINDInstitute.“Ittakesalotoftimetobuildtheinfrastructureofalargestudy.We’renowreapingthebenefitsofinvestmentswemadestartingmorethantenyearsago,andtheworkisbeginningtouncoverenvironmentalriskfactors,”sheexplained.“Thisisonlypossiblebecauseofthefundingthathelpedbuilditandisstillsupportingit.”

Tyson, right with orange tie, joined in the ribbon cutting that officially opened the new building. (Photo courtesy of Dan Baden)

Among the dignitaries speaking at the dedication of the new building was McIntyre, who represents the state’s seventh congressional district, which includes Wilmington and much of southeastern N.C. (Photo courtesy of Dan Baden)

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New directions in research — exploring the mind-gut connectionAnotherstudy(seestory),examiningtheincidenceofgastrointestinal(GI)symptomsandASD,ispartofagrowinginterestinchronicco-occurringconditions.“Thisstudyconfirmswhatwehearfromalotofparents,especiallyregardinghowsomeofthecomorbidities,suchasGIissues,areasimportantasthecoresymptomsofautismintermsoftheimpactonfamilies,”explainedLawler.

However,moreresearchisneededtodiscoverwhethertheGIsymptomscontributetothecoresymptomsorthereverse,orwhetherotherchangesmightbeattherootofbothgroupsofsymptoms.

WorkconnectingGIdisturbancestoASDalsohasimplicationsforotherstudiesthatarebeginningtoexplorethemicrobiome,acommunityofmicroorganismsinhabitinganareasuchasthehumangut.Verylittleisknownabouthowthemicrobiomeofchildrenwithautismcomparestothatoftypicallydevelopingchildren,orofchildrenwithdevelopmentaldisabilitiesbutnotautism.

LawlerpointedoutthatfindingsrelatedtoGIdisturbancesmayadvanceknowledgeofASD,aswellasleadtotreatmentapproachesthatmayprovidereliefforfamilies.

Listening to familiesItwasinformationfromfamilies,specifically,SomalifamiliesinMinneapolis,thatledtheUniversityofMinnesotatoinvestigatetheprevalenceofautismamongtheirchildren(seestory).

“TheprevalenceinSomaliswashigh,withonein32childrenaffected,butitwasnotdifferentfromtheprevalenceinwhites.TherateinHispanicsandblacknon-Somalichildrenwassignificantlylower,”Lawlerobserved.

Inaddition,intellectualdisabilityamongchildrenwithASDwasfoundmuchmoreofteninSomalichildrenthaninallothergroups,butthereasonsareunknown.

“ArethereculturalissuesrelatedtoassessingIQintheSomalipopulation,orthatmakeitlesslikelyforschoolsandhealthserviceproviderstoidentifyASDinSomalichildrenwhohaveaverageoraboveaverageintelligence?”Lawlercontinued.“IfthereisatruedifferenceinthecharacteristicsofSomalichildrenwithASD,furtherstudyisneededtodeterminewhichfactorsmaybeinvolved,forexample,factorsrelatedtorace,ethnicity,healthcarepractices,socioeconomics,orimmigration.”

Advancing autism researchFromuncoveringgene-environmentinteractions,toexpandingunderstandingofconnectionsbetweenco-occurringsymptoms,tobreakthroughsinepidemiology,researchersaremakingwide-rangingdiscoveriesandansweringquestionsthatwillhelpguidefutureautismresearch.

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Lawler is the NIEHS program lead for autism research. (Photo courtesy of Steve McCaw)

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New evidence of gene–environment interaction in autism By Kelly Lenox

Childrenpossessingaspecificgeneticriskfactorappearmorelikelytodevelopautismspectrumdisorder(ASD)whenprenatalexposuretoairpollutionoccurs,accordingtoastudyledbyNIEHS-fundedresearchersattheKeckSchoolofMedicineattheUniversityofSouthernCalifornia(USC).Thestudy,publishedonlineinthejournalEpidemiology,establishesasynergisticinteractionbetweenageneticriskfactor,theMETrs1858830genotype,andanenvironmentalfactor,airpollution.

“Ourresearchshowsthatchildrenwithboththeriskgenotypeandexposuretohighairpollutantlevelswereatincreasedriskofautismspectrumdisorder,comparedtothosewithouttheriskgenotypeand[with]lowerairpollutionexposure,”explainedHeatherVolk,Ph.D.,assistantprofessorofresearchinpreventivemedicineandpediatricsatUSC.

ThestudybuildsonearlierresearchdemonstratingindependentcontributionstoautismriskfromMETandfromexposuretoairpollutants.

Results may clarify effect of allele on risk of autismThefindingthatfactorssuchasairpollutionexposuremaybeinvolvedinASDissignificant,becausegene-onlyanalyseshaveshowninconsistentevidenceofalinkbetweencommonalleles,oralternativeformsofagene,anddevelopmentofASD.

“Althoughgene-environmentinteractionsarewidelybelievedtocontributetoautismrisk,thisisthefirstdemonstrationofaspecificinteractionbetweenawell-establishedgeneticriskfactorandanenvironmentalfactorthatindependentlycontributetoautismrisk,”notedstudyco-authorDanielCampbell,Ph.D.,assistantprofessorofpsychiatryandthebehavioralsciencesatUSC.

Theauthorscallforindependentreplicationoftheirfindingsandnotetheneedforamoredetailedunderstandingoftheunderlyingmechanisms.

Campbell noted that much work is yet to be done. “It will be important to replicate this finding and to determine the mechanisms by which these genetic and environmental factors interact to increase the risk for autism.”(Photo courtesy Don Milici)

Volk is lead author of the study finding that children with both a genetic risk factor and prenatal exposure to air pollutants experienced increased risk for ASD. (Photo courtesy of Heather Volk)

Linked video:Watch Volk discuss her research on how environmental factors work together with genetics to increase risk of disorders such as ASD. (1:32)

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Citation:Volk,HE,KerinT,LurmannF,Hertz-PicciottoI,McConnellR,CampbellDB.2014.AutismSpectrumDisorder:InteractionofAirPollutionwiththeMETReceptorTyrosineKinaseGene.Epidemiology25(1):44-47.

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Parents are right: autistic children experience more GI symptoms By Kelly Lenox

ResearchersattheUniversityofCalifornia,Davis(UCD),havefoundthatyoungchildrenwithautismspectrumdisorder(ASD)anddevelopmentaldelaysareatleastthreetimesmorelikelytoexperiencefrequentgastrointestinal(GI)problemsthanaretypicallydevelopingchildren.

ThestudyfindingsappearedintheNovember2013issueoftheJournalofAutismandDevelopmentalDisorders.

ParentsofchildrenwithASDreportedfrequentoccurrenceofcertainGIsymptoms,includingdiarrhea,constipation,andsensitivitytofoods,sixtoeighttimesmoreoftenthandoparentsoftypicallydevelopingchildren.Furthermore,amongallchildrenwithASD,thepresenceofGIsymptomswasassociatedwithbehaviorssuchasirritability,socialwithdrawal,andhyperactivity.

Results parallel parent reports“Afteryearsofparentsraisingconcernsaboutsuchsymptoms,thehugedifferenceswesee…puttoresttheideathatgastrointestinalproblemsamongchildrenwithautismspectrumdisorderarejustanaccumulationofcasereports,”observedIrvaHertz-Picciotto,Ph.D.,leadresearcheronthestudy.

Namedoneofthe2013Top10AdvancesinAutismResearchbyAutismSpeaks,thestudyisnotableforitsinvolvementofalarge,ethnicallydiversepopulation.Researchersenrollednearly1,000children,aged24-60months,approximatelyone-halfofwhomwerewhite,one-thirdHispanic,andone-sixthfromotherracialandethnicbackgrounds.

Hertz-Picciotto, lead researcher on the study, also launched the CHARGE study, the first large, comprehensive population-based study of environmental factors in autism, and the landmark MARBLES study of early environmental and biologic predictors of autism. (Photo courtesy UC Regents)

“GI problems may create behavior problems, and those behavior problems may create or exacerbate GI problems,” noted Virginia Chaidez, Ph.D., a postdoctoral researcher at UCD at the time of the study. “One way to try to tease this out would be to begin investigating the effects of various treatments and their effects on both GI symptoms and problem behaviors.” (Photo courtesy UC Regents)

Linked video:Watch Chaidez discuss findings on GI problems in children with autism and developmental delays (02:36)

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Determining causality requires further studyResearchersnotethat,althoughmechanismsandcontributingfactorsexplainingthedifferencestheyfoundarenotyetunderstood,achronicproblemcausingpain,discomfort,oranxietycouldplausiblycontributetoincreasedirritabilityandsocialwithdrawal,especiallyinapersonwithdeficitsinsocialandcommunicativeskills.Also,becauseneurotransmittersystemsthatareactiveinthebrainalsofunctioninthegut,furtherresearchintoGIsymptomscouldprovideinsightintoneurobiologicalaspectsofthedisorder.

Citation:ChaidezV,HansenRL,Hertz-PicciottoI.2013.Gastrointestinalproblemsinchildrenwithautism,developmentaldelaysortypicaldevelopment.JAutismDevDisord;doi:10.1007/s10803-013-1973-x[Online6November2013].

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Autism in Minneapolis higher among Somalis and whites than other groups By Kelly Lenox

Theprevalenceofautismspectrumdisorder(ASD)in2010amongSomaliandwhitechildreninMinneapoliswasgreaterthanamongblacknon-SomaliandHispanicchildren,accordingtoanewUniversityofMinnesota(UM)projectandresultingcommunityreport.TheprojectwasfundedjointlybyseveralNIHinstitutes,theCentersforDiseaseControlandPrevention(CDC),andAutismSpeaks,aswellasothers.SomalichildrenwithASDwerealsomorelikelytohaveanintellectualdisabilitythanchildrenwithASDinallotherracialandethnicgroups.

ChildrenwithASDinMinneapolisweretypicallydiagnosedaroundage5,whichmeanschildrenarenotbeingdiagnosedasearlyastheycouldbe,accordingtotheresearchers.TheyfurtherreportthattheoverallprevalenceofASDinthecityin2010washigherthaninmostothercommunitiesstudiedbytheCDCin2008,thoughdifferencesintimingandsizeofcommunitiesmakecomparisondifficult.

TheMinneapolisSomaliAutismSpectrumDisorderPrevalenceProjectwasdevelopedaftera2009studybytheMinnesotaDepartmentofHealthfoundhigherthanexpectedenrollmentofSomalichildreninthecity’spreschoolspecialeducationprogramforchildrenwithASD.Theprojectwasdesignedtodeterminewhether,amongchildrenwholiveinMinneapolis,theprevalenceofASDwashigherinSomalichildrenthaninnon-Somalichildren.

Records screening reveals questions for further research“Thisproject,basedonanalysisofnumerousandvariedrecords,producedfascinating,complexresults,”notedCindyLawler,Ph.D.,chiefoftheNIEHSGenes,Environment,andHealthBranch,whichadministerstheInstitute’sfundingforautismresearch.

In the early 1990s, thousands of Somali refugees came to United States after civil war erupted in Somalia, a country located in the horn of Africa. Many were resettled in Minnesota, especially Minneapolis. (Image courtesy of Minneapolis Somali Autism Spectrum Disorder Prevalence Project)

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AmyHewitt,Ph.D.,directoroftheResearchandTrainingCenteronCommunityLivingatUM,suggestshowtheseresultspointtonextsteps.“FutureresearchcanandshouldbuilduponthesefindingstobetterunderstandhowASDaffectsSomaliandnon-Somalichildren,”shesaid.“Thisprojectwasnotdesignedtotelluswhythesedifferencesexist,butitsfindingssupporttheneedformoreresearchonwhyandhowASDaffectsSomaliandnon-Somalichildrenandfamiliesdifferently.”

Resources to support earlier diagnosis and interventionNotingthatincreasedawarenesscouldlowertheageofdiagnosisandassistfamiliesinprovidingthebestpossibleenvironmentfortheirchild’sdevelopment,thereportconcludesbydirectingfamiliestoawiderangeofresources,bothintheMinneapolisareaandonline.

Resourcesincludechilddevelopmenttrackers,clinicsfordiagnosisandassessment,interventionprogramsdesignedtomeetindividualneeds,andorganizationsengagedinadvocacyandresearch.OneSomaliparentquotedinthereportsharedherchild’sexperiencewithtargetintervention.“Ihaveseenmychildmaketremendousgainswhenherspecificneedswerematchedtotheservicesshereceived.Whatworksforonechilddoesnotworkforanother.”

NIHfundingfortheprojectwasprovidedbyNIEHS,alongwiththeEuniceKennedyShriverNationalInstituteofChildHealth,NationalInstituteofMentalHealth,andNationalInstituteonMinorityHealthandHealthDisparities.

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Hewitt directed the project, comparing Somali and non-Somali children in Minneapolis, in response to community concerns about ASD in the Somali community. (Photo courtesy University of Minnesota)

ASD prevalence among children aged 7-9 in Minneapolis in 2010, by race and ethnicity (Graphic courtesy of Minneapolis Somali Autism Spectrum Disorder Prevalence Project)

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Latoni tapped to head Scientific Review Branch By Eddy Ball

NIEHSwelcomeditsnewScientificReviewBranch(SRB)chiefNov.18,asAlfonsoLatoni,Ph.D.,joinedtheleadershipranksoftheDivisionofExtramuralResearchandTraining(DERT).

Latonileadsastaffoffivescientificreviewofficers(SROs)andfourextramuralsupportassistants(ESAs).SRBisakindoffrontdoorforaspiringNIEHSgrantees,responsiblefortheinitialscientificandtechnicalmeritreviewofgrantapplicationsandcontractproposalssubmittedtoNIHforfunding.

Latoniandthereviewofficershavearesponsibilitytothepublicandtothescientificcommunity,foridentifyingthemostmeritoriousscientificresearchtosupport,andtoapplicants,forgivingeverygrantapplicationandcontractproposalanexpert,objective,timely,andfairinitialpeerreview.“Weneedtoshowtheworldthatwehavethebestscientists,”hesaid.“Our[reviewpanel]rostershavetobetopnotch.”

Not just more of the sameAnativeofPuertoRico,LatonireceivedhisundergraduateeducationfromtheUniversityofPuertoRico(UPR),andlaterwentontoearnhisPh.D.fromBostonCollegeinsociology,withafocusonsocialeconomyandsocialpolicy.PriortojoiningNIHin2002,hewasassociateprofessorattheUPRMayagüez,from1986-2000,anddirectoroftheMinorityAffairsProgramattheAmericanSociologicalAssociationinWashington,D.C.,from2000-2002.

Duringhis11-yearcareeratNIHinBethesda,Md.,LatoniservedasanSROattheNationalInstituteonAging(NIA),from2002-2005,andattheCenterforScientificReview,from2005-2008,beforereturningtoNIAtoserveasdeputychiefofitsScientificReviewBranch,from2008-2013.

ForLatoni,hisnewpositionisthenaturalnextstepinhiscareeratNIHinscientificpeerreview.Although,inmanyways,thepoliciesandproceduresarestandardized,hewasquicktoadd,“It’sreallynotjustmoreofthesame.”

SimilarinsizetoNIEHS,NIAisalsooneofthebiologicalprocess,ratherthandisease-specificororgan-specificinstitutes,andhasabroadportfolioofgrants.Still,NIEHSoffersevengreaterchallenges,withitsmorevariedinterdisciplinaryportfolio.GrantsatNIEHSdealwithjustabouteverythingenvironmental,rangingfrombasicandclinicalresearch,publichealth,andenvironmentaljustice,todisaster-responseworkertraining,developmentofpersonalenvironmentalmonitors,andthedesignoftechnologiesforremediatingSuperfundsites.

“This[topicrangeofgrants]isnewforme,”hesaid.“I’mlearningalongwiththem[theSROsandESAs].Myinitialapproachistolearnhoweachofthemdoesthejob,aswellastobringmyexperience,andtobuild,withthem,anexceptionalanduniquereviewbranch.”

Latoni said his wife, Carmen, who is a financial person with an M.B.A., crunched the numbers during their search for a home near NIEHS. One of his daughters plans to continue her graduate work in early childhood and elementary education in N.C., while his other daughter, Elena, who lives in Puerto Rico, has done work with the U.S. Department of Agriculture as a scientist and soil conservationist. (Photo courtesy of Steve McCaw)

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Life down south in the slow(er) laneLatonilaughed,ashetalkedabouthisrelocationfromBethesdatotheN.C.Trianglearea,andrecalledanearlierdiscussionofcollegeswithhisyoungerdaughter,Angélica.WhenshetoldherparentsshewantedtoattendtheUniversityofNorthCarolinaatCharlotte,he’daskedher,“WhywouldyouwanttogotoNorthCarolina?”

Threeyearslater,whenLatoniacceptedthepositionatNIEHS,hisdaughter,whoisnowatElonUniversityandhasakeensenseofirony,turnedthetablesbyaskinghimthesamequestion.Hisanswerwon’tsurprisemanytransplantsatNIEHS.

Latonipointedtoqualityoflifeandfamily—andathree-hourcommuteeachdayfromsuburbanMontgomeryCounty,Md.,intoBethesdathatcouldeasilybecomefourhoursifanythingwentwrongwithtrafficortheweather.

“I’mstilltryingtogetoverthatcommutingmindset,”hesaid.“I’vefoundmyselfarrivingatmeetingsherehalfanhourearly,becauseI’dbecomesousedtogettingaheadstart.”

Now,LatoniismeasuringhistripsfromanewhomeinnearbyCary,N.C.,toNIEHSintermsofminutes,andspendingthehourshewouldhavewastedbehindthewheelinBethesdawithhisfamilyinstead.“Ifeelwecanmakealifehere,”hesaid.“Therearesomanygoodthingshappeningtomenow,andIlookforwardtoourfuturehere.”

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Students in NIEHS program WOW! supporters with interactive presentations By Jacqueline Powell

NIEHSscientistsreapedtherewardsofteachingandservice,astheyparticipatedintheCitizenSchoolsWOW!EventDec.12atLowe’sGroveMiddleSchoolinDurham,N.C.Afterspending10weekslearningaboutcellsandDNAinanewlearningmoduledesignedandtaughtbyNIEHSvolunteers,itwastimeforstudentstosharewhattheyhadlearnedwithfamily,friends,andteachers.

Thedoortothepresentationroomwasdecoratedasanionchannelwithinacellmembrane.Inside,studentspresentedpostersandguidedadultsthroughhands-oncellbiologypresentations.Onegroupillustratedcelldivision,bypresentingaposter,makingmodelcellsoutofclay,andusingalightmicroscope.AnotherteamofstudentsfocusedonthepropertiesofDNA,byperformingastrawberryDNAextraction,whileothersillustratedcellularstructures,bydecoratingcookieswithdifferenttypesofcandy.

No one, except Latoni himself, was more excited by his appointment than DERT Deputy Director Pat Mastin, Ph.D., who served as acting chief following the retirement of former branch chief Terry Nesbitt, Ph.D. (Photo courtesy of Steve McCaw)

A Lowe’s Grove Middle School student, right, described two forms of cell division, mitosis and meiosis, before using handmade clay model cells to illustrate the physical changes that accompany different stages of cell division. Visitors were also encouraged to observe cells on a slide, using a light microscope. (Photo courtesy of Steve McCaw)

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Whenoneofthemiddleschoolstudentswasaskedabouthisfavoritepartoftheapprenticeship,hesaid,“Idon’tevenknow.Ilikedallofit.”HethenquicklyreturnedtoextractingDNAfrommashedupstrawberries.

“Ithinkthisnewcurriculumoncellbiologyreallylets[NIEHSscientists]playtotheirstrengths.AllofusdealwithcellsandDNAinsomeway,soit’seasytopickatopicthatyou’reexcitedabout,”saidShannonWhirledge,Ph.D.,anIntramuralResearchTrainingAward(IRTA)fellowintheNIEHSMolecularEndocrinologyGroup.

Citizen School apprenticeships depend on volunteer teachersInthereceptionprecedingthestudentpresentations,CitizenSchoolsstaffemphasizedtheutilityofthisacademicallyfocusedafterschoolprogram,whichdependsoncommunityvolunteerstoteach21stcenturyskillsinabroadrangeofareas.

Coordinatingsuchanambitiousprogramrequiredcommitmentonbothsides,andJesulaCharles,CitizenSchoolsteachingfellowandliaisontoNIEHSvolunteers,servedmanyimportantfunctions.Shecoordinatedthechildren’safterschoollearningactivities,oversawenrollment,andmonitoredstudents’performancetomakesureeveryonewasprogressing.NIEHSscientistsandstaffalsomadesignificantcontributions,bydevelopingthestudents’curriculum.Huei-ChenLao,K-12scienceeducationandoutreachcoordinatorwiththeNIEHSOfficeofScienceEducationandDiversity(OSED),playedacrucialroleinhelpingvolunteerssharetheresponsibilityofteaching.

“WhileIplayaleadershiproletokeepthingsmovingalong,Huei-Chenmakesithappen,”saidErickaReid,Ph.D.,OSEDdirector.She’sgreatandshereallyknowsthescience.

Another of the students, left, helped a Citizen Schools supporter, right, extract DNA from a strawberry, as volunteer instructor Hewitt, an NIEHS biologist, looked on. (Photo courtesy of Steve McCaw)

One of the program’s students, center, guided visitors through an interactive game that demonstrated his newfound knowledge of DNA. (Photo courtesy of Steve McCaw)

Volunteers for the fall Citizen Schools apprenticeship

• FloydAdsit• SaraAndres,Ph.D.• MirandaBernhardt,Ph.D.• TerryBlankenship-Paris,D.V.M.• ChristopherCampos,Ph.D.• FelicityDavis,Ph.D.• BillFitzgerald• DavidGoulding• SylviaHewitt• JacquelineLocklear,D.V.M.• PageMyers• PalmyraRomeo• KirstenVerhein,Ph.D.• ShannonWhirledge,Ph.D.• TanyaWhiteside• KimberlyWiggins,Ph.D.• Wipawee(Joy)Winuthayanon,Ph.D.• GaryZeRuth,Ph.D.

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(FormerNIEHSpostdoctoralfellowJacquelinePowell,Ph.D.,isawriterandanalystwithEducationandTrainingSystemsInternational[ETSI].)

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Duke brings Superfund research to the Elizabeth River Learning Barge By Sara Mishamandani

Theendof2013marksthefirstfullsemesterofDukeUniversitySuperfundResearchProgram(SRP)fieldworkandoutreachontheElizabethRiverProject(ERP)DominionVirginiaPowerLearningBarge.

DukeSRPpartneredwithERPtodevelopcontentandmaterialsforthefloatingclassroom,nowinitsfifthyearofoperation,aswellascomplimentarymaterialsforfourthgradeteachersbackintheclassroom.ERPisanonprofitorganizationthatleadscommunityeffortstorestoretheenvironmentalhealthoftheElizabethRiverinsoutheasternVirginia.

Volunteers and OSED staffers showed off the poster for the NIEHS program, “It’s a Small World: Cells and DNA.” Shown, from left, are Davis, Reid, Hewitt, Lao, Wiggins, and author Powell, a veteran of the spring 2013 outreach effort. (Photo courtesy of Steve McCaw)

The Learning Barge is the world’s first floating wetland classroom, powered by sun and wind, and equipped with live wetlands, an enclosed classroom, composting toilets, and a rainwater filtration system. (Photo courtesy of the Elizabeth River Project)

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HundredsofelementaryschoolstudentsintheChesapeakeBayareamakefieldtripstotheLearningBargeeachyear,tolearnaboutriverenvironmentalstewardshipandhowtomakethepollutedElizabethRiverswimmableandfishableby2020.MembersoftheDukeSRPResearchTranslationCore(RTC)developedanewteachingmoduleonadaptation,usingDukeSRPresearchconcepts,whichlaunchedontheLearningBargeinfall2013.

“Adaptationispartofthefourthgradesciencecurriculum,butsomethingstudentsoftentestpoorlyon.Itisadifficultconceptforstudentstounderstandwithoutseeingitfirsthand,”saidRobinDunbar,theERPEducationDirector.“Duke’sactivityontheLearningBargehelpsstudentsmaketheconnectionandunderstandtheconceptofadaptationinawaythatcannotbedoneintheclassroom.”

Duke research on the Elizabeth River ResearchersattheDukeSuperfundResearchCenter,ledbyRichardDiGiulio,Ph.D.,areconductingresearchontheAtlanticWoodIndustriesSuperfundsitelocatedontheElizabethRiver(seestory).Thesite,aformerwoodtreatmentfacility,lefttheElizabethRiverheavilycontaminatedwithpolycyclicaromatichydrocarbons(PAHs).

DukeinvestigatorsareworkingtobetterunderstandhowthePAHcontaminationintheElizabethRiverisaffectingfishpopulations.TheyhavediscoveredthatasmallkillifishspeciesintheElizabethRiver,theFundulus heteroclitus,ormummichog,hasdevelopedresistancetoacutetoxicity,heartdeformities,andcancersthatarelinkedtoPAHexposure.DukeresearcherscontinuetostudyhowthisadaptationtoPAHsmayimpactkillifishhealthlaterinlife.

Translating findings to fourth gradersOntheLearningBarge,studentsattendafifteen-minutefishingstationwheretheycanfishoffthesideofthebargeforsamples.Studentsobservetheircatch,astheyhearabouthoworganismslivingintheElizabethRiver,suchasthemummichog,havehadtoadapttosurvive,andthecostsofthatadaptation.Thescript,developedbyDukeRTC,broughtinelementsofDukeSRPresearch,whilefulfillingspecificconcepts,inaccordancewiththeVirginiaScienceStandardsofLearning.

“Dukeinvestigatorsarestudyingtheconceptofadaptationataveryhighlevel,”saidDunbar.“TheDukeRTCwasabletotakeitdowntowhereitbegins,sostudentscanunderstand.”

Fourth graders on the Learning Barge examine their catch from the Elizabeth River. (Photo courtesy of the Elizabeth River Project)

Duke researcher Savannah Volkoff, right, sorted mummichogs during a fish collection trip on the Elizabeth River. She worked with Kroeger to develop the Learning Barge activity and materials. (Photo courtesy of Savannah Volkoff)

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Tocomplementthefieldtrip,DukeSRPstaffalsodevelopedresourcesonadaptationforfourthgradeteachers,availableontheDukeSRPwebsite.ResourcesincludeafactsheetonFundulus heteroclitus;aworksheetwithafictionalstorydescribingadaptationstoPAHexposuresandassociatedfitnesscosts;andquestionsforevaluatingstudentunderstanding.

“TheLearningBargeactivitywasagreatopeningintoworkingwiththeElizabethRiverProject,andwehopetohaveamoreactiverolewiththeorganizationinthefuture,”saidGretchenKroeger,theDukeRTCprojectcoordinator.“Itwasalsoalotoffuntoseethelearningmoduleinactionandtoseehowthestudentswerereallyengagedintheactivities.”

(SaraMishamandaniisaresearchandcommunicationspecialistforMDBInc.,acontractorfortheNIEHSSuperfundResearchProgramandDivisionofExtramuralResearchandTraining.)

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Industry-academic collaboration streamlines decades of data By Raj Gosavi

Knowingthetoxiceffectsofpharmaceuticaldrugsisimportantindrugdevelopmentaswellasinenvironmentalscience,buttherelevantdataaretypicallyscatteredthroughoutthescientificliteratureandahostofindependentdatabases.Increasingly,scientistsarerecognizingthecompellingneedforfindingandintegratingthisinformation,systematically,usingcommonsearchterminologytomakethedatausefulandaccessibleforacademicandindustrialresearchers,aswellasthegeneralpublic.

Asdemonstratedbyanewstudy,fundedinpartbyNIEHS,scientistsatthepharmaceuticalcorporationPfizerInc.andacademicresearchersaffiliatedwiththeComparativeToxicogenomicsDatabase(CTD)havemademajorprogresstowardthatgoal,byintegratinginformationaboutthetoxicityofmorethan1,200pharmaceuticaldrugs.

MoleculartoxicologistCarolynMattingly,Ph.D.,associateprofessoratNorthCarolinaStateUniversity(NCSU)andleadresearcheronthestudy,hasbeendirectingdevelopmentofCTDwithNIEHSsupportsince2001(seestory).“Wefeltthattheinformationthatwaslackingwerethemechanismsthatconnectexposuretoenvironmentalchemicalswithdiseases,”shesaid.

CTDisapubliclyavailableresearchresourcedevelopedinitiallyattheMountDesertIslandBiologicalLaboratory,whereMattinglywasaffiliatedpriortomovingtoNCSUinJanuary2012.“Thisistheonlydatabaseouttherethatconnectsmechanismsofchemicalactiontopotentialimpactsonhumanhealth,”Mattinglysaid.ThecollaborationwithPfizer,whichtookCTDbiocurators—professionalscientistswhocurate,collect,annotate,andvalidateinformation—ayeartocomplete,significantlyincreasedinformationaboutpharmaceuticalandenvironmentalchemicals.

Shown, above, at a data integration meeting in July 2013 (see story), Mattingly, like many of her colleagues working in big data applications, feels that networking data about chemical-gene and chemical-protein interactions, as well as chemical-disease and gene-disease relationships, can help scientists develop novel hypotheses about the origins of environmentally influenced diseases. (Photo courtesy of Steve McCaw)

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Mapping hundreds of thousands of chemical-disease interactionsThedatabaseprovideschemical-gene-diseaseinformationandassociatedfunctionalandpathwaydata.ThePfizercollaborationspecificallyaddeddataforchemicalsthatmaybeinvolvedincardiovascular,neurological,kidney,andliverdisorders.

Currentscreeningmethodsfordrugs,althoughadvanced,needtobecomplementedwithnewermethodsforassessingcompoundtoxicity.Withtheabilitytopredicttoxicsideeffectsofdrugs,thedatabasecanpotentiallyimprovedrugdevelopment,byallowinggenerationofnewearly-stagemechanisticscreeningofthedrugs.

DatacollectionandintegrationtookadvantageofPfizer’sefficienttext-miningprocedures,focusingonselectchemicals,combinedwithCTD’smanualcurationofmorethan88,000researcharticles.Theinformationfromthescientificliteraturewasthenintegratedwiththeexistingdatabasetoexpanditsnetworkofchemical-gene-diseaseinteractions.

HighlightingthecommongoalofthecollaborationwithPfizer,Mattinglysaid,“Itwasawin-winsituation.Whatpharmaceuticalcompaniesaretryingtodoisessentiallywhatenvironmentalscientistsaretryingtodo—understandandpreventtoxicity.”

“ThetypeofpartnershipdemonstratedbythesuccessofthisjointPfizer-CTDeffortisessentialtotranslatingscientificdataandknowledgeintomeaningfulinformationthatcanbeutilizedtoadvanceourunderstandingofenvironmentalagentsandtheirimpactsandultimatelytoimprovingpublichealth,”saidAllenDearry,Ph.D.,directoroftheNIEHSOfficeofScientificInformationManagement.

DatafromCTDisincreasinglycitedandintegratedwithotherbiologicaldatabases,therebyenhancingaccesstotheinformation.AsshelookedforwardtofurtherdevelopmentsinCTD,Mattinglyobserved,“Wecontinuetoworkcloselywithcollaboratorstodevelopadditionaltoolsanddatamodulestoimprovetheutilityofthedatabase.”

Citation:DavisAP,WiegersTC,RobertsPM,KingBL,LayJM,Lennon-HopkinsK,SciakyD,JohnsonR,KeatingH,GreeneN,HernandezR,McConnellKJ,EnayetallahAE,MattinglyCJ.2013.ACTD-Pfizercollaboration:manualcurationof88,000scientificarticlestextminedfordrug-diseaseanddrug-phenotypeinteractions.Database2013;doi:10.1093/database/bat080.

(RajGosavi,Ph.D.,isaresearchfellowintheNIEHSStructureandFunctionResearchGroup.)

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Science Notebook2013 papers of the yearFromthemorethan2,800NIEHS-fundedstudiespublishedin2013,leadersoftheInstitute’sthreeresearchdivisionsselected30forspecialrecognitionasPapersoftheYear.

Research funded by grants (click title for abstract)• Flame retardant Firemaster 550 confirmed as endocrine disruptor

• Tributyltin linked to transgenerational obesity

• Reducing air pollution continues to increase life expectancy

• Early pregnancy inflammation could increase autism risk

• Cost of mercury pollution

• BPA exposure in the NICU

• Global cost of childhood lead exposure

• Using membrane transporters to improve crops for sustainable food production

• Metabolomics reveals early changes in metabolic pathways for Alzheimer’s disease

• Epigenetic effects of DDT lead to obesity in later generations

• Mechanism for amyloid-beta accumulation in Alzheimer’s disease

• DNA methylation in the human genome

• Graphene sheets pierce and enter cells

• Improving health for low-income workers

• Father’s obesity could have epigenetic effects

In-house research (click title for abstract)• Consequences of ribonucleotide removal by topoisomerase 1

• The role of p53 during bacterial pneumonia

• DNA methylation could predict breast cancer risk

• Observing a DNA polymerase using time-resolved crystallography

• Early mouse development influences norepinephrine neuron diversity

• APOBEC cytidine deaminases generate many mutations in human cancers

• Tanning gene linked to increased risk of testicular cancer

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• Assessing cockroach allergen exposure via its structure

• Probiotics use during pregnancy may reduce diseases in children

• Identification of novel immune regulatory elements and epigenetic plasticity in memory lymphocytes

National Toxicology Program research (click title for abstract)• Spontaneous mesotheliomas in F344/N rats are characterized by dysregulation of cellular growth and

immune function pathways

• Chronic exposure of renal stem cells to inorganic arsenic induces a cancer phenotype

• RNASeq profiling reveals novel hepatic gene expression pattern in aflatoxin B1 treated rats

• Recruitment of normal stem cells to an oncogenic phenotype by noncontiguous carcinogen-transformed epithelia depends on the transforming carcinogen

• Bisphenol A affects androgen receptor function via multiple mechanisms

Research funded by grants

Flame retardant Firemaster 550 confirmed as endocrine disruptorAnanimalstudyconductedbyNIEHSgranteesshowsthatperinatalexposuretotheflameretardantFiremaster550,commonlyfoundinhousedust,isassociatedwithendocrinedisruptingeffects.Thefindingsrevealtheneedformoreresearchonthemechanismsinvolvedandthehealtheffectsofhumansexposedtotheproduct.

TheresearchersevaluatedtheeffectsofFiremaster550inratsandfoundthatitscomponentsaccumulatedintissuesofexposedmiceandtheiroffspring.Theoffspringexhibitedadvancedfemalepuberty,weightgain,malecardiachypertrophy,andproblemswithexploratorybehaviors.TheresultssuggestthatFiremaster550mayaffectgrowthandneurodevelopment.

Citation:PatisaulHB,RobertsSC,MabreyN,McCaffreyKA,GearRB,BraunJ,BelcherSM,StapletonHM.2013.AccumulationandendocrinedisruptingeffectsoftheflameretardantmixtureFiremaster550inrats:anexploratoryassessment.JBiochemMolToxicol27(2):124-136.[Synopsis]

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Tributyltin linked to transgenerational obesity AnNIEHS-supportedstudyshowedthatmiceprenatallyexposedtotheendocrinedisruptortributyltin(TBT)weremorelikelytobeobese,andtheeffectspersistedinsubsequentgenerationsnotdirectlyexposedtoTBT.Thefindingsholdimportantimplicationsforunderstandingobesityinpeople.

TBTisusedasanantifungalagentinsomepaints,certainplastics,andconsumerproducts.ResearchersexposedpregnantmicetodosesofTBTthatwerecomparabletotheestablishedhumantolerabledailyintake.TheoffspringofthepregnantmiceexposedtoTBT,andthesubsequenttwogenerationsofmice,hadagreaternumberoffatcells,largerfatcells,andheavierfatdepots.IfTBThassimilareffectsonpeople,thenexposure

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toitandotherendocrinedisruptorscouldreprogramthemetabolismofexposedindividuals,aswellasfuturegenerations,predisposingthemtoweightgain.

Citation:Chamorro-GarciaR,SahuM,AbbeyRJ,LaudeJ,PhamN,BlumbergB.2013.Transgenerationalinheritanceofincreasedfatdepotsize,stemcellreprogramming,andhepaticsteatosiselicitedbyprenatalexposuretotheobesogentributyltininmice.EnvironHealthPerspect121(3):359-366.[Synopsis]

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Reducing air pollution continues to increase life expectancyNIEHSgranteesreportthatairpollutionreductionsoccurringfrom2000to2007wereassociatedwithimprovedlifeexpectancy.Theseresultsshowthatthelastdecadeofairpollutioncontrolcontinuestopositivelyaffectpublichealth.

From2000to2007,U.S.levelsofparticulatematterlessthan2.5micrometersindiameter(PM2.5)havedeclined,butataslowerratethanbetween1980and2000.Tofindoutiftheselevelscontinuedtoimprovelifeexpectancy,theresearcherslookedatyearlyaveragePM2.5andlifeexpectancydatafor545ruralandurbanU.S.countiesfrom2000to2007.Controllingforsocioeconomicstatus,smokingprevalence,anddemographiccharacteristics,theyfoundthattheaveragelifeexpectancyincreasedby0.35yearsforevery10microgramspermeterdecreaseinPM2.5concentration.Theassociationbetweenlifeexpectancyandairpollutionlevelswasstrongerinmoreurbananddenselypopulatedcounties.

Citation:CorreiaAW,PopeCA3rd,DockeryDW,WangY,EzzatiM,DominiciF.2013.EffectofairpollutioncontrolonlifeexpectancyintheUnitedStates:ananalysisof545U.S.countiesfortheperiodfrom2000to2007.Epidemiology24(1):23-31.[Synopsis]

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Early pregnancy inflammation could increase autism riskInflammationduringpregnancycouldbeassociatedwithanincreasedriskforautism,accordingtoresearchthatwaspartiallyfundedbyNIEHS.TheresearcherslookedataninflammatorybiomarkercalledgestationalC-reactiveprotein(CRP)intheFinnishMaternityCohort,whichcontainsanarchiveofserumsamplescollectedfromapproximately810,000pregnantwomeninFinland.

Analysisofserumcorrespondingto677childhoodautismcases,andanequalnumberofmatchedcontrols,revealedthattheriskofautismamongchildreninthestudyincreasedby43percentamongmotherswithCRPlevelsinthetop20thpercentile,andby80percentformaternalCRPinthetop10thpercentile.Thesefindingscouldnotbeexplainedbymaternalage,paternalage,gender,previousbirths,socioeconomicstatus,pretermbirth,orbirthweight.Theresearcherscautionthattheresultsshouldbeviewedinperspective,sincetheprevalenceofinflammationduringpregnancyissubstantiallyhigherthantheprevalenceofautism.

Citation:BrownAS,SouranderA,Hinkka-Yli-SalomäkiS,McKeagueIW,SundvallJ,SurcelHM.2013.ElevatedmaternalC-reactiveproteinandautisminanationalbirthcohort.MolPsychiatry;doi:10.1038/mp.2012.197[Online22January2013].[Synopsis]

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Cost of mercury pollutionAccordingtoastudysupportedinpartbyNIEHS,eachyearinEurope,morethan1.8millionchildrenarebornwithunsafeprenatalmethylmercuryexposures.Exposuretomethylmercurytypicallyoccursfromeatingfish,whichbioconcentratethecontaminant.MethylmercuryaffectsbraindevelopmentleadingtoalowerIQand,thus,lowerearningpotential.

Tocalculatethecostsassociatedwiththisexposure,theresearchersexaminedmercuryconcentrationsinhairsamplesfromtheDEMOCOPHESstudyofexposuretoenvironmentalchemicals,aswellasotherstudies.Theyassumedthatmercurylevelsbelow0.58microgramspergramofhairwouldhavelittleadverseeffect.TheresearchersestimatedthatpreventingexposurewithintheEuropeanUnionwouldbringanannualbenefitequivalentto600,000IQpointsperyear,correspondingtotheestimatedannualeconomicbenefitof8-9billioneuro.PreventionwouldhavethemostimpactinsouthernEurope,wherehair-mercuryconcentrationswerethehighest.

Citation:BellangerM,PicheryC,AertsD,BerglundM,CastanoA,CejchanovaM,CrettazP,DavidsonF,EstebanM,FischerME,GurzauAE,HalzlovaK,KatsonouriA,KnudsenLE,Kolossa-GehringM,KoppenG,LigockaD,MiklavcicA,ReisMF,RudnaiP,TratnikJS,WeiheP,Budtz-JorgensenE,GrandjeanP.2013.EconomicbenefitsofmethylmercuryexposurecontrolinEurope:Monetaryvalueofneurotoxicityprevention.EnvironHealth12:3.[Synopsis]

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BPA exposure in the NICUAstudy,supportedinpartbyNIEHS,identifiedmedicaldevicesasapotentialsourceofexposuretobisphenolA(BPA)amongprematureinfantsinneonatalintensivecareunits(NICU).BPAisusedtomanufacturepolycarbonateplastics,whichareusedinmedicaldevicessuchasintravenousadministrationsets,syringes,andcatheters.

TheresearchersexaminedurinaryBPAconcentrationfor55infantsandcategorizedeachinfant’smedicaldeviceuseasloworhigh,basedonthenumberandinvasivenessofdevices.TheyfoundthatthemedianurinarytotalBPAconcentrationofinfantswhohadrequiredfourormoremedicaldevicesforthreepreviousdayswassignificantlyhigher,36.6microgramsperliter,thanfortheinfantsrequiringthreeorfewerdevices,13.9microgramsperliter.TheresearchersalsocollectedandanalyzedbreastmilkorformulasamplesandfoundthattheincreasedBPAconcentrationwasnotassociatedwiththeinfants’nutritionalintake.

Citation:DutySM,MendoncaK,HauserR,CalafatAM,YeX,MeekerJD,AckermanR,CullinaneJ,FallerJ,RingerS.2013.PotentialsourcesofbisphenolAintheneonatalintensivecareunit.Pediatrics131(3):483-489.[Synopsis]

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Global cost of childhood lead exposureAccordingtoresearchsupportedbyNIEHS,low-incomeandmiddle-incomecountriesexperiencethelargestburdenofleadexposure,withcostmeasuredinwhatareknownasinternationaldollars.Aninternationaldollarisahypotheticalcurrencyusedtocomparecostsfromvariouscountries.IthasthesamepurchasingpowerasadollarwouldhaveintheU.S.

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Theresearcherscalculatedlead-associatedlossbydevelopingaregressionmodeltoestimateaveragebloodleadlevelsandestimatingthelead-attributableeconomiccostswithanenvironmentallyattributablefractionmodel.Theyexaminedonlytheneurodevelopmentaleffectsoflead,whichwereassessedusingIQpoints.Theinvestigatorsestimatethatthetotallead-associatedeconomiclossrangesfrom$728.6billionto$1.1625trillioninternationaldollars,including$134.7billioninAfrica,$142.3billioninLatinAmericaandtheCaribbean,and$699.9billioninAsia.

Citation:AttinaTM,TrasandeL.2013.Economiccostsofchildhoodleadexposureinlow-andmiddle-incomecountries.EnvironHealthPerspect121(9):1097-1102.[Synopsis]

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Using membrane transporters to improve crops for sustainable food productionNIEHSgranteespublishedfindingsthatindicateunderstandingthebiologyofplantmembranetransportersmaybeakeycontributortothegoalofglobalfoodsecurity.Withtheglobalpopulationpredictedtogrowbyatleast25percentby2050,theneedforsustainableproductionofnutritiousfoodswillbecrucialforhumanandenvironmentalhealth.

Theauthorsdiscussexampleswherefundamentalresearchiscurrentlybeingtranslatedintopracticalapplications,suchasshowinghowspecializedplantmembranetransporterscanbeusedtoenhanceyieldsofstaplecrops,increasenutrientcontent,andincreaseresistancetokeystresses,includingsalinity,pathogens,andaluminumtoxicity.Theyalsoexaminepotentialapplicationslinkedtobreakthroughsinbasicresearchthatareyettobeappliedtocropplants.

Citation:SchroederJI,DelhaizeE,FrommerWB,GuerinotML,HarrisonMJ,Herrera-EstrellaL,HorieT,KochianLV,MunnsR,NishizawaNK,TsayYF,SandersD.2013.Usingmembranetransporterstoimprovecropsforsustainablefoodproduction.Nature497(7447):60-66.[Story]

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Metabolomics reveals early changes in metabolic pathways for Alzheimer’s diseaseWithfundingfromNIEHS,researchersfoundchangesinmetabolicpathwaysthatweredetectableinbloodplasmaofAlzheimer’spatients..ThefindingssuggestthatitmightbepossibletoidentifyplasmabiomarkersforearlyAlzheimer’sdiseasediagnosis,monitoringdiseaseprogression,andevaluatingtherapeuticapproaches.

Theresearchersusedanontargetedmetabolomicsapproachbasedonliquidchromatographyandmassspectrometrytoanalyzecerebrospinalfluidandplasmasamplesfrom45peopleintheMayoClinicStudyonAging,andMayoClinicAlzheimer’sDiseaseResearchCenter.Intotal,theinvestigatorsfound342plasmaand351cerebrospinalfluidsignificantlyalteredmetabolites.PatientswithmildcognitiveimpairmentandAlzheimer’sdiseaseshowedsignificantimpairmentinenergymetabolismandotherphysiologicalfunctions.Theresearcherssaythatadditionalresearch,usingtargetedmetabolomics,couldidentifyspecificpanelsofbiomarkers.

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Citation:TrushinaE,DuttaT,PerssonXM,MielkeMM,PetersenRC.2013.IdentificationofalteredmetabolicpathwaysinplasmaandCSFinmildcognitiveimpairmentandAlzheimer’sdiseaseusingmetabolomics.PLoSOne8(5):e63644.[Synopsis]

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Epigenetic effects of DDT lead to obesity in later generationsAmousestudy,supportedinpartbyNIEHS,indicatesthatancestralexposuretotheinsecticidedichlorodiphenyltrichloroethane(DDT)canpromoteobesityandassociateddiseaseinlatergenerations.Thefindingsimplythatenvironmentalexposuresexperiencedseveralgenerationsagomightinfluencetoday’sratesofobesity,althoughthedegreeofinvolvementisnotknown.

TheresearchersfounddifferentialDNAmethylationregions,whichwereepigeneticchanges,inspermofthethirdgeneration.Genesassociatedwiththeseregionswerepreviouslyshowntobeassociatedwithobesity.AlthoughbannedintheU.S.,DDTisusedtocontrolmalariainotherpartsoftheworld.Theresearchersstressedthatlong-termhealthandeconomiceffectsofDDTexposureonfuturegenerationsshouldbeconsideredinareaswhereDDTisused.

Citation:SkinnerMK,ManikkamM,TraceyR,Guerrero-BosagnaC,HaqueM,NilssonEE.2013.Ancestraldichlorodiphenyltrichloroethane(DDT)exposurepromotesepigenetictransgenerationalinheritanceofobesity.BMCMed11:228.[Synopsis]

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Mechanism for amyloid-beta accumulation in Alzheimer’s diseaseAnNIEHSgranteeandhiscolleaguesreportthatlowlevelsofcoppercanaccumulateinthebrain,leadingtoamyloid-betaplaquesthatarethehallmarkofAlzheimer’sdisease.Theresearchprovidesusefulinformationfordevelopingpreventativeortherapeuticapproachesforcontrollingneurotoxicamyloid-betalevelsintheagingbrain.

Theresearchersusednormalmice,amousemodelofAlzheimer’sdisease,andhumanbrainendothelialcellsinthestudy.Innormalagingmice,theyfoundthatcopperaccumulatedinbraincapillaries,whichwasassociatedwithareductioninaproteinthatremovesamyloid-betafromthebraincalledlow-densitylipoproteinreceptor-relatedprotein1(LRP1).ThesameLRP1decreaseappearedinhumancells.InthemousemodelofAlzheimer’sdisease,copperaccumulatedinbraincapillariesandtheparenchyma,unlikenormalagingmice.Overall,thisworkdemonstratedthatcopper’seffectonamyloid-betahomeostasisinthebraindependsonwhetheritaccumulatesincapillariesorintheparenchyma.

Citation:SinghI,SagareAP,ComaM,PerlmutterD,GeleinR,BellRD,DeaneRJ,ZhongE,ParisiM,CiszewskiJ,KasperRT,DeaneR.2013.Lowlevelsofcopperdisruptbrainamyloid-betahomeostasisbyalteringitsproductionandclearance.ProcNatlAcadSciUSA110(36):14771-14776.[Synopsis]

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DNA methylation in the human genomeInmammals,70-80percentofallcytidine-phosphateguanosine(CpG)dinucleotidesaremethylated,butNIEHS-supportedresearchersreportthatonlyafractionoftheseCpGslikelyparticipateingenomeregulationinadevelopmentalcontext.TheDNAmethylationsignatures,calleddifferentiallymethylatedregions,maybeusedtoguidenew,moreeffectiveapproachesthatexaminethemostinformativeportionofCpGs.

Genome-wideassociationstudiesshowedthatdifferentiallymethylatedregionsoftencontainedsinglenucleotidepolymorphismsassociatedwithcancerandAlzheimer’sdisease.Theinvestigatorsusedtheirsetofdifferentiallymethylatedregionstocorrectlyidentifyanunknowntissuesampleandtoclassifythetypesofcellspresentinaheterogeneoussample.

Citation:ZillerMJ,GuH,MullerF,DonagheyJ,TsaiLT,KohlbacherO,DeJagerPL,RosenED,BennettDA,BernsteinBE,GnirkeA,MeissnerA.2013.ChartingadynamicDNAmethylationlandscapeofthehumangenome.Nature500(7463):477-481.[Synopsis]

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Graphene sheets pierce and enter cellsNIEHSgranteesreportthatgraphenematerialswithmicrometer-scaledimensions,knownasgraphenemicrosheets,canentercellswhentheirsharpprotrusionspiercethecellmembrane.Understandinghowthesegraphenesheetsinteractwithcellscanhelpscientistsdevelopmaterialsthatarenotharmfultothebody.

Confocalfluorescenceandelectronmicroscopyconfirmedthatgraphene’sroughedgesandcornerscouldpierceprimaryhumankeratinocytes,humanlungepithelialcells,andmurinemacrophages.Theimagingalsoshowedthatcellscouldcompletelyinternalizegraphenesheetswithlateraldimensionsof0.5-10micrometers.Moreresearchisneededtounderstandhowthemicrosheetsaffectcells,buttheresearcherssaythatmicrosheetsmightdisruptcytoskeletonandcellmotilityandcauseproblemswithepithelialbarriers.

Citation:LiY,YuanH,vondemBusscheA,CreightonM,HurtRH,KaneAB,GaoH.2013.Graphenemicrosheetsentercellsthroughspontaneousmembranepenetrationatedgeasperitiesandcornersites.ProcNatlAcadSciUSA110(30):12295-12300.[Synopsis]

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Improving health for low-income workersAnNIEHSgranteeco-authoredapaperthatcallsforimprovingthehealthoflow-incomeworkersbyintegratinghealthprotectionandhealthpromotionprogramsthatcanbedeliveredatworksites,stateandlocalhealthdepartments,communityhealthcenters,andcommunity-basedorganizations.Low-incomeworkersexperienceoverlappingoccupationalandnonoccupationalrisksthatcanbeworsenedbylimitedresourcesandsocietalracism.

Theauthorsprovidesixbroadrecommendationsforreducinghealthinequitiesamonglow-incomeworkers—improveaccessandqualityofwork-relateddata,integrateworkenvironmentalfactorsintocareatcommunity

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healthcenters,improvetheexchangeofinformationandideas,increasetheintegrationofhealthandoccupationalhealtheducationandtraining,testandevaluatenewapproaches,andimproveworkerandcommunityengagement.

Citation:BaronSL,BeardS,DavisLK,DelpL,ForstL,Kidd-TaylorA,LiebmanAK,LinnanL,PunnettL,WelchLS.2013.Promotingintegratedapproachestoreducinghealthinequitiesamonglow-incomeworkers:applyingasocialecologicalframework.AmJIndMed;doi:10.1002/ajim.22174[Online26March2013].[Synopsis]

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Father’s obesity could have epigenetic effectsAstudy,partiallysupportedbyNIEHS,foundthatnewbornswithobesefathershadsignificantlylessDNAmethylationoftheinsulin-likegrowthfactor2(IGF2)gene.SincereducedDNAmethylationofthisgeneisassociatedwithahigherriskofdevelopingcertaincancers,thestudyfindingssuggestthatafather’sobesitycouldinfluencehischild’sfuturehealth.

TheyexaminedDNAfrom79newbornswhosemothersparticipatedintheNewbornEpigeneticsStudyduringpregnancyandalsogatheredinformationaboutbothparentsusingquestionnairesandmedicalrecords.Evenafteradjustingforseveralmaternalandnewborncharacteristics,theyobservedapersistentinverseassociationbetweenDNAmethylationintheoffspringandpaternalobesity.TheresearcherssaythatthechangesinDNAmethylationcouldresultfromobesity-relatedfactors,suchasdietorhavingdiabetes,thatwerenotmeasuredinthestudy.

Citation:SoubryA,SchildkrautJM,MurthaA,WangF,HuangZ,BernalA,KurtzbergJ,JirtleRL,MurphySK,HoyoC.2013.PaternalobesityisassociatedwithIGF2hypomethylationinnewborns:resultsfromaNewbornEpigeneticsStudy(NEST)cohort.BMCMed11:29.[Synopsis]

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In-house research

Consequences of ribonucleotide removal by topoisomerase 1NIEHSresearchers,togetherwithcollaboratorsatUmeaUniversityinSweden,havedeterminedthattopoisomerase1(Top1),anenzymeimportantforuncoilingDNAduringreplicationandtranscription,canalsoremoveribonucleotidesincorporatedintoDNAduringreplication.

Usingyeastasamodelsystem,thescientistsstudiedstrainsthatweregeneticallyengineeredtoincorporatealargenumberofribonucleotidesintoDNA,andweredefectiveinRER,Top1,orboth.IntheabsenceofRER,Top1incisedtheDNAbackbonewhereribonucleotideswerepresent,therebyinitiatingtheremovalofabout5,000ribonucleotidesfromthegenome.BecausetheenzymesinvolvedinprocessingribonucleotidesinDNAareconserved,theauthorssuggestthatthegenomeinstabilityresultingfromTop1cleavageatribonucleotidesinDNAmayberelevanttoAicardi-Goutieressyndrome,andpossiblytootherautoinflammatorydisorders.

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Citation:WilliamsJS,SmithDJ,MarjavaaraL,LujanSA,ChabesA,KunkelTA.2013.Topoisomerase1-mediatedremovalofribonucleotidesfromnascentleading-strandDNA.MolCell49(5):1010-1015.[Synopsis]

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The role of p53 during bacterial pneumoniaNIEHSresearchersrecentlydiscoveredthatthetranscriptionfactorp53modulateshostdefensethroughregulatingmicrobicidalfunctionandfateofphagocytesduringbacterialpneumonia.Thisstudyrevealedafundamentallinkbetweendefenseofgenomeandhostduringenvironmentalinsult.

Theauthorsusedmicethathadtheirp53genesdeleted(p53-/-)orinwhichp53waspharmacologicallyinhibited.Bothsetsofmicedisplayedenhancedclearanceofextracellularbacteriaduringpneumonia.Thelungsofp53-/-micedisplayedgenome-wideinductionofNF-kappaBresponseelement-enrichedproinflammatorygenesinthesteadystate,andenhancedinductionofcytokinesuponinfection.Despiteenhancedbacterialclearance,infectedp53-/-micesufferedincreasedmortalityfrompneumonia,likelyduetoaggravatedlunginjuryfromanoverexuberantimmuneresponse.

Citation:MadenspacherJH,AzzamKM,GowdyKM,MalcolmKC,NickJA,DixonD,AloorJJ,DraperDW,GuardiolaJJ,ShatzM,MenendezD,LoweJ,LuJ,BushelP,LiL,MerrickBA,ResnickMA,FesslerMB.2013.p53integrateshostdefenseandcellfateduringbacterialpneumonia.JExpMed210(5):891-904.[Synopsis]

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DNA methylation could predict breast cancer riskNIEHSscientistshavediscoveredDNAmethylationinbloodcouldprovetobeaneffectiveindicatorofwhowilldevelopbreastcancer.UsingtheNIEHSSisterStudy,anationwidecohortofwomen,ages35-74,whosesistershadbreastcancer,researchersusedDNAextractedfromwhitebloodcellsamplesandassessedmethylationat27,000sitesacrossthegenome.

Theteamfoundevidencethatwomenwhosubsequentlydevelopbreastcancerhavedifferentbloodmethylationprofilesthanwomenwhoremaincancerfree,andthatthesemethylationdifferencesaredetectablemonthstoyearsbeforetheclinicaldiagnosisofbreastcancer.Thescientistsalsofoundthatepigeneticmodificationsweresignificantlymoreaccurateinpredictingwhowilldevelopbreastcancerthantheknownriskfactorsandpolymorphisms,althoughtheycautiontheirtestisnotyetaccurateenoughforclinicaluse.

Citation:XuZ,BolickSC,DeRooLA,WeinbergCR,SandlerDP,TaylorJA.2013.Epigenome-wideassociationstudyofbreastcancerusingprospectivelycollectedSisterStudysamples.JNatlCancerInst105(10):694-700.[Synopsis][Story]

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Observing a DNA polymerase using time-resolved crystallographyNIEHSscientistsutilizedatechniquecalledtime-resolvedcrystallographytoexaminehowamodelhumanDNApolymerasebeta(polbeta)choosesanucleotideduringDNAsynthesis.Thetechniqueconfirmedfeaturesofthecomputationalresultstheresearchershadgeneratedearlier,butalsorevealedpolbetachangesitsshape,dependingonwhetheritincorporatesacomplementarybasepairorcorrectnucleotide.

Thestudyalsofoundthatpolbetaformsathirdmetalbindingsiteduringcorrect,butnotincorrect,nucleotideinsertion,andpyrophosphatemoreeasilydissociatesafterincorrectnucleotideinsertion.Priortothisevidence,researchersbelievedthatonlytwometalion-bindingsiteswereusedbyallpolymerasesintheirmechanismofactionandpyrophosphatewasreleasedinstantly.Theresearchershopethisinformationwillleadtoabetterunderstandingofthepotentialcausesofdisease.

Citation:FreudenthalBD,BeardWA,ShockDD,WilsonSH.2013.ObservingaDNApolymerasechooserightfromwrong.Cell154(1):157-168.[Synopsis][Story]

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Early mouse development influences norepinephrine neuron diversityApplyingatechniqueknownasintersectionalgeneticfatemappingtothedevelopingmousebrain,NIEHSresearcherscharacterizedneuronsthatproduceandreleasenorepinephrine(NE),ahormoneandneurotransmitter.Asaresult,theywerethefirsttodevelopamapofcommunicationpathwaysinthegrowingmousebrain.SinceNEneuronsareinvolvedinseveralphysiologicalprocesses,suchasfoodintakeandsleep,andarelostinParkinson’sandAlzheimer’sdiseases,understandingNEneuronswillleadtoimprovementsinhumanhealth.

ThescientistsfoundthatNEneuronsderivedfromaspecificrhombomere,orsegmentinthedevelopinghindbrain,sharedcommonfeaturesintheadultbrain.ThegroupalsodeterminedthatthesevarioussubgroupsofNEneuronsweretalkingtomanydifferentpartsoftheadultmousebrain.Priortothisstudy,neuroscientistsbelievedonlyonegroupofNEneuronscommunicatedwiththecerebralcortex.

Citation:RobertsonSD,PlummerNW,deMarchenaJ,JensenP.2013.Developmentaloriginsofcentralnorepinephrineneurondiversity.NatNeurosci16(8):1016-1023.[Synopsis][Story]

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APOBEC cytidine deaminases generate many mutations in human cancersNIEHSresearchersandcolleaguesattheBroadInstituteofMITandHarvardinCambridge,Mass.,reportthatasetofproteins,knowntoprotectagainstretrovirusesandretrotransposons,cancausemutationsthatarewidespreadinhumancancers.

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Thesemutations,whichhaveacharacteristicmutationsignature,areproducedbyapolipoproteinBmRNA-editingenzyme,catalyticpolypeptide-like(APOBEC)cytidinedeaminases.ScientistsfromtheteamdevelopedananalysistodetectandstatisticallyevaluatetheprevalenceofAPOBECmutationsin2,680tumorsamples,collectedfrom14typesofcancer.Usingthisstrategy,theydiscoveredthatAPOBECenzymesproducethemajorityofmutationsinsomebladder,cervical,breast,headandneck,andlungtumors.TheyalsofoundAPOBECsignaturemutationsspecificallyingenesthathavebeenimplicatedincancerdevelopmentandprogression,highlightingapotentiallinkbetweenAPOBECenzymesandcarcinogenesis.

Citation:RobertsSA,LawrenceMS,KlimczakLJ,GrimmSA,FargoD,StojanovP,KiezunA,KryukovGV,CarterSL,SaksenaG,HarrisS,ShahRR,ResnickMA,GetzG,GordeninDA.2013.AnAPOBECcytidinedeaminasemutagenesispatterniswidespreadinhumancancers.NatGenet45(9):970-976.[Synopsis][Story]

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Tanning gene linked to increased risk of testicular cancerCollaborativeeffortsbetweenNIEHSandtheUniversityofOxfordhavefoundthatavariantinagenethatpromotesskintanningisassociatedwithanincreasedriskoftesticularcancer.Thisvariant,alsoknownasasingle-nucleotidepolymorphism(SNP),islocatedintheKITLGgene,agenethatiscontrolledbythetumorsuppressorp53,themostcommonlymutatedgeneinhumancancers.

TheSNPconfersprotectiontotheskinagainstsundamage,byincreasingproductionofpigmentedcellscalledmelanocytes.Theauthorssuggestthatduringhumanevolution,thisSNPhasbecomemorecommoninpopulationswithlightskinforthisbeneficialreason.However,intesticularcells,thesituationappearsreversed.TheresearchershypothesizethatincreasedcelldivisiondrivenbytheKITLGSNPmaypermitthegrowthoftumorcells,increasingcancerriskforthosethatcarrythegenevariant.

Citation:Zeron-MedinaJ,WangX,RepapiE,CampbellMR,SuD,Castro-GinerF,DaviesB,PeterseEF,SacilottoN,WalkerGJ,TerzianT,TomlinsonIP,BoxNF,MeinshausenN,DeValS,BellDA,BondGL.2013.Apolymorphicp53responseelementinKITligandinfluencescancerriskandhasundergonenaturalselection.Cell155(2):410-422.[Synopsis][Story]

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Assessing cockroach allergen exposure via its structureNIEHSscientistsandtheircollaboratorshaveobtainedthecrystalstructureofthecockroachallergenBlag1.Itisthefirststructuretobesolvedforthisgroupofinsectproteins.DeterminingthestructureofBlag1allowsforthestandardizationofassaysthatmeasureitinabsoluteunits.

TheX-raycrystallographyrevealedthatBlag1hadanovelfoldwiththecapacitytobindvariouslipids.FurtheranalysisusingmassspectrometryandnuclearmagneticresonanceindicatedthatBlag1couldaccommodateavarietyofhydrophobicligandsthatcouldbeimportantforavarietyofphysiologicalpurposes,includingsensitizinghumans.Overall,theauthorsbelievethatthisworkwouldallowabetterassessmentofBlag1exposure,whichisimportantinevaluatingnewinterventionstrategies.Additionally,thestructuremaybeusefulindesigningnewimmunotherapies.

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Citation:MuellerGA,PedersenLC,LihFB,GlesnerJ,MoonAF,ChapmanMD,TomerKB,LondonRE,PomesA.2013.ThenovelstructureofthecockroachallergenBlag1hasimplicationsforallergenicityandexposureassessment.JAllergyClinImmunol132(6):1420-1426.[Synopsis]

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Probiotics use during pregnancy may reduce diseases in childrenBasedondatafromtheNorwegianMotherandChildCohortStudy(MoBa),aresearchteamledbyNIEHSscientistshavedeterminedthat,forthegeneralpopulation,probioticsconsumedduringpregnancyandinfancymayhelppreventatopiceczemaandrhinoconjunctivitisinearlychildhood.

Theresearchersuseddatafrommorethan40,000motherandchildrenpairsparticipatingintheMoBastudy,whichrecruitedNorwegianwomenbetween1999and2008.Thirty-sevenpercentofpregnantmothersinthestudyconsumedtheseprobioticmilkandyogurtproducts,and18percentofthemalsogavetheirchildprobioticmilkproductsafter6monthsofage.Theresearchersfoundthatmaternalprobioticmilkconsumptioninpregnancy,aswellasconsumptionduringearlychildhood,wasassociatedwithaslightlyreducedrelativeriskofatopiceczemaat6months,andrhinoconjunctivitissymptomsbetween18-36months.

Citation:BertelsenRJ,BrantsaeterAL,MagnusMC,HaugenM,MyhreR,JacobssonB,LongneckerMP,MeltzerHM,LondonSJ.2013.Probioticmilkconsumptioninpregnancyandinfancyandsubsequentchildhoodallergicdiseases.JAllergyClinImmunol;doi:10.1016/j.jaci.2013.07.032[Online10September2013].[Synopsis]

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Identification of novel immune regulatory elements and epigenetic plasticity in memory lymphocytesAcollaborativeteam,ledbyNIEHSinvestigators,determinedthattheglobalreprogrammingoftheepigenome,ortheepigeneticmodificationsofDNA,permitsadultsomaticcellstodifferentiateintodiversecelltypes.

ToinvestigatethefunctionofDNAmethylationchangesassociatedwithimmuneactivation,theauthorsdeterminedwhetheractivation-induceddifferentiallymethylatedregionswereenrichedforregulatoryelementsandalsofoundthatAluelementsdisplaydifferentialmethylationpatterns,correlatedwithdecreasedexpressionofthedenovomethyltansferaseDNMT3AinGCBcells.TheauthorsproposethatthelossofDNAmethylationduringthenaivetoGCBcelltransitionpermitsthesecellstodifferentiatetowardmemoryorplasmacellfates,andtogeneratethedifferentialresponsetoantigenicchallenge.

Citation:LaiAY,MavD,ShahR,GrimmSA,PhadkeD,HatziK,MelnickA,GeigermanC,SobolSE,JayeDL,WadePA.2013.DNAmethylationprofilinginhumanBcellsrevealsimmuneregulatoryelementsandepigeneticplasticityatAluelementsduringB-cellactivation.GenomeRes23(12):2030-2041.[Synopsis]

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National Toxicology Program research

Spontaneous mesotheliomas in F344/N rats are characterized by dysregulation of cellular growth and immune function pathwaysScientistswantedtounderstandwhyagedmaleFischer344/Nratsarepronetodevelopingspontaneousperitonealmesotheliomasthatarisepredominantlyfromthetunicavaginalisofthetestes.

Globalgeneexpressionprofilesofspontaneousmesotheliomasfromtheseratsweretakenfrom2-yearNationalToxicologyProgram(NTP)carcinogenicitybioassays.Theanalysesdeterminedthatthesetumorswereassociatedwithupregulationofvariousgrowthfactors,oncogenes,cytokines,patternrecognitionresponsereceptors,andpathogen-associatedmolecularpatternsreceptors,andtheproductionofreactiveoxygenandnitrogenspecies,aswellasdownregulationofapoptosispathways.Alterationsinthesepathways,inturn,triggermolecularresponsesthatstimulatecellproliferationandpromotetumorsurvivalandprogression.

Citation:BlackshearPE,PandiriAR,TonTV,ClaytonNP,ShockleyKR,PeddadaSD,GerrishKE,SillsRC,HoenerhoffMJ.2013.SpontaneousmesotheliomasinF344/Nratsarecharacterizedbydysregulationofcellulargrowthandimmunefunctionpathways.ToxicolPathol;doi:10.1177/0192623313501894[Online26August2013].

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Chronic exposure of renal stem cells to inorganic arsenic induces a cancer phenotypeEvidenceindicatedthatdevelopmentalarsenicexposureimpactsrenalcarcinogenesisinhumansandmice,andsinceemergingtheorysuggestedcancermaybeadiseaseofstemcells(SCs),theresearcherswantedtoseeifinorganicarsenictargetsSCs,orpartiallydifferentiatedprogenitorcells(PCs),foroncogenictransformation.

ScientistschronicallyexposedtheratkidneySC/PCcellline,RIMM-18,tolow-levelarsenite(500nM)forupto28weeks,andfoundthatdysregulationofSCmaintenancegenesandsignalingpathwaysarecommonduringoncogenesis.Duringarseniteexposure,expressionofseveralgenesassociatedwithnormalkidneydevelopmentandSCregulationanddifferentiation,suchasWt-1,Wnt-4,andBmp-7wereaberrantlyaltered.ThesedatarevealthatmultipotentSCsmaybetargetsofarsenicduringrenalcarcinogenesis.

Citation:TokarEJ,PersonRJ,SunY,PerantoniA,WaalkesMP.2013.Chronicexposureofrenalstemcellstoinorganicarsenicinducesacancerphenotype.ChemResToxicol26(1):96-105.

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RNASeq profiling reveals novel hepatic gene expression pattern in aflatoxin B1 treated ratsResearchersuseddeepsequencing(DESeq)toinvestigatethesubchroniceffectsof1ppmaflatoxinB1(AFB1),apotenthepatocarcinogen,onthemaleratlivertranscriptomepriortoonsetofhistopathologicallesionsortumors.

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DESeqanalysisidentified1,026differentiallyexpressedtranscriptsatgreaterthantwo-foldchangecomparedto626transcriptsbymicroarrayduetobasepairresolutionoftranscriptsbyRNA-Seq,probeplacementwithintranscriptsoranabsenceofprobestodetectnoveltranscripts,splicevariantsandexons.Theyfoundthattherattranscriptomecontainsmanypreviouslyunidentified,AFB1-responsiveexonsandtranscriptssupportingRNA-Seq’scapabilitiestoprovidenewinsightsintoAFB1-mediatedgeneexpressionleadingtohepatocellularcarcinoma.

Citation:MerrickBA,PhadkeDP,AuerbachSS,MayD,StiegelmeyerSM,ShahRR,TiceRR.2013.RNA-SeqprofilingrevealsnovelhepaticgeneexpressionpatterninaflatoxinB1treatedrats.PLoSOne8(4):e61768.

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Recruitment of normal stem cells to an oncogenic phenotype by noncontiguous carcinogen-transformed epithelia depends on the transforming carcinogenNTPscientistswantedtoknowwhethertherecruitmentofnormalstemcell(NSCs)intocancerstemcells(CSCs)bynoncontactco-culturewasspecifictoarsenic-transformedisogenicmalignantepithelialcells(MECs).Therefore,theyutilizedco-culturetoexaminetheeffectsofneighboringnoncontiguouscadmium-transformedMECs(Cd-MECs)andN-methyl-N-nitrosourea-transformedMECs(MNU-MECs)onNSCs.

TheyfoundthatCd-MECscanrecruitnearbyNSCsintoaCSC-likephenotype,butMNU-MECsdonot.Thus,therecruitmentofNSCsintoCSCsbynearbyMECsisdependentonthecarcinogenoriginallyusedtomalignantlytransformtheMECs.

Citation:XuY,TokarEJ,PersonRJ,OrihuelaRG,NgalameNN,WaalkesMP.2013.Recruitmentofnormalstemcellstoanoncogenicphenotypebynoncontiguouscarcinogen-transformedepitheliadependsonthetransformingcarcinogen.EnvironHealthPerspect121(8):944-950.

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Bisphenol A affects androgen receptor function via multiple mechanismsBPAisanendocrinedisruptingcompoundthataffectsthedevelopmentandfunctionofthefemaleandmalereproductivesystem.Sinceitsmechanismofactionisunclear,theresearchteaminitiatedthestudytoinvestigatehowBPAmayaffecttendifferentnuclearreceptors.

Thescientistsexaminedstablecelllinesthatcontainedanindividualnuclearreceptorligandbindingdomain-linkedtothebeta-GalreporterusingaquantitativehighthroughputscreeningformatintheTox21screeningprogram.Theresultsshowedthattworeceptors,estrogenreceptoralpha(ERalpha)andandrogenreceptor(AR),areaffectedbyBPAinoppositedirection.Theteamalsoperformedtransienttransfectionexperimentswithfull-lengthreceptorsandtheircorrespondingresponseelementslinkedtoluciferasereporters,aswellasevaluatingBPAeffectsinnucleartranslocationassaysusingEGPF-taggedreceptors.TheauthorsfoundthatBPAenhancedERalphanuclearfociformation,butata100-foldhigherconcentration.BPAwasunabletoactivateAR.

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Citation:TengC,GoodwinB,ShockleyK,XiaM,HuangR,NorrisJ,MerrickBA,JettenAM,AustinCP,TiceRR.2013.BisphenolAaffectsandrogenreceptorfunctionviamultiplemechanisms.ChemBiolInteract203(3):556-564.

ThecontributingwriterfortheNIEHSgranteeresearchsummarieswasNancyLamontagne,asciencewriterwithMDBInc.,acontractorfortheNIEHSDivisionofExtramuralResearchandTraining,SuperfundResearchProgram,andWorkerEducationandTrainingProgram.

NIEHSresearchsummarieswerewrittenbyAleksandraAdomas,Ph.D.,aresearchfellowintheNIEHSLaboratoryofMolecularCarcinogenesisEukaryoticTranscriptionalRegulationGroup;JacquelinePowell,Ph.D.,aformerNIEHSpostdoctoralfellowandawriterandanalystwithEducationandTrainingSystemsInternational;MonicaFrazier,Ph.D.,anIRTAfellowintheNIEHSLaboratoryofMolecularGeneticsMechanismsofMutationGroup;MelissaKerr,achemistrystudentatNorthCarolinaCentralUniversityandinternintheNIEHSOfficeofCommunicationsandPublicLiaison;MallikarjunaMetukuri,Ph.D.,aresearchfellowintheMetabolism,Genes,andEnvironmentGroupoftheNIEHSLaboratoryofSignalTransduction;BaileySchug,ahealthpromotionandnutritionstudentatAppalachianStateUniversityandaninternintheNIEHSOfficeofCommunicationsandPublicLiaison;DeepaSingh,Ph.D.,avisitingfellowintheNIEHSLaboratoryofMolecularGeneticsMechanismsofMutationGroup.

NTPresearchsummarieswerecontributedbyNTPstaffandsubmittedbytheirbranchchiefs.

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Lewis Cantley discusses cancer metabolism in Rodbell Lecture By Sheila Yong

TheprestigiousDr.MartinRodbellLectureSeriesSeminarDec.10featuredLewisCantley,Ph.D.,discussinghisresearchintophosphoinositide3-kinase(PI3K)signalinganditsroleincancerprogression.Inhistalk,“PI3Kandcancermetabolism,”CantleypresentedexcitingdiscoveriesheandhiscolleagueshavemadeoverthepastseveraldecadesinPI3Ksignaling,andhowtheyhavetranslatedtheirfindingsintonewtreatmentstrategiesforvariouscancersanddiseases.

CantleyisdirectoroftheCancerCenteratWeillCornellMedicalCollegeandNewYork-PresbyterianHospital,andtheMargaretandHermanSokolProfessorinOncologyResearchatWeillCornell.

JamesPutney,Ph.D.,headoftheNIEHSCalciumRegulationGroupintheLaboratoryofSignalTransduction,andalongtimefriend,comparedCantley’sscientificcareertoRodbell’s.“LewisanespeciallyappropriatespeakerfortheRodbell

Cantley’s research has spurred drug development efforts for treating various cancers and hereditary familial syndromes. One significant success is everolimus, a drug used to treat lymphangioleiomyomatosis (LAM), a rare lung disease that affects mostly women. “In the past, LAM patients would have to undergo lung transplant. Unfortunately, the transplanted lung would eventually fail and the patients would die anyway,” Cantley explained. With everolimus, LAM patients can now lead normal lives, without relying on supplemental oxygen or undergoing lung transplant. (Photo courtesy of Steve McCaw)

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lecture,becausebothheandMartyinitiallyconductedexperimentsthatyieldedunexpectedresults.Whilemostpeoplewouldhavemovedontosomethingelse,theyrealizedthattheseresultswereactuallytellingthemsomethingimportant.”

Cantley’sscientificinstinctanddedicationledhimtothediscoveryofPI3Ksignalingin1988,andsubsequentadvancesincancerresearch.

Crossing the line between normal cell growth and cancerCantleybeganhislecturewithadescriptionoftheinsulinsignalingpathway,whichcontrolsglucosemetabolism.Uponinsulinstimulation,insulinreceptorsundergophosphorylationandbecomeactive.ThisphenomenontriggersasignalingcascademediatedbyclassIAPI3Ks,whichgeneratephosphatidylinositol(3,4,5)-triphosphate(PIP3)fromphosphatidylinositol(4,5)-bisphosphate(PIP2),aphospholipidfoundinthecellmembrane.PIP3servesasadockingsiteforseveraldownstreamproteins,includingproteinkinasesAKTandPDK1.

Theseproteins,inturn,becomeactivatedandtranslocatetootherlocationsinthecelltofacilitatevariousdownstreamprocesses,thuspromotingsurvivalandgrowth.Producedbyoncogenes,theseproteinscausecancerwhentheirfunctionsaremisregulated.

Ontheotherhand,severalproteinsalongthepathway,suchasPTENandtuberin,serveasbrakestohaltcellgrowthwhennutrientsandgrowthfactorsarelow.Thisregulatorymechanismensuresthatthepathwayisactiveonlywhenconditionsarefavorable.Thesetumorsuppressorsprotectthecellsfromcancer.

Cancerformswhencellsgrow,evenwhennutrientsorgrowthfactorsareabsent,duetocontinuousactivationofthegrowthpathway.“Mutationsoramplificationoftheseoncogenes,andthelossoffunctionofthesetumorsuppressorgenes,accountforanincrediblefractionofhumancancers,”Cantleyemphasized,citingtheCancerGenomeDatabase.

AccordingtoCantley,70-95percentofcommonhumancancerspresentwithatleastonemutationinthePI3Ksignalingnetwork,especiallywomen’scancers.Cantleynowleadsateamofprominentresearchersfundedbya$15milliongrantfromStandUpToCancertodesignclinicaltrialsthatwilldeterminewhichpatientsarelikelytobenefitfromPI3Kinhibitors.

Cantley’s lecture appealed to people across the Institute, such as Sean Chiou, Ph.D., contractor for the NIEHS Computer Technology Branch. A former bench scientist, Chiou performed research on insulin signaling during his graduate school days. (Photo courtesy of Steve McCaw)

Researchers from across many disciplines attended Cantley’s lecture, many of whom were seated in the front row. Shown, right to left, are senior scientists Jerrel Yakel, Ph.D., and Serena Dudek, Ph.D., from the NIEHS Laboratory of Neurobiology; Division of Intramural Research and Division of NTP senior scientist Richard Paules, Ph.D.; NTP Associate Director John Bucher, Ph.D.; biologist Wendy Jefferson, Ph.D., from the NIEHS Reproductive Medicine Group; and NIEHS Scientific Director Darryl Zeldin, M.D. (Photo courtesy of Steve McCaw)

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A new player in cancer metabolismTenyearsafterdiscoveringPI3K,Cantley’sgroupidentifiedphosphatidylinositol5-phosphate4-kinase(PI5P4K),whichconvertsphosphatidylinositol5-phosphatetoPIP2.“Ithasbeenveryfrustratingtofigureoutwhatthisenzymedoes,”Cantleysaid.MicethatlackeitherthealphaorbetaisoformofPI5P4Kexhibitlittletonophenotype,whilemicelackingbothisoformsarenotviable.Interestingly,micethatlackbothcopiesofp53,whileretainingonecopyofPI5P4K-beta,areprotectedfromcancer.

p53isamongthemostheavilystudiedtumorsuppressors,andisfrequentlylostinmanytypesofcancers.Notsurprisingly,manyofthesetumorsalsoexhibithighlevelsofPI5P4Kexpression.Throughdetailedexperimentation,usingmousemodelsandhumancancercelllines,Cantley’sgroupdeterminedthatbothp53andPI5P4Kprovidealternativepathwaysforregulatingglucosemetabolismandsuppressingoxidativestress.

Whencellslosep53,thePI5P4Kpathwaybecomesessentialincombatingoxidativestress.Therefore,cancercellslackingp53upregulatethePI5P4Kpathwaytopromotecellsurvival.“WebelievethatPI5P4Kisagoodtargetfortreatingtumorsthatlackp53whilesparingnormaltissues,”heconcluded.

(SheilaYong,Ph.D.,isavisitingfellowintheNIEHSInositolSignalingGroup.)

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Speakers in the Rodbell Lecture Series receive a statue depicting the hand of Nobel laureate and former NIEHS Scientific Director, Martin Rodbell, Ph.D., holding the three key elements involved in cell signaling. Sculptor Carl Regutti, who created the statue and attended the Rodbell lecture in 2012 as a family guest, died in April 2013. (Photo courtesy of Steve McCaw)

With his Rodbell statue in hand, Cantley joined, left to right, NIEHS and NTP Director Linda Birnbaum, Ph.D., Barbara Rodbell, and Putney for a group photo. Barbara, Rodbell’s widow and honored guest, has attended every Rodbell lecture, since Rodbell gave the first talk in the series in 1998. (Photo courtesy of Steve McCaw)

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Seminar showcases Toxicogenetics Challenge winners By Ernie Hood

Some60scientistsgatheredDec.2atNIEHSforaninformativeseminar,“CrowdsourcingTox21QualitativeHighThroughputScreeningData,”focusingontheNIEHS–NCATS–UNCDREAMToxicogeneticsChallenge.

SpeakersdescribedtheTox21projectthatgeneratedthedatausedintheChallenge,theinnovativeapproachesemployedbytheteamsthatwonthetwosubchallenges,andthevalueofcrowdsourcingtoadvanceandacceleratescientificknowledge.

TheJune11-Sept.15Challengewasco-sponsoredbyNIEHS,theNationalCenterforAdvancingTranslationalSciences(NCATS),theCarolinaCenterforComputationalToxicology(CCCT)attheUniversityofNorthCarolinaatChapelHill(UNC),DREAM(DialogueforReverseEngineeringAssessmentsandMethods),andSageBionetworks.NIEHSandNTPDirectorLindaBirnbaum,Ph.D.,moderatedtheseminar.“TheChallengerepresentsagroundbreakingnewdirectionfortoxicitytesting,”shesaid.

The challenge data sourceNourAbdo,adoctoralstudentintheDepartmentofEnvironmentalSciencesandEngineeringatUNC,spokeaboutaTox21projectknownasthe1000genomestoxicityscreeningproject,whichutilizesthepowerofhumangenomevariationforpopulation-scalein vitrotesting.

TheprojectprovidedtherawdatasuppliedtotheChallengecompetitors.Cytotoxicitydatawasgeneratedon1,086humanlymphoblastcelllines,representingninepopulationsfromfivecontinents,inanassaywith179environmentalchemicalsateightconcentrations.Thestudygeneratedroughly2.6milliondatapoints—thelargest-scaleexperimenttodate,intermsofthenumberofcelllinesusedandchemicalsscreened.

AsAbdoexplained,thepopulation-basedapproachappearstobefarmorepowerfulthantraditionalin vitrotoxicitytesting.“Thecurrenttoxicitytestingapproachesusuallyincludemodelsystemswithveryhomogeneousgenetics,soonlythehazardcanbeevaluated.Ourapproachincorporatesgeneticdiversity,allowingtestingofnotonlyhazards,butalsothevariabilityinthepopulation,”shesaid.

The bigger picture of challenges — the strength of crowdsourcing

DREAMrepresentativeGustavoStolovitzky,Ph.D.,fromtheIBMComputationalBiologyCenter,calledintotheseminartodiscuss“DataRe-useandtheWisdomofCrowds.”Heprovidedahistoryofcrowdsourcingincomputationalbiology,andexplainedwhyitmakessensetoconductchallengesandleveragethewisdomofcrowdstoadvancebiomedicalresearch.Hepointedoutthatdatasetsmultiplytheirimpactbybecomingaccessibletoawidesegmentofthescientificcommunity,andnotedthatafteracompetitioniscomplete,thecrowd’swisdomcanbefurthertappedbyfosteringcollaborativeresearch.

Abdo presented data from the 1000 genomes toxicity screening project. She said that the current paradigm in toxicity screening is based on using in vivo data to derive a human reference dose for individual chemicals, but the future paradigm being developed will use in vitro data for human reference dose determination. (Photo courtesy of Steve McCaw)

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Thepopulation-basedapproachallowsquantitativeassessmentofbothhazardandinterindividualvariabilityinchemicaltoxicity,aswellasidentificationofsusceptiblesub-populations,newunderstandingofthegeneticdeterminantsofinterindividualvariability,andgenerationoftestablehypothesesabouttoxicitypathways.Thedatacanalsobeusedtobuildpredictivein silicomodels.

The challenge winnersThechallengeincludedtwosubchallenges.Subchallenge1,whichgenerated99submissionsfrom34teams,involvedusingthesupplieddatatoaccuratelypredictindividualresponsestocompoundexposure,basedongenomicinformation.Subchallenge2,with85submissionsfrom24teams,calledfordevelopmentofamodeltoaccuratelypredicthowaparticularpopulationwouldrespondtocertaintypesofchemicals.Teamsfromthesameinstitution,theQuantitativeBiomedicalResearchCenter(QBRC)attheUniversityofTexasSouthwesternMedicalCenter,werenamedbestperformerinbothofthesubchallenges.

HaoTang,Ph.D.,leadscientistforthesubchallenge2teamandamemberofthesubchallenge1team,describedthemethodstheteamsemployedsuccessfullytocomeinfirstinbothsegmentsofthecompetition.Insubchallenge1,thekeytorobusttoxicitypredictivityinthemodelwastheuseoffinemappingbasedonthegeographicareawhereacelllineoriginated.Forsubchallenge2,themodelwasenhanced,byincorporatingsupervisedfeatureselectionandmultimodaldistribution-basedanalysisintostandardquantitativestructure-activityrelationshipmodeling.

“Thoseapproaches,alongwithotherscontributedbymanyoftheotherchallengeteams,willundoubtedlyimproveourabilitytousebothgenomicdataandchemicaldatatoaccuratelypredictcytotoxicityin vitro,”saidNTPBiomolecularScreeningBranchChiefRaymondTice,Ph.D.“TheChallengeaccomplishedexactlywhatwehadhopeditwould.”

ResultsofthechallengewillbepublishedinthejournalNatureBiotechnology.

(ErnieHoodisacontractwriterwiththeNIEHSOfficeofCommunicationsandPublicLiaison.)

Among the many attentive listeners at the challenge seminar were, from right, NTP Associate Director John Bucher, Ph.D., and Health Scientist Administrator Jerry Heindel, Ph.D. (Photo courtesy of Steve McCaw)

Joined at the podium by Birnbaum, Tang, right, was clearly delighted with the response to her presentation. (Photo courtesy of Steve McCaw)

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Biostatistician Fred Wright, Ph.D., from CCCT, said the 1000 genomes toxicity screening project has shown that, while there is much evidence of heritability in susceptibility to environmental exposures, it can be difficult to isolate. “What Nour has shown is that, somehow, there is signal lurking there, but it’s spread out amongst a lot of small effect variants throughout the genome,” he said, in response to a question from the audience. (Photo courtesy of Steve McCaw)

Stolovitzky said that the wisdom of crowds means that the aggregate results from multiteam competitions are more robust and more predictive than any individual results. (Photo courtesy of Gustavo Stolovitzky)

Ivan Rusyn, M.D., Ph.D., also from CCCT, elaborated on a point made by Tang, as he responded to a question from an attendee. “To me, as a toxicologist, one of the most important outcomes of these challenges was that it’s not necessarily that we need to collect more data, but what we can do with the data that we have.” (Photo courtesy of Steve McCaw)

Environmental Genomics Group lead Douglas Bell, Ph.D., asked about the relative merits of the array data versus RNA-Seq data, as used in the challenge. (Photo courtesy of Steve McCaw)

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NTP panel peer reviews substances for potential listing as carcinogens By Ernie Hood

Apanelofexpertspeer-reviewedthetwomostrecentNTPdraftReportonCarcinogens(RoC)documents,knownasmonographs,atapublicmeetingDec.12-13atNIEHS.

Thepanelwaschargedwithreviewingthedraftmonographsforortho-Toluidineandpentachlorophenolandby-productsofitssynthesis.ThemonographscontaintherationaleandbackgroundinformationtosupportNTPlistingrecommendationsforinclusionintheRoC.Thepanelvotedonwhetherthescientificevidencesupportsthelistingrecommendations,whichcancharacterizeasubstanceaseither“knowntobehumancarcinogens”oras“reasonablyanticipatedtobehumancarcinogens.”

Afterthoughtfuldiscussions,thepanelchairedbyKennethMcMartin,Ph.D.,aprofessorintheDepartmentofPharmacology,Toxicology,andNeuroscienceatLouisianaStateUniversityHealthSciencesCenter,recommendedlistingortho-Toluidineasaknownhumancarcinogenandpentachlorophenolandby-productsofitssynthesisasreasonablyanticipatedtobeahumancarcinogen.

Monograph on ortho-ToluidineThesubstanceortho-Toluidineisusedtomakedyes,rubberchemicals,herbicides,andthelocalanestheticprilocaine.IthasbeenlistedintheRoCsince1983asreasonablyanticipatedtobeahumancarcinogen.Sincethen,severalcancerstudieshavebeenpublishedinpeer-reviewedliterature,andtheInternationalAgencyforResearchonCancer(IARC)hasconcludedthatthecompoundiscarcinogenictohumans.Forthesereasons,itwasselectedforareevaluationandapossiblechangeinRoClistingstatus.

NTPstaffhighlightedstudies,presentedinthedraftmonograph,showingcredibleevidenceofanassociationbetweenurinary-bladdercancerandexposuretoortho-Toluidine,basedonconsistentfindingsacrosshumanstudies.Evidencefromstudiesinexperimentalanimalsandonmechanismsofcarcinogenicityalsosupportsthatfinding.Thepeer-reviewpanelunanimouslyconcurredwiththeNTP’spreliminarylistingrecommendationthatortho-Toluidineisknowntobeahumancarcinogen.

Monograph on pentachlorophenol and by-products of its synthesisStudiesevaluatingthecarcinogenicityofpentachlorophenolandby-productsofitssynthesiswerediscussedingreatlengthand

Ruth Lunn, Dr.P.H., director of the Office of the Report on Carcinogens, briefed the peer review panel on the process for preparing the draft monographs, and presented much of the information on ortho-Toluidine. (Photo courtesy of Steve McCaw)

NTP Health Scientist Gloria Jahnke, D.V.M., presented most of the information on pentachlorophenol and by-products of its synthesis to the panel. (Photo courtesy of Steve McCaw)

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detailamongthepeer-reviewpanelandRoCstaff,todetermineiftherewassufficientevidencetosupportNTP’spreliminarylistingrecommendationofknowntobeahumancarcinogen,withnon-Hodgkin’slymphomaastheprimarycancerendpointofconcerninthesestudies.

PentachlorophenolisachlorinatedaromaticcompoundthatwasusedintheU.S.asacommercialandresidentialwoodpreservativeandmultipurposebiocide,untilitwasrestrictedinthemid-1980stonon-residentialuse.Today,itislimitedtocommercialwoodpreservationinitemssuchasutilitypoles,fenceposts,andrailroadties.

Thepanelmembersstatedthatoveralltheevidenceofcarcinogenicityfromthestudiesinhumancancerwaslimited.Theyagreedthattherewasoneverygoodstudythatfoundanassociationbetweenexposuretopentachlorophenolandby-productsofitssynthesis,butthoughttheevidencefromtheotherstudieswasmuchmorelimited,duetotheirsmallsizeandpotentialforconfoundingfactors.

Thepanelalsostruggledoverwhetherthecandidatesubstanceshouldbepentachlorophenolitselforpentachlorophenolandthebyproductsofitssynthesis.Technical-gradepentachlorophenolisamixture,withupto10percentofthesubstancebeingby-productsofitssynthesis,manyofwhicharedioxin-likecompoundsthatmaycontributetoitscarcinogenicity.

Attheendoftheday,thepanelvotedtorecommendchangingtheNTPpreliminarylistingdecisionofknowntobehumancarcinogen,toreasonablyanticipatedtobeahumancarcinogen,basedonlimitedevidencefromstudiesinhumans.Thelistingrecommendationalsotookintoconsiderationthesufficientevidenceofcarcinogenicityofpentachlorophenol,andpentachlorophenolandby-productsofitssynthesis,fromstudiesinexperimentalanimalsandsupportingmechanisticevidence.

Next StepsTheNTPwillconsiderthepanel’scommentsandpubliccomments,asitmakesrevisionstothedraftmonographs.TheupdatedmonographswillbepresentedtotheNTPBoardofScientificCounselorsatthenextmeetinginApril2014.

(ErnieHoodisacontractwriterwiththeNIEHSOfficeofCommunicationsandPublicLiaison.)

Panel member Laura Beane Freeman, Ph.D., tenure track researcher at the National Cancer Institute, agreed with the panel’s recommendation to change the pentachlorophenol and the by-products of its synthesis listing. “I don’t view the whole body of epidemiologic evidence as being supportive of pentachlorophenol being listed as a carcinogen,” she said. (Photo courtesy of Steve McCaw)

Following the robust discussion of pentachlorophenol and the by-products of its synthesis, NTP Associate Director John Bucher, Ph.D., right, praised the panel’s work. “This has been one of the more detailed and very careful reviews that I’ve seen any of our expert panels engage in,” he said. “The effort you’ve put in on this is quite remarkable.” Next to Bucher is Mary Wolfe, Ph.D., director of the NTP Office of Liaison Policy and Review, who briefed the panel on the scientific issues raised by public comments regarding both substances under review. (Photo courtesy of Steve McCaw)

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Panelist Allan Smith, M.D., Ph.D., of the University of California, Berkeley, center, contributed many thoughtful remarks during the discussions about the two draft monographs. (Photo courtesy of Steve McCaw)

Peer-review member Gabriele Sabbioni, Ph.D., of Tulane University, asked several pointed questions during the course of the proceedings on the review of ortho-Toluidine. (Photo courtesy of Steve McCaw)

Stephen Nesnow, Ph.D., a retired senior scientist at the National Health and Environmental Effects Research Laboratory at the U.S. Environmental Protection Agency in Research Triangle Park, N.C., paid close attention to the data being presented on the two substances under review. (Photo courtesy of Steve McCaw)

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Preterm birth linked with maternal phthalate exposure during pregnancy By Nancy Lamontagne

ResearchersledbyNIEHSSuperfundResearchProgramgranteeJohnMeeker,Sc.D.,fromtheUniversityofMichigan(UM),reportthatwomenwiththehighestlevelsofphthalateexposureduringpregnancyhaduptofivetimestheoddsofpretermbirth,comparedtowomenwiththelowestexposure.Phthalatescanbefoundinfoodstoredorprocessedinplastic;plasticproducts,suchasshowercurtainsandvinylflooring;andpersonalcareproducts,suchasdeodorantsandlotions.

“Pretermbirthisaseriouspublichealthchallenge,andratesaresignificantlyhigherthantheywere20to30yearsago,”Meekerexplained.“Explanationsforthisincreaseremainelusive.Ifenvironmentalfactors,suchasexposuretophthalates,areindeedacauseofpretermbirthitmayrepresentamodifiableriskfactorthatcouldleadtoeffectiveinterventions.”

Meeker is an associate professor of environmental health sciences and associate dean for research at the UM School of Public Health. (Photo courtesy of UM School of Public Health)

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Adding evidenceMeekerpreviouslypublishedresultsfromasmallpilotstudythatshowedalinkbetweenphthalateexposureandpretermbirth.Thenewstudy,publishedinJAMAPediatricsandco-authoredbyUMdoctoralstudentKellyFergusonandThomasMcElrath,M.D.,Ph.D.,ofBrighamandWomen’sHospital,buildsonthepilotstudy,byusinganestedcasecontroldesigntostudyamuchlargergroupofwomen.Theyalsoanalyzedurinesamplesfromuptothreetimepointsduringpregnancy,tobetterdetermineoverallphthalateexposure.

Thestudyincluded130motherswhohaddeliveredpriorto37weeksofcompletedgestation,and352controlmotherswhodeliveredatorafter37weeks.Theresearchersexaminedtheninephthalatemetabolitesoffourphthalatesandfoundthat,dependingontheindividualphthalate,womenwiththehighestlevelsofexposuretofourofthephthalatesduringpregnancyhadtwo-tofive-timestheoddsofpretermbirthcomparedtothosewiththelowestexposure.

Theresearchersfoundthestrongestdose-dependentassociationswithmaternallevelsofthetwodi-2-ethylhexylphthalate(DEHP)metabolites,mono-(2-ethyl)-hexylphthalate(MEHP)andmono-(2-ethyl-5-carboxypentyl)phthalate(MECPP),andthesummedlevelsofalltheDEHPmetabolites.

Subset of preterm births shows stronger associationTheresearchersalsoanalyzedasubsetof57motherswithpretermdeliveriesprecededbyspontaneouspretermlabororpretermprematureruptureofthemembranes.Whenthisgroupwasexaminedalone,theoddsratiosincreasedforallthephthalatemetabolites.Thisfindingindicatesastrongerassociationbetweenphthalateexposureandspontaneouspretermbirth,thantheassociationwithallpretermbirths.

“Oneofthelimitationstostudyingfactorsassociatedwithpretermbirthhasbeenthatitisaheterogeneousoutcomewithanumberofdifferentunderlyingconditionsorbiologicalmechanismsthatarepossible,”Meekersaid.“Restrictingcasestothosewithspontaneouspretermbirthwasimportanttotryandnarrowdownapotentiallymorehomogeneousgroup.Ourhypothesiswasthatphthalatesmaycausebiologicalresponses,suchasalteredendocrinefunction,inflammation,oroxidativestress,whichmayleadtoaspontaneouspretermbirth.”

Theresearcherscautionthat,beforeimplementinginterventionsaimedatdecreasingphthalateexposure,morestudiesareneededtoconfirmthesefindings,toexaminethesourcesofthephthalates,andtobetterunderstandthemechanismsinvolved.Phthalateexposuremightbereducedbyeatingfreshfoodsthathaveundergonelessprocessingandpackaging,andbypurchasingphthalate-freeplasticsandpersonalcareproducts,butMeekernotedthatresearchontheeffectivenessoftheseactivitiesinreducingexposureremainslimited.

Theresearchersarecontinuingtoexplorebiologicalmechanismsthatmaybeinvolvedintheassociationstheyobserved,andwhethercertainpopulationsmaybeparticularlysusceptibletoenvironmentalinfluencesonpretermbirth.Theyarealsoexaminingsources,pathways,androutesofexposureforpregnantwomen,tohelpinforminterventions.

Ferguson, a doctoral student in environmental health sciences at UM, is first author of the new paper. (Photo courtesy of Kelly Ferguson)

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Citation:FergusonKK,McElrathTF,MeekerJD.2013.Environmentalphthalateexposureandpretermbirth.JAMAPediatr;doi:10.1001/jamapediatrics.2013.3699[Online18November2013].

(NancyLamontagneisasciencewriterwithMDBInc.,acontractorfortheNIEHSDivisionofExtramuralResearchandTraining.)

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LSB speaker discusses the role of mobile DNA elements in nature By Deepa Singh

UnderstandingthesignificanceofmobileDNAelementsisimportant,becausehalfofhumangenomeisderivedfromthem,accordingtoPhoebeRice,Ph.D.RicepresentedherworkonDNAtranspositionandsite-specificrecombination,bothprocessesthatinvolvemovementofDNAfromonelocationtoanother,inaseminarDec.12sponsoredbytheNIEHSLaboratoryofStructuralBiology.

MobileDNAelements,alsoknownasthetransposonsortransposableelements,representapotentforceforchangewithinbothprokaryoticandeukaryoticgenomes,andcanbeamajorsourceofmutation.“Inbacteria,itcanfacilitateevolutionandantibioticresistance,andoftenprovideenzymesthatmakeusefulbiotechtools,”explainedRice,pointingtothetranslationalpotentialofherresearch.

ThehostofRice’sseminarwasMatthewSchellenberg,Ph.D.,avisitingfellowintheGenomeStabilityStructuralBiologyGroupheadedbyScottWilliams,Ph.D.RiceisaprofessorintheDepartmentofBiochemistryandMolecularBiologyattheUniversityofChicago.HergroupcombinesbiochemistryandX-raycrystallographytostudydifferentstagesofprotein-DNAinteractionsduringtranspositionandrecombination.

Convergent and divergent evolution of bacteriophage Mu transposomeForDNAtransposition,RiceusedtheexampleofbacteriophageMu,abacterialvirusthatpropagatesitselfbyrepeatedtranspositionandintegrationintoitshostgenome.Cancer-causingretroviruses,suchasHIV,useasimilarmechanismtointegrateintotheirhostgenomes.Therefore,understandingthemechanismofMutranspositionisimportantineffortstopreventandcureretroviraldiseases.

Rice, left, joined Williams and host Schellenberg, right, following her talk. (Photo courtesy of Steve McCaw)

Rice played with a handmade stuffed DNA prop she used during her talk to illustrate the structure of recombinases in complex with DNA. (Photo courtesy of Steve McCaw)

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StructuralstudiesofDNAtransposaseMuA,incomplexwithbacteriophageDNAendsandthetargetDNA,determinedintertwinednetworksofprotein-proteinandprotein-DNAcontacts.MuA,intheabsenceofDNA,consistsofasinglesubunitthathasfivedomainsandisusuallyrepresentedorcartoonedasbeadsonastring.ButinthepresenceofDNA,foursubunitsofMuAassembleontheDNA,whilethesamedomainsondifferentsubunitshavedifferentfunctions.

AccordingtoRice,“Thestructureisquitecompact,butismadeupofatangledmessofthreeDNAsegmentsandfourproteins.”

ComparedtootherDNAtransposasesandretroviralintegrases,theMuAcomplexhasadifferentarrangementoftheDNA-bindingdomainsandregulatorydomains,butthedomaincontainingthecatalyticsiteisquitesimilar.Inherconclusion,RicenotedthatallDNAtransposasesdivergedalongtimeagofromacommoncatalyticdomain,buthaveallconvergedbacktotranscatalysis,sincetheyallrecognizeoneendofDNAandengagechemicallyontheotherend.

Proposed model for the site-specific recombination of serine recombinasesInthesecondpartofhertalk,Ricefocusedonsite-specificrecombinationthatmovesmobileDNAelementsbetweennonhomologoussiteswithinagenomeandproducesgeneticvariantsuponwhichevolutiondepends.Therecombinasesareoftenclassifiedintoserine-recombinasefamiliesandtyrosine-recombinasefamilies,basedontheiractivesitenucleophile.

Manyserinerecombinasesfunctionasresolvases.“TheresolvasesarerequiredtocleanupaftersomeDNAtransposasesandalsoafterreplication,”explainedRice.TheyresolvetheoriginalhostDNAthatisstillfusedtothetargetDNAwithatransposonatthejunction,andconvertlargeDNAmoleculesintosmallerones.

ThestructureoftheseveralrecombinasesincomplexwithDNAisknown,butthereisstillconfusionabouthowtheyexploitDNAtopologytoregulaterecombination.Aftercomparingseveraldifferentrecombinases,Rice’slabproposedadivergent-convergentevolution,sincetheyallhavesimilarsequence,structure,andtopology,butthedetailsofhowtheyexploitthattopologyareverydifferent.

Concludinghertalk,Ricedescribedherlatestworkonadifferentpairofserinerecombinasesthatareencodedbythemobilegeneticelementthatturnsgarden-varietyStaphylococcusaureusintothemethicillin-resistantformofthebacterium,MRSA.Infectionisincreasinglycommonincrowdedsettings,suchashospitals,posingasignificantpublichealthchallenge,duetothedifficultyoftreatingnewstrains,astheyevolve,withcurrentlyavailablemedications.

(DeepaSingh,Ph.D.,isavisitingfellowintheNIEHSMechanismsofMutationGroup.)

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Researchers’ work translated into positive results for public health By Keith Herrell and Joe Balintfy

AnNIEHS-fundedstudyofchemicalsinthebloodof6-8year-oldgirlsintheCincinnati-NorthernKentuckymetropolitanarea,alsoknownasGreaterCincinnati,andSanFranciscoBayarea,collectedbetween2005and2009,showedadirectrelationshipbetweenthedurationofbeingbreastandthechildren’sbloodlevelsofcertainpolyfluoroalkylchemicals(PFCs).ThestudywaspublishedinthescientificjournalEnvironmentalPollution.

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PFCsareinanumberofhouseholdproducts,andthesechemicalscanfindtheirwayintothewatersupply,eventuallyendingupinbreastmilk.Theirhealtheffectsarestillbeingstudied,butotherresearchershavefoundseriousconcernsthatincludeincreasedriskofcancer.

“Thisprojectrepresentsasuccessstoryofresearchfindingsbeingtranslatedtopublichealth,”saidSusanPinney,Ph.D.,professorofenvironmentalhealthanddeputydirectoroftheCenterforEnvironmentalGeneticsattheUniversityofCincinnati(UC).

High levels of PFCs in Greater Cincinnati areaEarlyinthestudy,apreliminarylistofchemicalstobetestedwassharedwithAntoniaCalafat,Ph.D.,headofthePersonalCareProductsLaboratoryattheCentersforDiseaseControlandPrevention(CDC),whosuggestedthatPFCsandotherrelevantenvironmentalchemicalsbeaddedtothelist.ItwassubsequentlydiscoveredthatabouthalfofthegirlsinoneparticularareaofGreaterCincinnatihadsignificantconcentrationsofperfluorooctanoicacid(PFOA),atypeofPFC,intheirblood.

Atthatpoint,NIEHS,theNationalCancerInstitute(NCI),whichco-fundedthestudy,andCDCagreedtomeasurethebloodconcentrationinallofthestudyparticipantsfromtheNorthernKentuckyarea.

Study results lead to changes in water intake filtrationUsingpreliminarydatafromthesemeasurements,in2007,studyinvestigatorsvisitedofficialsfromtheGreaterCincinnatiWaterWorks(GCWW)andNorthernKentuckyWaterDistrict(NKWD)toinformthemofthefindings.AmeetingwiththeparentsofstudyparticipantsfromNorthernKentuckywasalsoheld.

Overthenextfiveyears,theNKWDandGCWWconsideredthestudyresultsindeterminingtheappropriatefrequencyforreactivatingitsgranulatedactivatedcarbonfilters.NKWDdrawsitswaterfromtheOhioRiverandLickingRiver,whileGCWWreceivesitswaterfromtheOhioRiverandtheGreatMiamiAquifer.

Priortopublicationofthestudy,theresearchersagainmetwiththeleadershipofthewaterdepartments,sharingfindingsthathadbeenpresentedattheInternationalSocietyforEnvironmentalEpidemiologyAugustmeetinginBasel,Switzerland.

“Themessageisnotthatyoushouldn’tbreastfeed,”Pinneysaid.“Themessageisthatifwedon’ttakecareofgettingthesechemicalsoutofthewater,notonlyarethepersonsthemselvesexposed,buttheexposurecarriesthroughtochildrenwhoarebreastfed.”

Among the findings• GranularactivatedcarbonfiltrationcanreducePFOAexposurethroughdrinkingwatersources.

• ReductionofPFOAexposurethroughdrinkingwatertreatmentalsoreducesinternalexposureinbreastfedgirls.

Pinney said it’s especially rewarding when research points to effective strategies for primary prevention. (Photo courtesy of Cincinnati Children’s Hospital Medical Center)

Second author Frank Biro, M.D., is director of research, adolescent and transition medicine, and professor in the UC Department of Pediatrics. (Photo courtesy of Cincinnati Children’s Hospital Medical Center)

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Citation:PinneySM,BiroFM,WindhamGC,HerrickRL,YaghjyanL,CalafatAM,SuccopP,SucharewH,BallKM,KatoK,KushiLH,BornscheinR.2014.SerumbiomarkersofpolyfluoroalkylcompoundexposureinyounggirlsinGreaterCincinnatiandtheSanFranciscoBayArea,USA.EnvironPollut184:327-334.

(ThisstorywasadaptedfromanarticlebyKeithHerrell,apublicinformationofficerwithhealthNEWS,theUCAcademicHealthCenterPublicRelationsandCommunicationspublication.JoeBalintfyisapublicaffairsspecialistintheNIEHSOfficeofCommunicationsandPublicLiaison.)

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New study finds toenails help trace arsenic exposure from foods By John Cramer and Joe Balintfy

Dietalonecanbeasignificantsourceofarsenicexposure,regardlessofarsenicconcentrationsindrinkingandcookingwater,accordingtoastudyledbyDartmouthCollege,fundedinpartbyNIEHS,andpublishedinNutritionJournal.Thestudyalsoconfirmsthattoenailclippingsareagoodbiomarker,orindicator,oflong-termexposuretoarsenicfromconsumingalcohol,Brusselssprouts,anddarkmeatfish.

Previousstudieshaveshownthatdietcanbeanimportantsourceoftotalarsenicexposure,butthisnewstudyalsotookintoaccountarsenicindrinkingandcookingwater.Householdwateristhoughttobethemostsignificantsourceofarsenicexposureinregionswherewaterarsenicconcentrationsareelevated.Exposuretoarsenichasbeenlinkedtoavarietyofhealthproblems.

“Itisobviouslyaknowncarcinogenandhaseffectsonthecardiovascularsystemandlungfunctioning,”saidWilliamSuk,Ph.D.,headoftheNIEHSHazardousSubstancesResearchBranch.“Becausethereisnoknownmechanism,itishardtodeterminehowlowadosecanbetolerated.”

Foods found to contain arsenicResearchersasked852studyparticipantsabouttheiraverageconsumption,overthepreviousyear,of120differentfoods,includingdairy,fruits,vegetables,eggs,meat,breads,beverages,andbakedgoods.TheyfoundarsenicintoenailclippingsismoststronglylinkedwithconsumptionofBrusselssproutsandalcohol,especiallybeerformenandwhitewineforwomen.ThosewhodrankmorealcoholandatemoreBrusselssproutshadmorearsenicintheirtoenailclippings,whichmakessensebecausealcoholicbeveragescanhavehigherarseniccontentandareknowntointerferewiththemetabolicpathwaysthatdetoxifyarsenic.

Cottingham said some high-arsenic foods are important as part of a healthy diet — they just shouldn’t be consumed every day or multiple times a day. (Photo courtesy of Kathryn Cottingham)

Listen as Cottingham describes the study findings and their public health significance (01:52)

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“WithBrusselssprouts,thereissomeemergingevidencethatshowsvegetablesinthisparticulargroupcontainsulfurmoleculesthathelptheplantsdetoxifyarsenic,”explainedDartmouthProfessorKathrynCottingham,Ph.D.,thestudy’sleadauthor.“WethinkthatBrusselssproutsarehighinarsenicbecausethecompoundsthatgivethemtheircharacteristicsmellalsocausethemtohavepotentiallyhigherarsenicconcentrations.”

Researchersalsofoundincreasedtoenailarsenicinpeoplewhoeatdarkmeatfish,whichincludestunasteaks,mackerel,salmon,sardines,bluefish,andswordfish.Fishgenerallycontainaformofarsenicthatisthoughttosafelypassthroughthehumanbodywithoutbeingmetabolized,butdarkmeatfishalsocontainsarseniccompoundsthatcanbemetabolized.

Water is still a main sourceBothCottinghamandSukemphasizedthatitisimportanttolimitarsenicexposure,inparticularinorganicarsenic,whichisfoundinwater.“Filteringwaterthatiscontaminateddoeswork,”saidSuk.Cottinghamencouragedeveryonewhohasaprivatewelltogetittested,because,asshenoted,everyonedrinkswatereveryday.

ThestudyincludedresearchersfromDartmouthCollege,StonyBrookUniversity,UniversityofNorthCarolinaatChapelHill,GeiselSchoolofMedicineatDartmouth,andUniversityofMissouri.TheresearchwasconductedbytheChildren’sEnvironmentalHealthandDiseasePreventionResearchCenteratDartmouth,oneof14centerswhoseaimistodevelopstrategiestoprevent,detect,andtreatenvironmentallyrelatedhealthconditionsandcommunicatethesestrategiestofamilies,healthprofessionals,andpolicymakers.ThecentersarefundedbyNIEHSandEPA.ThisstudyalsoreceivedsupportfromtheNationalCancerInstitute.

“Wecontinuetoseenewemergingscienceonothersourcesofarsenicinourfoodsupply,”saidKimberlyGray,Ph.D.,NIEHSprogramleadforthecenters.“Thisvalidatestheneedforcontinuedmonitoring.”Sheaddedthatmoreresearchisneededtofullyunderstandthehealthimpacts,andthatitistimetoconsidersafetystandardsforarsenicinfood.

Citation:CottinghamKL,KarimiR,GruberJF,ZensMS,SayarathV,FoltCL,PunshonT,MorrisJS,KaragasMR.2013.DietandtoenailarsenicconcentrationsinaNewHampshirepopulationwitharsenic-containingwater.NutrJ12(1):149.

(ThisstorywasadaptedfromanarticlebyJohnCramer,associatedirectorformediarelationsatDartmouthCollege.JoeBalintfyisapublicaffairsspecialistintheNIEHSOfficeofCommunicationsandPublicLiaison.)

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Researchers find elevated flame retardant exposure among U.S. gymnasts By Sara Mishamandani

Gymnastsmaybeingestingorinhalingdustcreatedbyfoamblocksthatcontainhormone-disruptingflameretardantchemicals,accordingtoanewstudyfromtheBostonUniversity(BU)SchoolofPublicHealth,supportedinpartbyNIEHS.

“Ourresultssuggestthatthestudygymnastsarehighlyexposed,butit’sunclearwhathealthrisks,ifany,theywouldfaceasaresultofthisexposure,”saidCourtneyCarignan,Ph.D.,leadauthorofthestudypublishedonlineDec.3inthejournalEnvironmentalScienceandTechnology.

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Thestudydetected4-6.5timesmoreflameretardantsinthebloodofcollegiategymnaststhaninthegeneralU.S.population.

Measuring exposure to flame retardantsNIEHS-fundedresearchersaffiliatedwiththeBUandDukeUniversitySuperfundResearchProgram(SRP)Centerscollectedbloodandsampleswipedfromhandsof11femalegymnasts,aged18-22,whoweretrainingatacollegiategymintheeasternUnitedStates.Eachparticipantfilledoutaquestionnaireaboutherpersonalcharacteristics,gymnasticshistory,gymuse,andhabits,includinghandwashing,transportation,anddiet.Allparticipantsreportedpracticinggymnasticsforatleast12yearsandaveraging19hoursaweekinthegymatthetimeofthestudy.

Thegymnasts’bloodcontainedthecompoundbromodiphenylether(BDE)-153,acomponentoftheflameretardantPentaBDE,atlevelscomparabletogroupswithhighoccupationalexposure,suchasU.S.foamrecyclersandcarpetinstallers.

PentaBDE,whichwaswidelyusedinpolyurethanefoamforfurniture,wasvoluntarilyphasedoutbyU.S.manufacturersin2005,andisnowbannedin172countries..However,PentaBDE,whichcanaccumulateinlivingorganisms,isalong-lastingchemicalintheenvironmentandisstillpresentinU.S.productsmanufacturedbefore2005.

PreviousstudiesshowedthatPentaBDEcandisruptendocrineactivityandaffectthyroidregulationandbraindevelopment.EarlyexposuretoPentaBDEhasbeenlinkedtolowbirthweight,loweredIQ,andimpairedmotorandbehavioraldevelopmentinchildren.

Getting to the source of exposureMostgymscontainalargepitfilledwithhundredsoffoampolyurethaneblocks,whichprovideasoftlandingforgymnastslearningnewacrobaticmoves.Samplesofdustandfoamtakenfromthestudyparticipants’gym,aswellastwootherU.S.gyms,suggestthatthefoamblocks,someofwhichwereupto20yearsold,werethelikelysourceofexposure.Handwipesamplesfromthegymnastsafterpracticecontained2-3timesmoreflameretardantsthanbeforepractice.

Toreduceexposure,Carignanrecommendswashinghandsaftertouchingequipmentatthegymandshoweringafterleavingthegym.CarignanalsostartedtheGymnastFlameRetardantCollaborative,whichprovidesinformationaboutflameretardantsandgymnasticsthroughawebsite.

ThestudywasfundedbyNIEHSindividualresearchgrantsandanNIEHStraininggrant.SRPgranteesWendyHeiger-Bernays,Ph.D.,HeatherStapleton,Ph.D.,ThomasWebster,Sc.D.,andMichaelMcClean,Sc.D.,areprincipalresearchersonthegrantsandstudyauthors.

Citation:CarignanCC,Heiger-BernaysW,McCleanMD,RobertsSC,StapletonHM,SjödinA,WebsterTF.2013.FlameretardantexposureamongcollegiateUnitedStatesgymnasts.EnvironSciTechnol47(23):13848-13856.

Carignan graduated from BU this spring with her Ph.D. She is now training as a postdoctoral researcher at the Children’s Environmental Health and Disease Prevention Center at Dartmouth College. (Photo courtesy of Courtney Carignan)

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(SaraMishamandaniisaresearchandcommunicationspecialistforMDBInc.,acontractorfortheNIEHSSuperfundResearchProgramandDivisionofExtramuralResearchandTraining.)

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NIEHS study identifies protein involved in DNA damage removal By Robin Arnette

Foryears,scientiststhoughtthatthemajorityofDNAdamageoccurredasaresultofradiation,toxicantexposures,orsomeotherenvironmentalinsult,butNIEHSresearchhasdeterminedthattheinsertionofRNAintoDNAmaybeanunderappreciatedsourceofmanymoreunknownlesions.Inthegeneticarmsrace,organismsfromyeasttohumanshaveaproteinweaponcalledaprataxinthatcounterstheRNA-triggeredonslaught.

Researchers used a scanning electron microscope with energy-dispersive X-ray spectroscopy to create an image of the dust from a gymnastics foam pit. The presence of brominated flame retardants in fragments of foam are indicated in green. Red indicates magnesium, presumably from gym chalk. (Photo courtesy of Simon C. Roberts, Duke University)

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Theteam,ledbyScottWilliams,Ph.D.,headoftheNIEHSGenomeStabilityStructuralBiologyGroup,publishedtheresultsonlineDec.22inNature.ThescientistsusedX-raycrystallographytovisualizehowhumanaprataxinhandlesRNA-DNAdamage,andarethefirsttoidentifyanenzymeremovingalesionarisingfromRNA-DNA.TheycallthisprocesstheRNA-DNAdamageresponse,anditsdiscoverymayhelpuncoversomeofthegeneticmishapsthatcontributetoneurodegenerativediseases,aswellasleadtopotentialnewtherapiesforcancerpatients.

Targeting RNAScottWilliamssaidRNAincorporationintoDNAhappensbyaccidentduringreplicationandhaslargelyunknownconsequences.HeexplainedwhyremovingRNAfromDNAwassoimportant.

“WhenyouhaveRNAinplaceofDNA,DNAligase,theenzymethatsealsDNAends,stopspartwaythroughitsreaction,”hesaid.“Ratherthanprotectingthegenome,itleavesalesionthatmakesthedamageworse.”

ThelesionspreventtheDNAfrommakingcopiesofitself,sothecellhastoaddresstheinjury.AsoneoftheproteinsinvolvedinDNArepairpathways,aprataxinspotstheseRNA-DNAlesionsandremovesthem.However,mutationsinthehumanaprataxinproteinaffectitsabilitytobindandeliminateRNA-DNAdamage,andresultinarare,heritablecerebellar-wastingdiseaseknownasataxiawithaculomotorapraxia1,aswellasotherdisorders,includingmultiplesystematrophy,aParkinson’s-likecondition.

ThisstudyalsofurtherstheworkdonebyThomasKunkel,Ph.D.,headoftheNIEHSDNAReplicationFidelityGroup,andresearchfellowJessicaWilliams,Ph.D.,whoareco-authorsonthepaper.KunkelandJessicaWilliamsstudyDNApolymerases,theenzymesthatreplicateDNAandalsoincorrectlyinsertRNAintoDNA.RNAincorporationisamajorcauseofgeneticinstabilityandactuallyhappensquitefrequently.

“CurrentestimatesforthenumberofribonucleotidesincorporatedperroundofDNAsynthesisare13,000foryeastandgreaterthan1,000,000foramammaliancell,”saidJessicaWilliams.“ThisnumberexceedsthetotalofallotherDNAlesionsstudiedintheDNArepairfieldandprovidesanenormouspotentialtocreatetoxiclesionsthatrequireaprataxinforrepair.”

The molecular structure depicts how human aprataxin processes an RNA-DNA lesion. Aprataxin (blue) binds to the lesion (red) that results from the insertion of RNA (green) into DNA (yellow). (Graphic courtesy of Scott Williams)

Scott Williams reiterated that RNA-triggered lesions were a new idea in the field of DNA repair. (Photo courtesy of Steve McCaw)

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Designing cancer therapiesThisrecentaprataxinworkbringsscientistsclosertofiguringoutcausesofneurodegenerativedisease,butmayalsobenefitcancerpatients.PercyTumbale,Ph.D.,anNIEHSIntramuralResearchTrainingAwardfellowinScottWilliams’groupandco-firstauthoronthepaper,saidthat,undertherightcircumstances,blockingaprataxinfunctionmightcausecancercelldeath.

“Weareexploringthepossibilitythatwecanuseaprataxin’satomicstructuretodevelopinhibitorsofthisenzyme,”Tumbalesaid.“WhencombinedwithagentsthatcreateDNAdamageorblockotherDNAdamageresponsepathways,aprataxininhibitorsmayhaveutilityincancertherapy.”

Citation:TumbaleP,WilliamsJS,SchellenbergMJ,KunkelTA,WilliamsRS.2013.AprataxinresolvesadenylatedRNA-DNAjunctionstomaintaingenomeintegrity.Nature;doi:10.1038/nature12824[Online22December2013].

Thanks to Tumbale’s expertise in X-ray crystallography, the Scott Williams group was able to crystallize mutant forms of aprataxin engaged with RNA-DNA lesions. (Photo courtesy of Steve McCaw)

Jessica Williams’ work with DNA polymerase epsilon was essential to the research. (Photo courtesy of Steve McCaw)

Matthew Schellenberg, Ph.D., is a visiting fellow in the Scott Williams group. He, Tumbale, and Jessica Williams share first authorship of the article. (Photo courtesy of Steve McCaw)

Kunkel is a leading authority on DNA replication fidelity. About five years ago, his group found that RNA is transiently incorporated into human genomes and removed. (Photo courtesy of Steve McCaw)

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NIEHS research helps unlock one of the secrets of stem cells By Ernie Hood

Whatmakesstemcellssospecial?Thequesttoanswerthatseeminglysimplequestionhasspawnedthousandsofbasicscientificstudiesatlabsacrosstheworldinrecentyears.Lastmonth,theNIEHSStemCellBiologyGroupintheLaboratoryofMolecularCarcinogenesispublishedtheresultsofanewstudythathelpexplainthemolecularbasisofself-renewalanddifferentiationinembryonicstemcells(ESCs).

Thepaper,“TheTHOcomplexregulatespluripotencygenemRNAexportandcontrolsembryonicstemcellself-renewalandsomaticcellreprogramming,”appearedintheDec.5editionofthejournalCellStemCell.

ESCscangiverisetomanydifferentcelltypescommonlyfoundintheadultbody.Becauseofthatpotential,theyareofgreatinteresttobothbiomolecularresearchersandregenerativemedicinescientists.Atanygiventime,ESCsfaceachoicebetweendifferentiation,whentheyrespondtospecificdevelopmentalcuestotransformintospecificcelltypes,andself-renewal,whentheydividebutretaintheirstemcellstatus.

AlthoughthetranscriptionalregulationofESCself-renewalandpluripotency—thecapabilitytodifferentiateintooneofmanycelltypes—hasbeenextensivelyinvestigated,post-transcriptionalmechanismshavebeenpoorlyunderstood,untilnow.Usingadvancedexperimentaltechnologies,theNIEHSgroupledbyGuangHu,Ph.D.,discoveredaproteincomplexthatapparentlyexertspost-transcriptionalregulationofgeneexpressioninESCs.

The THO complex as a rheostatTheTHOproteincomplexhaslongbeenknownasahousekeepingcomplexinvolvedinmRNAexport,butitsroleinregulatingESCshasonlynowcometolight,afterHuandhisteamassayedgenesacrosstheentiremousegenome.“Inadditiontothisgeneralhousekeepingrole,weshowedthattheTHOcomplexalsohasaregulatoryfunctioninthatitpreferentiallyregulatesasubsetofgenesthatareuniquelyimportantforESCs,”saidHu.

AsHuexplained,transcriptionalcontrolislikeasetoflightswitches,wheregenescanbeturnedonoroff.However,apost-transcriptionalregulator,suchastheTHOcomplex,actsasarheostat,orvariableresistor,allowingrefinedcontrolwithoutfullyturningonorofftheswitch.“TheTHOcomplexprovidesanon-committalwaytoallowthecellstorespondtoenvironmentalcues,sotheycaneitherchoosethefateofdifferentiatingtoaparticularcelltypeormaintainthestemcellstatewithoutfullycommitting,asthecomplexregulatesthemRNAexportwithoutimpactingtranscriptionitself,”hesaid.

“ESCs need to respond to developmental cues in the proper way, but the exact connection between which cue goes through which pathway, to link to which particular mechanism, to flip on the switch or the rheostat, is a key question that most people are still trying to answer,” said Hu. “We have not uncovered that particular link in the connection with the THO complex yet, but we are actively searching for it.” (Photo courtesy of Steve McCaw)

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Potential applicationsAsidefromthesignificantcontributionthisdiscoverymakestothebasicunderstandingofmechanisticprocessesinESCs,itmayeventuallyleadtonewcell-basedtherapies,basedonmanipulatingtheTHOcomplextogenerateinducedpluripotentstemcells.Itcouldalsospawnnewapproachesinregenerativemedicine,byfosteringthemanipulationofcellfateintheculturedish,tomakevariouscelltypesforspecifictherapeuticpurposes.

Characterizingthenetworkorpathwayisanotherkeyobjective.“Atthismoment,wedon’tknowwhytheTHOcomplexcanspecificallyrecognizeandregulatetheseESC-specificgenes,butyouwouldimaginethat,atsomepoint,thispost-transcriptionregulationmusttalktothetranscriptionregulation,sothatthereisnoconflictbetweenthetwo,”saidHu.

Mouse experiments confirm relevanceTheNIEHSReproductiveMedicineGroup,ledbyCarmenWilliams,M.D.,Ph.D.,alsocontributedtotheresearch,byconductingexperimentsinvolvingmousepreimplantationembryos,whichshowedthatTHOproteinsareneededforproperembryodevelopmenttotheblastocyststage,whentheembryoisbeginningtogeneratepluripotentstemcells.“ThisfindingmeansthatGuang’sexperimentsinEScellsareactuallyrelevanttothephysiologicalsituationinvivo,ratherthanapplyingonlytoculturedcells,”sheexplained.

Citation:WangL,MiaoYL,ZhengX,LackfordB,ZhouB,HanL,YaoC,WardJM,BurkholderA,LipchinaI,FargoDC,HochedlingerK,ShiY,WilliamsCJ,HuG.2013.TheTHOcomplexregulatespluripotencygenemRNAexportandcontrolsembryonicstemcellself-renewalandsomaticcellreprogramming.CellStemCell13(6):676-690.

(ErnieHoodisacontractwriterwiththeNIEHSOfficeofCommunicationsandPublicLiaison.)

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NTP seminar explores functional ecology By Eddy Ball

AnongoinglectureseriessponsoredbyNTPmadeanunexpectedturnintoanimalecologyDec.10withatalkatNIEHSbyzoologistVladimirVershinin,D.Sc.

HostedbyBiomolecularScreeningBranchChiefRayTice,Ph.D.,thetalk,on“AmphibianPopulationsinUrbanandNaturalEnvironmentinUrals,”exploredtheimpactofurbanpollutionandecologicalchanges,inandaroundtheindustrialcityofYekaterinburg,Russia,tofrogs,newts,andsalamandrella.

Tice,wholeadstheTox21predictivetoxicologyinitiativeforNTP,saidafterwards,“Thiswasadifferentkindoftalk—onewe’renotusedtohearing.”But,headdedthatseeingtheseeffects,onwhatmanyconsiderasentinelspecies,mayofferinsightintothekindsofchangesinbiochemistry,morphology,lifespan,andreproductionthatchemicalsmayproduceinhumanpopulations.

Williams is also a lead researcher in the Laboratory of Reproductive and Developmental Toxicology. She has been at NIEHS since 2007. (Photo courtesy of Steve McCaw)

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Studying amphibians for 36 yearsVershininisaprofessoranddepartmentchairofzoologyatUralFederalUniversityinYekaterinburg,whosegrouphasgatheredandanalyzeddataonamphibianpopulationsat26geographicallocationsalongthelandborderbetweenEuropeandAsiasince1977.HeisalsoheadoftheDepartmentofFunctionalEcologyofTerrestrialAnimalsattheInstituteofPlantandAnimalEcologyoftheRussianAcademyofSciences.

Earlyinhistalk,Vershinindescribedacentralpremisebehindthesestudies,saying,“Amphibiansareaprototypeofterrestrialvertebrates…[whose]developmentisstronglyaffectedbyenvironment.”Hedescribedtheassociationsbetweentheamphibian’sskeletalstructure,fertility,rateofphysicalabnormalities,andcardiacfunctionoverthepastthreedecadeswithincreasedurbanization.

The down side of urbanizationVershinin’sgroupdividedYekaterinburg,Russia’sthirdlargestcity,intofourzones,bylevelsofdevelopmentanddensity,rangingfromthecitycentertoforestland.Theteamanalyzedwaterchemistry,averagetemperature,andabroadrangeofresponsesandoutcomesovertimeintheseareas.

Theresearcherscollecteddataonchangesinrelativelivermass,sexualdifferentiation,skinpermeability,andcardiacfunction,specificallyisometricalmyocardialforceandmyocardialcontraction.Theyalsoobservedchangesinreproductivestrategy,findingchangesinonsetofpuberty,bodylength,andsize,aswellasfertilityandeggsize.Afewofthechangeshelpedamphibiansadapttoamorethreateningenvironment,butmostwerealmostexclusivelynegativeintermsofimpactonpopulationsurvival.

SomeofVershinin’smostdramaticexamplesinvolvedexternalandinternalabnormalitiesthatreducedthequalityofthepopulation.Dramaticchangesineggclutchesandovariansymmetrycontributedtolowfertility.Theresearchersobservedsignificantchangesineyepigmentation,thenumberandformoffingersandtoes,andinternalskeletalformation.

Theamphibians’relationshipswithotherorganismsintheirenvironmentalsochanged,withanincreaseincystsandahigherpercentageofeosinophils,orwhitebloodcells,reflectingariseinparasiteinfection.

“The Urals represent a complicated biochemical situation,” Vershinin said at the beginning of his talk. “Yekaterinburg is one of the Uralian cities that appeared as a settlement around [metallurgical and heavy machinery] factories … which are some of the complicated sources of pollution.” (Photo courtesy of Steve McCaw)

Among his many slides of dramatic changes in the amphibian population was the one above, which shows anomalies in egg clutches among the outlying population of Siberian salamanders living in and around Yekaterinburg. (Photo courtesy of Steve McCaw)

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Detailed observations, but few clear associationsThestrengthofVershinin’sdatacollectionwasitslong-termcomprehensivemonitoring.WhiletheNTPscientistsintheaudiencewereimpressedbythecollectionoflargeamountsofdatainthestudies,naturallyastoxicologists,theywantedmore.

Vershininpointedtolikelycauses,suchasleadandastrongassociationbetweensomeoftheabnormalitiesandradioactivity.WhenhewasquestionedabouteffectsofsomeofthechemicalsthatareofinterestinseveralNTPstudies,suchasendocrine-disruptingcompounds,Vershininconcededthelimitationsofhisobservationalapproachandhowmuchworkremainstobeperformed.

“Westillhavesomegapsinourknowledgeontheevolutionofamphibianpopulations,”hetoldtheaudience.But,aspeopleatthetalkseemedtoagree,Vershinin’sgrouphascreatedamodelforgatheringandanalyzingthedata—theimportantfirststepinconductingacomprehensivestudyofpopulationtoultimatelyteaseoutthehealtheffectsofexposuretoamixtureofmultiplechemicalsandotherenvironmentalfactors.

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This month in EHPTheJanuaryissueofEnvironmentalHealthPerspectives(EHP)highlightstheroleofenvironmentalfactorsinmyopiaandtheuniquequalitiesofwindturbinenoise.

Myopia: The Evidence for Environmental FactorsMyopia,ornearsightedness,waslongblamedongeneticsandbehavior,butdramaticincreasesinprevalence,inrecentdecades,pointtoenvironmentalfactorsaswell.Moreover,timespentoutdoorsappearstohaveaprotectiveeffectagainstmyopia,althoughinvestigatorsstillaren’tsurewhy.

Wind Turbines: A Different Breed of Noise?Sinceatleast1930,researchershaveamassedabodyofevidenceontheadversenonauditoryhealtheffectsofenvironmentalnoise.Morerecently,anewsourceofnoisehasenteredthescene—windturbines.Aswindfarmsbecomemorecommonnearpopulatedareas,researchersareinvestigatingtheuniquequalitiesofthenoisetheyproduce.

“This is one of those kinds of seminars that occur because somebody knows somebody who happens to be visiting here,” Tice said in his introduction. In Vershinin’s case that somebody was NIEHS grantee Alexander Kinev, Ph.D., of Creative Scientist Inc. Vershinin was a visiting scholar at NESCent, the National Evolutionary Synthesis Center, in Durham, N.C., presenting talks on his research and future plans for building a publicly accessible database. (Photo courtesy of Steve McCaw)

http://twitter.com/ehponline

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Featured research and related news articles this month include:• Maternal Blood, Plasma, and Breast Milk Lead: Lactational Transfer and Contribution to Infant

Exposure—LeadTransferDuringBreastfeeding:AStartTowardFillingintheDataGaps

• Pollutant Exposures From Natural Gas Cooking Burners: A Simulation-based Assessment for Southern California—CookingUpIndoorAirPollution:EmissionsFromNaturalGasStoves

• Maternal Concentrations of Persistent Organochlorine Pollutants and the Risk of Asthma in Offspring: Results From a Prospective Cohort With 20 Years of Follow-up—ALong-TermRisk?PrenatalPOPsExposureandAsthmainYoungAdults

• Air Pollution–mediated Susceptibility to Inflammation and Insulin Resistance: Influence of CCR2 Pathways in Mice—ToxicityBeyondtheLung:ConnectingPM2.5,Inflammation,andDiabetes

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Extramural papers of the month By Nancy Lamontagne

• Epigenetic changes associated with pancreatic cancer might lead to early detection

• Phthalate exposure linked to preterm birth

• A 3-D map of chromatin interactions

• Girls are reaching puberty earlier

Epigenetic changes associated with pancreatic cancer might lead to early detectionInworkfundedinpartbytheNIEHS,researchersidentifiedepigeneticmodificationsinBNC1andADAMTS1genesthatweredetectableinpeoplewithearly-stagepancreaticcancer,butnotincancer-freepeople.Thefindingsfromthissmallpreliminarystudypointtothepossibilityofabloodtestthatmightdetectearly-stagepancreaticcancer.Pancreaticcancerisalmostalwaysfatal,becauseitisn’tusuallydiscovereduntilithasspread.

Theresearchersusedmethylationonbeadstechnology,arecentlydevelopedapproachthatusesnanotechnologytocaptureandanalyzeverysmallamountsofDNA.Usingthismethod,theydetectedmethylationchangesinDNAcirculatingin42serumsamplesfrompatientswithpancreaticcancer.FortheBNC1genepromoter,theresearchersachievedasensitivityof79percentandspecificityof89percent,andfortheADAMTS1gene,thesensitivitywas48percentandspecificity92percent.Whenusingbothmarkers,theapproachachievedanoverallsensitivityof81percent(95percentconfidenceinterval[CI],69-93percent)andspecificityof85percent(95percentCI,71-99percent).

Theresearcherssaythat,althoughlargerstudiesareneeded,theirfindingsstronglysuggestthatBNC1andADAMTS1promotermethylationcouldbeusedasbiomarkersforidentifyingindividualsatriskforpancreaticcancer.

ReadthecurrentSuperfundResearchProgramResearchBrief.NewissuesarepublishedonthefirstWednesdayofeachmonth.

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Citation:YiJM,GuzzettaAA,BaileyVJ,DowningSR,VanNesteL,ChiappinelliKB,KeeleyBP,StarkA,HerreraA,WolfgangC,PappouEP,Iacobuzio-DonahueCA,GogginsMG,HermanJG,WangTH,BaylinSB,AhujaN.2013.Novelmethylationbiomarkerpanelfortheearlydetectionofpancreaticcancer.ClinCancerRes19(23):6544-6555.

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Phthalate exposure linked to preterm birthNIEHS-supportedresearchhasfoundthat,dependingonthephthalateexamined,womenwiththehighestlevelsofexposureduringpregnancyhad2-5timestheoddsofpretermbirth,comparedtowomenwiththelowestexposure.Thefindingspointtophthalateexposureasapotentiallypreventablecontributingfactortoprematurebirth.

Usinganestedcasecontrolstudydesign,theresearchersexaminedassociationsbetweenaveragelevelsofphthalateexposureduringpregnancyandpretermbirthin130motherswhohaddeliveredpriorto37weeksofcompletedgestation.Thestudyalsoincluded352controlmotherswhodeliveredatorafter37weeks.Todetermineoverallphthalateexposure,theresearchersusedmultipleurinesamplesduringpregnancy.Theyfoundthatpretermbirthshowedthestrongestdose-dependentassociationswithmaternallevelsofthetwodi-2-ethylhexylphthalate(DEHP)metabolites,mono-(2-ethyl)-hexylphthalate(MEHP)andmono-(2-ethyl-5-carboxypentyl)phthalate(MECPP),andthesummedlevelsofalltheDEHPmetabolites.

Theresearchersalsoanalyzedasubsetof57motherswithpretermdeliveriesprecededbyspontaneouspretermlabororpretermprematureruptureofthemembranes.Whenthisgroupwasexaminedalone,theoddsratiosincreasedforallthephthalatemetabolites.Thisfindingindicatesastrongerassociationbetweenphthalateexposureandspontaneouspretermbirththantheassociationwithallpretermbirths.

Phthalateexposurecanoccurfromfood,plastics,andpersonalcareproducts,suchasdeodorantsandlotions.Theresearcherscautionthat,beforeimplementinginterventionsaimedatdecreasingphthalateexposure,morestudiesareneededtoconfirmthesefindings,toexaminethesourcesofthephthalates,andtobetterunderstandthemechanismsinvolved.

Citation:FergusonKK,McElrathTF,MeekerJD.2013.Environmentalphthalateexposureandpretermbirth.JAMAPediatr;doi:10.1001/jamapediatrics.2013.3699[Online18November2013].(Story)

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A 3-D map of chromatin interactionsAnNIEHSgranteeandcolleaguesgeneratedahigh-resolutionmapofthree-dimensional(3-D)chromatininteractionsinhumancells.Themapsuggeststhattheloopingstructureofchromatinisrelativelystable,onceestablishedinacelltype.

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DNAcontainsareasknownascis-regulatorysequenceswheretranscriptionfactorscanbindtoregulategeneexpression.The3-Dloopsofchromatinhelpcontrolgeneexpression,bybringingcis-regulatoryDNAsequencesclosetotheirtargetgenes.Althoughscientistshaveidentifiedalargenumberofcis-regulatorysequencesinthehumangenome,manyofthetargetgenesforthesesequencesareunknown.Toidentifythesetargetgenes,theresearchersmappedthe3-Dinteractionsofcis-regulatorysequencesinhumanfibroblastcells,usingagenome-widechromosomeconformationcaptureanalysismethod.

Theresearchersdeterminedmorethan1millionlong-rangechromatininteractionsataresolutionof5-20kilobases.OneoftheirfindingswasthatDNAsequences,activatinggeneexpressionaftertreatmentofcellswiththetumornecrosisfactoralpha,arealreadyincontactwiththeirtargetpromotersbeforesignaling.

Thisunexpecteddiscoverysuggeststhatenhancer-promoterinteractionsformbeforesignalingandchangelittlewhenactivatedduringtranscription.Thus,theloopingstructureofchromatinislikelycell-typespecific,andcouldinfluencetheselectionoractivationoftargetgenesbyaubiquitoustranscriptionactivator.

Citation:JinF,LiY,DixonJR,SelvarajS,YeZ,LeeAY,YenCA,SchmittAD,EspinozaCA,RenB.2013.Ahigh-resolutionmapofthethree-dimensionalchromatininteractomeinhumancells.Nature503(7475):290-294.

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Girls are reaching puberty earlierResearchthatispartoftheNIEHSBreastCancerandtheEnvironmentResearchProgram,acohortofmorethan1200girls,foundthatbreastdevelopmentisoccurringatanearlierage,andthatearlierdevelopmentwasstronglyassociatedwithgreaterbodymassindex(BMI).Earlierthanaveragematurationisariskfactorforobesityandhypertension,aswellasbreast,ovarian,andendometrialcancer.

From2004to2011,theresearchersfollowedgirlsintheSanFranciscoBayArea,GreaterCincinnati,andNewYorkCitywhowere6-8yearsoldwhenenrolledinthestudy.Atregularintervals,trainedandcertifiedstaffusedTannerstagingtoassesssexualmaturity.Theyfoundthattheageatonsetofbreastdevelopment(stage2)variedbyrace/ethnicity,BMIatbaseline,andgeographicalsite.ForAfrican-American,Hispanic,whitenon-Hispanic,andAsianparticipants,themedianageatonsetofbreaststage2was8.8,9.3,9.7,and9.7years,respectively.GirlswithBMIsgreaterthanthe85thpercentilereachedbreaststage2atyoungerages.

Comparedtodatafromstudiesconductedinthe1990s,whitenon-Hispanicgirlsarenowmaturingatyoungerages,whilethematurationageforAfrican-Americangirlsissimilartothatfoundintheearlierstudies.

Citation:BiroFM,GreenspanLC,GalvezMP,PinneySM,TeitelbaumS,WindhamGC,DeardorffJ,HerrickRL,SuccopPA,HiattRA,KushiLH,WolffMS.2013.Onsetofbreastdevelopmentinalongitudinalcohort.Pediatrics132(6):1019-1027.

(NancyLamontagneisasciencewriterwithMDBInc.,acontractorfortheNIEHSDivisionofExtramuralResearchandTraining.)

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Intramural papers of the month By Kelly Lenox, Jacqueline Powell, Bailey Schug, and Deepa Singh

• tssRNAs associated with paused Poll II serve as scaffold for transcription factors

• Asthmatic reaction is dependent on dose and timing of endotoxins

• Modest changes in dNTP levels affect cell’s ability to repair mutations

• Distinct features of RNA binding protein make it unique among its family

tssRNAs associated with paused Poll II serve as scaffold for transcription factorsResearchersfromNIEHShavefoundthatnascenttranscriptionstartsite-associated(tss)RNAs,producedandstablyboundbyRNApolymeraseII(PolII)thathaspausedduringearlyelongation,couldprovideatargetfortherecruitmentoffactorsthatmodulategeneexpression.Sincetranscriptionisacriticalstepinthecreationofproteinsfrominformationwithinthegenome,thisworkmayprovideinsightintoenvironmentallyresponsivegeneexpressionandidentifynovelapproachesfortreatingdisease.

Thescientistsdevelopedahighlysensitivemethodofcharacterizingthedynamicsofpromoter-associatedPolIIandtssRNAsgeneratedduringearlyelongationinfruitfly,orDrosophila,cells.Theyperformedabiochemicalfractionationprocedurethatallowedseparationoftheshort,cappedRNAspecies,andidentifiedtheiroriginsgenome-wideusinghigh-throughputsequencing.TheyfoundthatpausedPolIIandassociatedtssRNAswereverystable,long-livedspecies,remainingneargenepromotersfortensofminutesbeforeresumingtranscriptionelongation.

TheresearchersproposethattssRNAsprovideaphysicalframeworkonwhichtranscriptionfactorsthatregulateproductiveelongationandpromoterchromatincouldbindtoreleasepausedPolIIintoproductiveelongation,therebymodulatinggeneexpression.(KL)

Citation:HenriquesT,GilchristDA,NechaevS,BernM,MuseGW,BurkholderA,FargoDC,AdelmanK.2013.StablepausingbyRNApolymeraseIIprovidesanopportunitytotargetandintegrateregulatorysignals.MolCell52(4):517-528.

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Asthmatic reaction is dependent on dose and timing of endotoxinsNIEHSscientistsshowedthatimmuneresponsestoinhaledallergensaredependentonquantityandtimeofexposuretoendotoxins.Twodifferentarmsoftheadaptiveimmuneresponsecontributetoallergicasthma—Thelper(Th)2cellsandTh17cells.Thesetwoarmsoftheimmuneresponse,whichresponddifferentlytofactorsintheenvironment,accountforsomeoftheheterogeneityseeninasthma.Thisknowledgeofferspotentialopportunitiesfortherapiesthatdisruptspecificpathwaysassociatedwithoneortheotherofthesetypesofasthma.

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Allergicsensitization,whichisthebiologicalbasisforallergicasthma,iscausedbyallergensfoundinplants,insects,andanimals.However,itisalsocausedbyadjuvants,oringredientsthatincreasetheimmuneresponse,suchasthosefoundinmicrobialproducts,includinglipopolysaccharide(LPS).TheresearchersusedamousemodeltodemonstratethatimmuneresponsestoinhaledallergensarehighlydependentonthedosesofinhaledLPS,includingtheamountsfoundnaturallyintheenvironment.TheydiscoveredthatlowdosesofLPSpromoteclassical,Th2-drivenallergicresponsestoinhaledallergens,whereasmoderatedosesofendotoxininducestrongerTh17responsesandassociatedneutrophilia.

TheresearchersalsodemonstratethatinhalationofmoderatedosesofLPSduringsensitizationinducesregulatoryresponsesthat,aftermultipleallergenexposures,limittheseverityandlongevityofasthma-likefeatures.(BS)

Citation:WhiteheadGS,ThomasSY,CookDN.2013.Modulationofdistinctasthmaticphenotypesinmicebydose-dependentinhalationofmicrobialproducts.EnvironHealthPerspect;doi:10.1289/ehp.1307280[Online29October2013].

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Modest changes in dNTP levels affect cell’s ability to repair mutationsRecentstudiesbyNIEHSresearchershaveindicatedthatthecellularlevelsofdeoxynucleoside-5’-triphosphates(dNTPs),thebuildingblocksforDNA,havetobestrictlyregulatedtomaintainlowmutationrates.ThemainenzymeresponsibleforcontrollingdNTPsisribonucleotidereductase(RNR)andmutationsinRNRhaveadirectbearingontherateofDNAmutations.

TheresearchersisolatedEscherichia colimutantRNRsandfoundtwonewallelesinwhichdGTPanddATPconcentrationswereaffectedalmosttwofold,upversusdown,respectively.Interestingly,despitethesemodestdNTPchanges,themutationrateintherpoBgeneencodingthebetasubunitofbacterialRNApolymerasewasincreasedmorethan3,000-fold.Theyhypothesizedthechangecouldbedue,inpart,tocollapseofthemismatchrepair(MMR)systemthatnormallyremovesmosterrorspost-DNAreplication.

ThescientistsusedseveralapproachestoexplainthehighmutabilityofthesetwoRNRmutants.TheymeasuredmutationfrequenciesinMMR-proficientanddeficientbackgrounds,andobservedthattheMMRisnolongeractiveinthesetwomutants.Similarly,overproductionofoneofthecomponentsoftheMMRsystem(mutL)ortheinclusionofadnaQ926antimutatoralleleloweredthemutationfrequencies,indicatingtherestorationofanactiveMMRsystem.

Overall,thesestudiesindicatethatabnormallevelsofdNTPscansaturateMMRandcanleadtohypermutabilityanderrorcatastrophe.(DS)

Citation:AhluwaliaD,SchaaperRM.2013.Hypermutabilityanderrorcatastropheduetodefectsinribonucleotidereductase.ProcNatlAcadSciUSA110(46):18596-18601.

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Distinct features of RNA binding protein make it unique among its familyNIEHSscientistsandtheircollaboratorsrecentlyuncovereduniquestructuralfeaturesofthetandemzincfinger(TZF)domainoftristetraprolin(TTP),anRNA-bindingprotein.TTPisthebest-knownmemberoftheTTPfamilyoftandemzincfingerproteinsthatpromotethedegradationoftargetmRNAs.

WhileTTPfamilyproteinshavehighlyconservedTZFdomainsthatarecriticalforRNAbinding,researchersperformedacross-speciesTZFdomainsequencealignmentanduncoveredsevenresiduesthatwerehighlyspecifictoTTP.BygeneratingastructuralmodelofTTPbasedontheknownstructureofanotherTTPfamilyprotein,ZFP36L2,theydiscoveredthatthesecondzincfingerofTTPwasstructurallydistinctfromthefirstzincfingerofTTPandbothzincfingersofZFP36L2.ThesedifferencesweremainlyobservedintheC-x8-Cintervals,wheresixofthesevenTTP-specificresidueswerelocated.ResearchersthenmutatedresidueswithintheTZFdomainofTTPtoexaminetheirroleinRNAbinding.MutatingsequenceequivalentresiduesinthefirstandsecondzincfingersofTTPoftenhaddifferenteffectsonRNAbinding,indicatingthatthetwozincfingersofTTPcontainfunctionallydistinctresidues.

ThisresearchsuggeststhatalthoughtheTZFdomainofTTPfamilyproteinsishighlyconserved,theymaybindtoRNAdifferently,basedonsubtlestructuraldifferences.(JP)

Citation:LaiWS,PereraL,HicksSN,BlackshearPJ.2013.Mutationalandstructuralanalysisofthetandemzincfingerdomainoftristetraprolin.JBiolChem;doi:10.1074/jbc.M113.466326[Online19November2013].

(KellyLenoxiseditoroftheEnvironmentalFactor.FormerNIEHSpostdoctoralfellowJacquelinePowell,Ph.D.,isawriterandanalystwithEducationandTrainingSystemsInternational.(ETSI).BaileySchugstudieshealthpromotionandnutritionatAppalachianStateUniversityandisaninternintheNIEHSOfficeofCommunicationsandPublicLiaison.DeepaSingh,Ph.D.,isavisitingfellowintheNIEHSMechanismsofMutationGroup.)

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Inside the InstituteEmployees make the 2013 Giving Tree a success By Kelly Lenox

The2013GivingTree,sponsoredbytheDiversityCouncil,gaveNIEHSemployeestheopportunitytobrightenChristmasforsomeareachildren.“It’sbeenanamazingjobofpartneringwiththeSalvationArmytoshareourricheswithalotofpeoplethisholidayseason,”observedJoellenAustin,NIEHSassociatedirectorformanagement.

AttheDec.5celebration,thesuccessoftheGivingTreeeffortwasevident.BillQuattlebaumrecalled,“Lastyearwedid160tags.Wegotin120,and,inthelastfewdays,hadtohavesomemorebroughtovertous.Thisyear,ithasbeenhardertoplan,withthefurloughandlateThanksgiving,sowehavebeenreallypleasedwiththeresponse.”

Gifts under the tree represented just a few of the many donations. (Photo courtesy of Steve McCaw)

TheNIEHSDiversityCouncilofferedthankstoall.“WearesoproudofthewaytheNIEHScommunitysteppeduptomaketheholidaysbrighterfor150deservingchildren.”

Diversity Council Members• BradCollins• VeronicaGodfreyRobinson

• Bill(qb)Quattlebaum• CynthiaRadford• JennEvans

• SymmaFinn• BillJirles• MyraWestmoreland• CherylThompson• GerardRoman• ErickaReid

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Allofthisyear’s150tagsweretaken,andsomeemployeeswenttheextramile.“GregorySolomonandsomeofhiselvesofferedtoassemblethebicyclesthathadbeendonated,”Quattlebaumsaid.Solomonhasalreadyrenewedtheofferfornextyear.“Wedon’twanttheassemblytokeepanyonefrombuyingabike.”

Alongwithadmiringthebicyclesandothergifts,largeandsmall,thegatheredemployeesusedthetimetosamplethefestivetreats,whilegettingbetteracquaintedwithoneanother. Austin and Collins welcomed employees to the Giving Tree

celebration. (Photo courtesy of Steve McCaw)

Steve Johnson, left, and William Ragland enjoyed a break from their hectic preholiday schedules. (Photo courtesy of Steve McCaw)

Diversity Council members Westmoreland, left, and Robinson joined in the festivities. (Photo courtesy of Steve McCaw)

Sophia Harlid, Ph.D., left, and Michelle Campbell quenched their thirst brought on by the plentiful treats. (Photo courtesy of Steve McCaw)

Dick Sloane, right, gestured as he described the size of the pile of gifts over at the NIEHS Keystone building to Rick Woychik, Ph.D., NIEHS deputy director. (Photo courtesy of Steve McCaw)

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NIEHS scientists join other volunteers to teach children about nutritionThankstovolunteersfromNIEHSandpublicservicegroups,sixchildreninaDurham,N.C.,programlearnedimportantlessonsabouthealthylifestyleanddiet.

NIEHSscientistsSharonBeardandElenaBraithwaite,Ph.D.,joinedfellowmembersoftheDurhamAlumnaeChapterofDeltaSigmaThetaSorority,aswellasvolunteersfromtheDurhamAlumniChapterofKappaAlphaPsiFraternityandtheDurhamChapteroftheLinksInc.

ChildrenlivingtemporarilyatGenesisHome,anonprofitorganizationthatworkstoendhomelessnessforfamilieswithchildren,participatedinahands-onsciencelessonDec.2abouttheimportanceoffruitsandvegetables,ahealthydiet,andexercise.Thelessonsincludedsomegraphicillustrations,suchasoneinvolvingcansofregularsoda,whichsankinwaterbecauseofthedensityofthe30-50gramsofsugartheycontain,andcansofdietsoda,whichfloatedbecauseoftheirlowersugarcontent,weight,anddensity.

Why is diet so important?ChildhoodobesityratesinAmericahavetripledinthepastthirtyyearsandtoday,intheU.S.,approximately30percentofallchildren,and40percentofAfrican-AmericanandHispanicchildren,areoverweightorobese.Sinceobesitycanleadtonumeroushealthcomplications,includingdiabetes,heartdisease,highbloodpressure,cancer,andasthma,itisimportanttotrytoreversethistrend.Somefactorsthatcontributetotheincreaseinobesityratesamongchildrenarediet,portionsize,andlackofexercise.

Beardstartedthediscussionbytalkingaboutthefivefoodgroupsthatserveasthebuildingblocksforahealthydiet.Inherpresentation,sheemphasizedtheimportanceofconsumingavarietyoffruitsandvegetables.

AsBeardsaid,“Teachablemomentsliketheseareessentialtohelpeliminateminorityhealthdisparities,aschildrenlearninafunenvironment.Wehopetheywillinternalizethesehealthyconcepts.Evidenceindicatesthatingestionofatleast21/2cupsoffruitandvegetablesperdayisassociatedwithareducedriskofcardiovasculardisease.”

The children, who may not have associated sugar in soda with weight before, certainly did after this graphic illustration. (Photo courtesy of Renaldo Dorsey)

Braithwaite is a regular volunteer in the Durham Alumnae Chapter of Delta Sigma Theta Sorority Science and Everyday Experiences (SEE) summer camp held each year in Durham, N.C. (see story). She is a staff scientist in the NIEHS Comparative Genomics Group and has also volunteered in the Citizen Schools program. (Photo courtesy of Steve McCaw)

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However,Beardnoted,accordingtotheCDC’s2013StateIndicatorReportonFruitsandVegetables,morethan40percentofadultsandadolescentsinN.C.consumelessthanonehelpingoffruitsandvegetableseachday.Shesaiditcontinuestobeimportanttoremindthegeneralpublicofthisnutritionalrecommendation.

Bringing the healthy diet message up close and personalBraithwaitecontinuedthediscussionbyteachingtheparticipantsaboutnutritionlabelsandhealthyfoodoptions,andemphasizedtheimportanceofexercise.Studentscalculatedthetotalcaloriesinatypicalmealtheywouldorderforlunchfrompopularfastfoodrestaurants.Manyweresurprisedtoseethatthisonemealcontainedalmosthalfthecaloriestheyshouldconsumeinanentireday.

Toencourageabalancedandnutritiousdiet,Braithwaiteledadiscussionofhealthyalternativesforpopularitemsandemphasizedtheimportanceofexercise.Thestudentsthenjoinedinanexercisewheretheywereaskedtodojumpingjacksforoneminute.

“Manyoftheparticipantsweresurprisedtoseehowmuchexerciseisrequiredtoequalthenumberofcaloriesinaservingoftomatoesonasandwich,”saidBraithwaite,whonotedthatinactivityisalsoabigprobleminN.C.Accordingtothe2013AnnualReportonAmerica’sHealthRankingsbytheUnitedHealthFoundation,24.9percent,orapproximately1.8million,adultsinN.C.arephysicallyinactive,and29.6percentareestimatedtobeobese.

“Ourhopeisthatthisknowledgewillassisttheparticipantsinmakingbetternutritionalchoicesandpromoteahealthierlifestyle,”Braithwaitesaidoftheprogram.

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The e-Factor, which is produced by the Office of Communications and Public Liaison, is the staff newsletter at the National Institute of Environmental Health Sciences. It is published as a communication service to NIEHS employees. We welcome your comments and suggestions. The content is not copyrighted. It can be downloaded and reprinted without permission. If you are an editor who wishes to use our material in your publication, we ask that you send us a copy for our records.

Director of Communications: Christine Bruske FlowersEditor-in-Chief: Kelly Lenox | Managing Editor: Eddy Ball | Science Editor: Robin Arnette

Beard is the coordinator of her sorority’s SEE camp each summer. At NIEHS, she is a program manager and industrial hygienist in the Worker Education and Training Program. (Photo courtesy of Steve McCaw)