1. 1. EndocrineEndocrine Disruptors:Disruptors: Child healthsChild healths Vichit Supornsilchai, MD, PhDVichit Supornsilchai, MD, PhD Endocrine Unit, Department of Pediatric,Endocrine Unit, Department of Pediatric, Faculty of Medicine,Faculty of Medicine, King Chulalongkorn MemorKing Chulalongkorn Memoriaial Hospitall Hospital
  2. 2. Overview Background animal experiences evidences in human Definition and classification of EDs Routes of human exposure The effects of EDs on the reproductive systems The effects of Bisphenol A (BPA) on PP and obesity in Thais children and adolescents
  3. 3. Background: Animal experiences Outbreak of infertility in Australian sheep (1940s)Outbreak of infertility in Australian sheep (1940s) ingestion of large amount of subterranean cloveringestion of large amount of subterranean clover estrogenic effects of phytoestrogens in the Cloverestrogenic effects of phytoestrogens in the Clover (Clover disease)(Clover disease) Reproductive dysfunction in the bald eagleReproductive dysfunction in the bald eagle and other wild birdsand other wild birds exposure of high doses of DDT and other chemicalsexposure of high doses of DDT and other chemicals development of thin-shelled, nonviable eggsdevelopment of thin-shelled, nonviable eggs Murkies AL et al., J Cli Endocrinol Metab, 1998, 83, 297-303Murkies AL et al., J Cli Endocrinol Metab, 1998, 83, 297-303 Garcelon DK et al., J Wildl Dis, 1997, 33, 299-303Garcelon DK et al., J Wildl Dis, 1997, 33, 299-303
  4. 4. BackgroundBackground :: AnimalAnimal experiencesexperiences Edwards TM et al., International Journal of Andrology 2006, 29, 109-121 Reproductive dysfunction inReproductive dysfunction in young male alligators in Lakeyoung male alligators in Lake Apopka, Florida (1970s)Apopka, Florida (1970s) small phallus sizesmall phallus size decreased serum testosteronedecreased serum testosterone levelslevels abnormal gonadal morphologyabnormal gonadal morphology Associate with elevated level ofAssociate with elevated level of DDT metabolitesDDT metabolites Guillette LT et al., Environ Health Perspect, 1994, 102, 680-688Guillette LT et al., Environ Health Perspect, 1994, 102, 680-688
  5. 5. Background:Background: Evidences in humansEvidences in humans DiethylstilbestrolDiethylstilbestrol (DES)(DES) is a prototype inis a prototype in humanhuman exposedexposed malemale offspringoffspring hypospadiashypospadias micropenismicropenis cryptorchidismcryptorchidism decreased fertilitydecreased fertility exposedexposed femalefemale offspringoffspring reproductive organ dysfunctionreproductive organ dysfunction decreased pregnancy ratedecreased pregnancy rate decreased fertilitydecreased fertility Bibbo M et al., Obstet Gynecol, 1997, 49, 1-7
  6. 6. Background:Background: Epidemiological evidences in humansEpidemiological evidences in humans Fisher JS, Reproduction 2004, 127, 305-315Fisher JS, Reproduction 2004, 127, 305-315 Carlsen et al., Environ Health Perspect 1995, 103, 137-139Carlsen et al., Environ Health Perspect 1995, 103, 137-139 Sperm countSperm count Paulozzi, Environ Healthe Perspect 1999, 107, 297-302Paulozzi, Environ Healthe Perspect 1999, 107, 297-302
  7. 7. Definition of EDs An exogenous substance, either anthropogenic or natural, that can alter endocrine functions by a variety of different mechanisms; By acting as either agonists or antagonists By altering the synthesis, transport and/or catabolism of endogenous hormones By modifying the levels of expression and/or functioning of hormone receptors
  8. 8. ClassificationClassification Estrogenic activity:Estrogenic activity: Dichlorodiphenyltrichloroethane (DDT)Dichlorodiphenyltrichloroethane (DDT) Phytoestrogens (at high concs)Phytoestrogens (at high concs) Polychlorinated biphenyls (PCBs)Polychlorinated biphenyls (PCBs) Bisphenol ABisphenol A Anti-androgenic activity:Anti-androgenic activity: AR antagonist:AR antagonist: vinclozolin, procymidone,vinclozolin, procymidone, linuron, pp DDElinuron, pp DDE Reduce androgen synthesis:Reduce androgen synthesis: phthalatephthalate estersesters
  9. 9. ClassificationClassification Anti-estrogenic activity:Anti-estrogenic activity: dioxin (TCDD),dioxin (TCDD), PCBs, phytoestrogens (at low concs)PCBs, phytoestrogens (at low concs) Androgenic activity:Androgenic activity: Testosterone,Testosterone, Trembolone acetateTrembolone acetate Thyroid hormonal effectsThyroid hormonal effects Evidences were mostly from animal experimentsEvidences were mostly from animal experiments Identified EDs are just a tip of icebergIdentified EDs are just a tip of iceberg
  10. 10. OtherOther mechanismsmechanisms nonnuclear steroid hormone receptornonnuclear steroid hormone receptor i.e.i.e. membrane receptormembrane receptor nonsteroid receptorsnonsteroid receptors i.e.i.e. neurotransmitterneurotransmitter receptors (serotoninreceptors (serotonin receptor, dopamine receptor)receptor, dopamine receptor) orphan receptororphan receptor i.e.i.e. Aryl-hydrocarbonAryl-hydrocarbon receptor (AhR)receptor (AhR) direct effect on the enzymes indirect effect on the enzymes in
  11. 11. Routes of humanRoutes of human exposureexposure Timing of exposure is critical !
  12. 12. Factors of endocrineFactors of endocrine disruption of EDsdisruption of EDs Age at exposureAge at exposure Latency from exposureLatency from exposure Importance of mixturesImportance of mixtures Nontraditional dose-response dynamicsNontraditional dose-response dynamics Transgenerational epigenetic effectsTransgenerational epigenetic effects Evanthia DK Endocrine Review 2009; 30: 293-342Evanthia DK Endocrine Review 2009; 30: 293-342
  13. 13. The effects of EDs on reproductive systems Male reproductive system Genital malformations and the TDS (Testicular dysgenesis syndrome) Female reproductive system Early and precocious puberty
  14. 14. Asklund C, BJU international 2004, 93, 6-11Asklund C, BJU international 2004, 93, 6-11 First introduced by Skakkebaek (Denmark)First introduced by Skakkebaek (Denmark) Genital malformations and the TDSGenital malformations and the TDS (Testicular dysgenesis syndrome)(Testicular dysgenesis syndrome) Reproductive disease in adult men may result from disruptionReproductive disease in adult men may result from disruption of embryonic programming and fetal gonadal developmentof embryonic programming and fetal gonadal development
  15. 15. Early and precociousEarly and precocious pubertypuberty The onset of puberty trend to be earlier,The onset of puberty trend to be earlier, particularly in girlparticularly in girl The precise trigger for the onset ofThe precise trigger for the onset of puberty is not known, but it is believed topuberty is not known, but it is believed to be a complex interaction betweenbe a complex interaction between genetics, hormones, and environmentalgenetics, hormones, and environmental influencesinfluences EDs may play an important role in timingEDs may play an important role in timing and disturbance of normal pubertyand disturbance of normal puberty
  16. 16. Exposure-outcome relationshipExposure-outcome relationship ExposureExposure ReferencesReferences Advanced pubertyAdvanced puberty Earlier menarche and pubarcheEarlier menarche and pubarche PBBPBB Blanck et al., 2000Blanck et al., 2000 Earlier thelarcheEarlier thelarche pesticides,pesticides, phthalatesphthalates Colon et al., 2000Colon et al., 2000 Earlier menarcheEarlier menarche DDEDDE Vasiliu et al., 2004Vasiliu et al., 2004 Central precocious pubertyCentral precocious puberty DDEDDE Krstevska-KonstantinovaKrstevska-Konstantinova et al., 2001et al., 2001 Earlier age at menarcheEarlier age at menarche DDTDDT Ouyang et al., 2005Ouyang et al., 2005 PBBs: Polybrominated biphenyls; DDE: Dichlorodiphenyldichloroethylene; DDT: Dichlorodiphenyltrichloroethane; PCBs: Polychlorinated biphenyls; PCDFs: Polychlorinated dibenzofurans; PCDDs: Polychlorinated dibenzodioxins)
  17. 17. The literatures: outbreaksThe literatures: outbreaks of early puberty in sub-of early puberty in sub- populationpopulation Related to exposure to exogenousRelated to exposure to exogenous hormones or hormone-like chemicalshormones or hormone-like chemicals High frequency of CPP in a region withHigh frequency of CPP in a region with high exposure to the estrogenichigh exposure to the estrogenic mycotoxin zearalenonemycotoxin zearalenone (Massart, J Pediatr 2008; 152: 690-95)(Massart, J Pediatr 2008; 152: 690-95) Premature thelarche in 4 pre-pubertalPremature thelarche in 4 pre-pubertal girls after consumption of tea containinggirls after consumption of tea containing a phytoestrogen (a phytoestrogen (Foeniculum vulgareFoeniculum vulgare)) (Turkyilmaz, J Peddiatr Surg 2008; 43: 2109-11)(Turkyilmaz, J Peddiatr Surg 2008; 43: 2109-11)
  18. 18. Evidences of PP andEvidences of PP and poultrypoultry An epidemic outburst of prematureAn epidemic outburst of premature breast development and ovarian cystbreast development and ovarian cyst in 2716 girls from Peurto Ricoin 2716 girls from Peurto Rico (1990-1995) with unknown cause,(1990-1995) with unknown cause, environmental factors (EDs: soy-environmental factors (EDs: soy- based formula, meat products) werebased formula, meat products) were suspected.suspected. (Larriuz-Serrano, P R Health Sci J 2001; 20:13-18)(Larriuz-Serrano, P R Health Sci J 2001; 20:13-18)
  19. 19. Evidences of PP andEvidences of PP and poultrypoultry US Department of Agriculture and PuertoUS Department of Agriculture and Puerto Rico Department of Health reported thatRico Department of Health reported that there was no abnormal levels of thethere was no abnormal levels of the suspected chemicals found in thesuspected chemicals found in the approximately 800 samples of meat andapproximately 800 samples of meat and dairy products that were analyseddairy products that were analysed (unpublished data)(unpublished data) Early breast development in both sexesEarly breast development in both sexes in Northern Italy due to estrogenin Northern Italy due to estrogen exposure through poultry and beef fromexposure through poultry and beef from school cafeteriaschool cafeteria (Scaglioni Lancet 1978; 1: 551-2)(Scaglioni Lancet 1978; 1: 551-2)
  20. 20. NeuroendocrineNeuroendocrine systemsystem Hypothalamus (GnRH neurons)-pituitary-Hypothalamus (GnRH neurons)-pituitary- target organtarget organ Highly complexHighly complex HPG axis: GnRH neurons expressHPG axis: GnRH neurons express steroid hormone receptorssteroid hormone receptors Other cells in the brain also expressOther cells in the brain also express steroid hormone receptors and cansteroid hormone receptors and can regulate GnRH i.e. neurotransmittersregulate GnRH i.e. neurotransmitters (Noradrenergic, serotonergic,(Noradrenergic, serotonergic, dopaminergic etc.)dopaminergic etc.)
  21. 21. Bisphenol A (BPA)Bisphenol A (BPA) synthetic estrogen (Xenoestrogen)synthetic estrogen (Xenoestrogen) Dose-dependent effectsDose-dependent effects Low dose: interacts with both ERLow dose: interacts with both ER andand ERER Higher dose: antiandrogenic activityHigher dose: antiandrogenic activity
  22. 22. Chemical structureChemical structure Bisphenol A Estrogen phenol group: bind to ER
  23. 23. One of the hightest volume chemicalsOne of the hightest volume chemicals produced worldwideproduced worldwide Epoxy resins and polycarbonate plasticEpoxy resins and polycarbonate plastic containers (hard, clean plastic)containers (hard, clean plastic)
  24. 24. Plastic usePlastic use considerationsconsiderations
  25. 25. Plastic usePlastic use considerationsconsiderations
  26. 26. Sources of BPASources of BPA exposureexposure Canned products Polycarbonate plastics Thermal paper products Food Most plastics with recycling code 07 Sales receipts Soda Intravenous tubing and medical equipments Lottery tickets Liquid infant formula (versus powder, which typically has no detectable BPA) Bottles, toys, pacifier shields, dental sealants Fax paper, recycling paper products (paper towels, toilet paper, pizza boxes) Factors that increase BPA migration from containers Increased temperature Damaged surfaces (scratches) Increased acidity
  27. 27. PolycarbonatePolycarbonate plasticsplastics
  28. 28. CannedCanned productproduct ss Thermal paperThermal paper productsproducts
  29. 29. BPA-free productsBPA-free products
  30. 30. Routes ofRoutes of exposureexposure Dietary:Dietary: majority (99%)majority (99%) Monomers of BPA: hydrolyse and leachMonomers of BPA: hydrolyse and leach from epoxy resins and polycarbonatefrom epoxy resins and polycarbonate plastics into food and liquids in contactplastics into food and liquids in contact with the containerwith the container Factors: thermal, acidic and basicFactors: thermal, acidic and basic conditionsconditions
  31. 31. The primary source of BPA exposure inThe primary source of BPA exposure in -- children age and adult:children age and adult: oral intake from canned foodoral intake from canned food -- infant:infant: breastmilk and polycarbonate feedingbreastmilk and polycarbonate feeding bottlesbottles Young children have higher urinary BPAYoung children have higher urinary BPA concentration than adults: reflect higher foodconcentration than adults: reflect higher food intake per kilogram of body massintake per kilogram of body mass
  32. 32. Nondietary exposureNondietary exposure Cashiers (Cashiers (occupational exposure)occupational exposure),, industries using BPA Human exposure toindustries using BPA Human exposure to BPA is widespread, small adverse effectsBPA is widespread, small adverse effects of BPA could have large public healthof BPA could have large public health implicationsimplications Infants in NICU have higher BPAInfants in NICU have higher BPA exposure than the general poppulationexposure than the general poppulation due to intensive medical interventionsdue to intensive medical interventions and proceduresand procedures
  33. 33. BPABPA 1919 25512551 BPABPA 11 25532553 BPA regulationsBPA regulations
  34. 34. BPA exposure inBPA exposure in childrenchildren In the US population, in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) data, 92.6% Age > 6 years expose BPA (Urine BPA mean 2.6 ug/, P10 0.9ug/g cr, P95 11.2ug/g cr). High level BPA in female, young age (6-11yrs), low annual household income (5.6) OR 2.08-2.57 < 0.001 2012: Bhandari R, et al USA 2003- 2008 2200 6-18 LCMS 0.3 4.8 17.7 16.7 1st Q (BPA 1.5) 2nd Q (1.5-2.7) 3rd Q (2.8-5.4) 4th Q (>5.4) OR 1.78-2.55 0.002 2012: Wang H, et al China 2011 259 8-15 LCMS 0.07 0.45 GM 31.7 20.4 Normal BPA 0.33 Obesity BPA 0.57 0.018 2013: Li D, et al China 2011 1,326 4-12 HPL/FD 0.31 NA 18.3 Girl: associated with overweight Significant , 95%CI Thai children Thailan d 2013- 2014 376 3-18 LCMS 0.05 0.68 (median) 11.3 9.0 OR 3.42 (NL vs. obese) 0.02 LOD: Lower limit of detection, OR: Odds ratio, LCMS: Liquid chromatography mass spectrometry
  35. 38. BMI Urine BPA (ng/mL) Urine adjusted BPA (ug/g Cr.) Estimated daily intake (ug/day) Median (IQR) Median (IQR) Median (IQR) Normal weight Overweight Obesity 0.67 (0-1.48) 0.62 (0-1.13) 0.87 (0.39-1.70) 0.51 (0-1.09) 0.36 (0-0.76) 0.71 (0.20-1.16) 0.50 (0-1.32) 0.45 (0-1.03) 0.65 (0.30-2.04) IQR: Interquatile range
  36. 39. BMI OR 95% Confident interval for OR P-value Normal weight Overweight Obesity 1.00 1.12 3.42 0.48-2.62 1.18 -9.95 1.00 0.79 0.02* OR: Odds ratio
  37. 40. BPA and pubertyBPA and puberty
  38. 41. 23/04/15Vichit Supornsilchai, MD 41 Integration of timing ofIntegration of timing of puberty influenced by bothpuberty influenced by both genetic and environmentalgenetic and environmental factorsfactors
  39. 42. BPA and pubertal onsetBPA and pubertal onset Pubertal developmentPubertal development No association between urine BPA concNo association between urine BPA conc at 6-8 yrs of age and breast or pubic hairat 6-8 yrs of age and breast or pubic hair development 1 yr later (Wolff et al):development 1 yr later (Wolff et al): prospective cohort study, n= 1151prospective cohort study, n= 1151 No association between urine BPA andNo association between urine BPA and pubertal develpoment (Wolff et al): crosspubertal develpoment (Wolff et al): cross sectional study, n= 192sectional study, n= 192
  40. 43. Study Year Country Number patients/ control Specimen/ Analysis method BPA Statistic significant patients control Sun Woo Lee et al 2009 Korea 30/30 Serum/ GCMS 11.2 10.3 16.2 12.5 No Yunje Kim et al 2013 Korea 150/90 Serum/ GCMS 7.56 5.6 (N.D.-29.53) ng/mL 3.53 4.11 (0.39-26.16) ng/mL no Cai D et al 2010 China 110/100 Serum/ HPLC 40.9% 2% yes Durmaz et al 2014 Turkey 28 Urine/ HPLC 8.34 (median; 0.84-67.35) g/g Cr 1.62 (median; 0.3-25.79) g/g Cr OR 8.68 95% CI: 2.03-32.72 Thai 2014 Thailand 29a /12b /43c a:precocious puberty, b:early puberty c:control Urine/ LCMSMS 1.62 (0.68, 3)/ 0.54 (0, 1.22) (median) g/g Cr 0.59 (0, 0.97) (median) g/g Cr yes BPA and precocious pubertyBPA and precocious puberty
  41. 44. Kiss1 neuron Kiss1 neuron Kiss1 neuron Kiss network GnRH neuron RFRP3 neuron TTF1 EAP1 YY1 AVP/PeN ARC MeA Pituitary FSH, LH Puberty ++ GnRH stimulator inhibitor ? + + GPR54 G PR147/ G PR74 + - - - - - - BPA BPA BPA
  42. 45. How to reduce theHow to reduce the endocrine disruptorsendocrine disruptors exposureexposure Eliminate any pesticide, herbicide andEliminate any pesticide, herbicide and insecticide use (recommend organicinsecticide use (recommend organic products)products) Wash non-organic fruits and vegetablesWash non-organic fruits and vegetables Make as much of your diet organic asMake as much of your diet organic as possible. This will eliminate the toxic,possible. This will eliminate the toxic, hormone-disrupting chemicals that arehormone-disrupting chemicals that are sprayed on fruits and vegetables.sprayed on fruits and vegetables. 23/04/15Vichit Supornsilchai, MD 47
  43. 46. How to reduce theHow to reduce the endocrine disruptorsendocrine disruptors exposureexposure Use organic personal care productsUse organic personal care products (shampoos, sunscreens, skin(shampoos, sunscreens, skin care, body care)care, body care)
  44. 47. How to reduce theHow to reduce the endocrine disruptorsendocrine disruptors exposureexposure Teach your children to wash their handsTeach your children to wash their hands frequently and not to lick their fingers orfrequently and not to lick their fingers or bite their nails.bite their nails. Avoid buying canned foods or foodsAvoid buying canned foods or foods wrapped in plastic. Make sure youwrapped in plastic. Make sure you remove foods from packaging as soon asremove foods from packaging as soon as possible. Use glassware for ovenpossible. Use glassware for oven cookingcooking
  45. 48. How to reduce theHow to reduce the endocrine disruptorsendocrine disruptors exposureexposure Carefully read the labels of foods,Carefully read the labels of foods, personal care products, householdpersonal care products, household cleaners, cosmetics etc.cleaners, cosmetics etc. Install a water filter (pesticides, otherInstall a water filter (pesticides, other chemicals and other debris combine inchemicals and other debris combine in drinking water and heavy metals fromdrinking water and heavy metals from household pipes and plumbing)household pipes and plumbing) 23/04/15Vichit Supornsilchai, MD 50
  46. 49. How to reduce theHow to reduce the endocrine disruptorsendocrine disruptors exposureexposure Don't let children chew on soft plasticDon't let children chew on soft plastic toys. Phthalates are added to soften PVCtoys. Phthalates are added to soften PVC plastic toys. These plastic toys alsoplastic toys. These plastic toys also retain any pesticides sprayed in theretain any pesticides sprayed in the house for up to two for up to two weeks.
  47. 50. Problems in the study ofProblems in the study of EDsEDs difficult to compare the results from eachdifficult to compare the results from each studystudy are the environmental levels sufficient toare the environmental levels sufficient to induce reproductive tract abnormalities?induce reproductive tract abnormalities? the mixture effects in the environmentsthe mixture effects in the environments (additive or synergistic manner)(additive or synergistic manner) organ specific effectsorgan specific effects
  48. 51. 23/04/15Vichit Supornsilchai, MD 53 ThankThank youyou forfor youryour attentionattention

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