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  • PH73CH07-Desvergne ARI 3 January 2011 16:15

    Endocrine Disruptors:From Endocrine toMetabolic DisruptionCristina Casals-Casas and Beatrice DesvergneCenter for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne,Lausanne, 1015 Switzerland; email: [email protected]

    Annu. Rev. Physiol. 2011. 73:13562

    First published online as a Review in Advance onNovember 5, 2010

    The Annual Review of Physiology is online atphysiol.annualreviews.org

    This articles doi:10.1146/annurev-physiol-012110-142200

    Copyright c 2011 by Annual Reviews.All rights reserved

    0066-4278/11/0315-0135$20.00

    Keywords

    persistent organic pollutants, phthalates, bisphenol A, obesity,diabetes, nuclear receptors

    Abstract

    Synthetic chemicals currently used in a variety of industrial and agri-cultural applications are leading to widespread contamination of theenvironment. Even though the intended uses of pesticides, plasticiz-ers, antimicrobials, and flame retardants are beneficial, effects on hu-man health are a global concern. These so-called endocrine-disruptingchemicals (EDCs) can disrupt hormonal balance and result in develop-mental and reproductive abnormalities. New in vitro, in vivo, and epi-demiological studies link human EDC exposure with obesity, metabolicsyndrome, and type 2 diabetes. Here we review the main chemical com-pounds that may contribute to metabolic disruption. We then presenttheir demonstrated or suggested mechanisms of action with respect tonuclear receptor signaling. Finally, we discuss the difficulties of fairlyassessing the risks linked to EDC exposure, including developmentalexposure, problems of high- and low-dose exposure, and the complex-ity of current chemical environments.

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    EDCs: endocrine-disrupting chemicals

    Metabolic syndrome:a combination ofdisorders includingimpaired glucosetolerance or insulinresistance,dyslipidemia, highblood pressure, andobesity

    NRs: nuclearreceptors

    1. INTRODUCTION

    1.1. Endocrine Disruption

    Endocrine disruptors are exogenous com-pounds with the potential to disturb hormonalregulation and the normal endocrine system,consequently affecting health and reproductionin animals and humans (1). Endocrine disrup-tors can interfere with the production, release,metabolism, and elimination of or can mimicthe occurrence of natural hormones (2). En-docrine disruptors may also be derived fromnatural animal, human, or plant (phytoestro-gen) sources; however, for the most part in-ternational concern is currently focused onsynthetic chemicals and endocrine-disruptingchemicals (EDCs). This concern is further am-plified by two factors, the expansion in chemicalproduction, which has now reached 400 milliontons globally, and the increased pollution fromthese chemicals. As such, the impact on humanhealth through known or unknown effects ofthese chemicals on hormonal systems is great.

    The term endocrine disruptors was firstcoined by Ana Soto and collaborators, whoidentified a number of developmental effectsof EDCs in wildlife and humans (3). AlthoughEDCs can target various hormone systems, anumber of observations concerning reproduc-tive development and sex differentiation, to-gether with early embryonic development andpuberty, have focused on EDC interferencewith sex steroid hormones.

    1.2. Metabolic Disruption:A Subdivision of Endocrine Disruption

    In addition to the developmental and repro-ductive effects, there is also a growing con-cern that metabolic disorders may be linkedwith EDCs. Global obesity rates have risen dra-matically over the past three decades in adults,children, and adolescents, especially in devel-oped countries. Obesity is frequently associatedwith metabolic disorders (including type 2 dia-betes, metabolic syndrome, cardiovascular andpulmonary complications, and liver disease) aswell as other health issues such as psycholog-

    ical/social problems, reproductive defects, andsome forms of cancer.

    A combination of genetic, lifestyle, and en-vironmental factors likely account for the rapidand significant increase in obesity rates. Al-though genetic factors may explain a portionof obesity predisposition, they alone are unableto account for the sudden appearance and pro-gression of the current worldwide obesity epi-demic. Modern lifestyles that include excessiveenergy intake, lack of physical activity, sleepdeprivation, and more stable home tempera-tures appear to be major contributing factorsof obesity. However, the increased incidenceof metabolic diseases also correlates with sub-stantial changes in the chemical environmentresulting from new industrial and agriculturalprocedures initiated over the past 40 years. Thischange in the environment has led to the hy-pothesis that some of the numerous environ-mental pollutants are EDCs, interfering withvarious aspects of metabolism and adding an-other risk factor for obesity (4, 5). This hy-pothesis is supported by laboratory and ani-mal research as well as epidemiological studiesthat have shown that a variety of environmen-tal EDCs can influence adipogenesis and obe-sity (reviewed in References 510). Such EDCshave been referred to as environmental obeso-gens (11). However, because adverse effects byEDCs may also lead to other metabolic diseasessuch as metabolic syndrome and type 2 diabetes,this subclass of EDCs would be better referredto as metabolic disruptors (12).

    1.3. A Common Molecular Mechanismfor Endocrine Disruptionand Metabolic Disruption

    Hormones function mainly through interac-tions with their cognate receptors, which can beclassified into two large groups: (a) membrane-bound receptors, which respond primarilyto peptide hormones such as insulin, and(b) nuclear receptors (NRs), which are activatedby interaction with small lipophilic hormonessuch as sex steroid hormones. EDCs may pos-sess multiple mechanisms of action; however,

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    Estrogen receptors(ERs): ER and ERare members of thenuclear receptorsuperfamily. Theyform homodimers tobind to DNA

    Retinoid X receptor(RXR): a member ofthe nuclear receptorsuperfamily and amajor partner of othernuclear receptors suchas PPAR, PXR, andCAR, with which itforms heterodimers

    Persistent organicpollutants: chemicalsthat persist in theenvironment andbioaccumulate withrisks of adverse effectsto human health andenvironment

    OCPs:organochlorinepesticides

    because many EDCs are small lipophilic com-pounds, one privileged route is through theirdirect interaction with a given NR, which pre-sumably perturbs or modulates downstreamgene expression. For example, most EDC-associated reproductive and developmental de-fects are thought to result from EDCs interfer-ing with the function of the estrogen receptor(ER) and/or androgen receptor (AR), therebydisrupting the normal activity of estrogens andandrogens ligands.

    In humans, the NR superfamily encom-passes 48 members that share a commonstructure and, once activated, bind as dimers tospecific response elements located near targetgene promoters. These dimers may be homo-dimers or heterodimers with retinoid X recep-tor (RXR), another member of the NR super-family. In addition to the sex steroid receptors,the NR superfamily includes transcription fac-tors that play pivotal roles in the integration ofthe complexities of metabolic homeostasis anddevelopment. The ability of EDCs to interactwith these NRs is supported by, and explains,the wide range of metabolic perturbations re-ported in both experimental and epidemiolog-ical studies. It also reinforces the concept of as-sociating endocrine and metabolic disruption.

    The present review focuses on metabolicdisruptors and is organized into three sections.The first section discusses the chemical com-pounds that are presently considered to be ma-jor potential endocrine/metabolic disruptors.Also summarized is the impact of these chem-icals on human health and metabolism on thebasis of available epidemiological studies. Thesecond section highlights recent advances inestablished or proposed mechanisms of EDC-mediated metabolic disruption. The last sectionhighlights the main challenges that scientistsand regulators face in this field.

    2. A MYRIAD OFENDOCRINE-DISRUPTINGCHEMICALS

    EDCs encompass a variety of chemical classes,including pesticides, compounds used in the

    plastic industry and in consumer products, andother industrial by-products and pollutants.They are often widely dispersed in the envi-ronment and, if persistent, can be transportedlong distances; EDCs are found in virtually allregions of the world (1317). Persistent organicpollutants are prevalent among environmen-tal contaminants because they are resistant tocommon modes of chemical, biological, or pho-tolytic degradation. Moreover, many EDCs canbe stored for years in animal and human fatmass. However, other EDCs that are rapidlydegraded in the environment or the humanbody, or that may be present for only short pe-riods of time, can also have serious deleteriouseffects if exposure occurs during critical devel-opmental periods.

    EDCs can be categorized according to theirintended use (e.g., pesticides) or their struc-tural properties (e.g., dioxins). The main cate-gories of chemicals with suspected metabolism-disrupting activity are presented below (seeTables 1 and 2). For more detailed informa-tion, the interested reader may refer to in-depthreviews focused on specific chemical categories,as discussed below.

    2.1. Pesticides

    Pesticides are any substance or mixture of sub-stances intended for preventing, destroying, re-pelling, or mitigating any pest (1, 18). Severalhundreds, if not thousands, of different chemi-cals are used as pesticides, and human exposureto these pesticides is widespread. Prominentchemical families include organochlorine pes-ticides (OCPs), organophosphates, carbamates,triazines, and pyrethroids. All OCPs are per-sistent. Even though OCPs such as the insec-ticide dichlorodiphenyltrichloroethane (DDT)are currently banned in most developed coun-tries and were subsequently replaced in 1975by organophosphates and carbamates, DDTcontamination still exists. OCPs are detectedin human breast milk and adipose tissueand may exhibit estrogenic, antiestrogenic,or antiandrogenic activity. Their associationwith breast cancer is suspected but not yet

    www.annualreviews.org Pollutants and Metabolic Disruption 137

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  • PH73CH07-Desvergne ARI 3 January 2011 16:15

    Tab

    le1

    ED

    Cs

    desc

    ribe

    das

    met

    abol

    icdi

    srup

    tors

    and

    thei

    ref

    fect

    son

    the

    met

    abol

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    .g.,

    DD

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    .,P

    CB

    ,TC

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    nvir

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    ptor

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    izat

    ion.

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  • PH73CH07-Desvergne ARI 3 January 2011 16:15

    Tab

    le2

    Hum

    anex

    posu

    reto

    ED

    Cs

    com

    pare

    dw

    ith

    conc

    entr

    atio

    nsex

    peri

    men

    tally

    used

    a

    ED

    Cs

    Hum

    anex

    posu

    reL

    evel

    sin

    the

    hum

    anbo

    dyB

    iolo

    gica

    lha

    lf-lif

    eC

    once

    ntra

    tion

    sex

    peri

    men

    tally

    used

    Ref

    eren

    ces

    Org

    anoc

    hlor

    ines

    (e.g

    .,D

    DT

    )B

    anne

    dSo

    ilha

    lf-lif

    e:22

    to30

    year

    sD

    DE

    :ver

    yva

    riab

    lera

    nge

    from

    15,0

    00m

    g(k

    gB

    W)

    15

    year

    sIn

    cells

    :20

    M

    p,p

    -DT

    T20

    ,24,

    157

    Dio

    xins

    (e.g

    .,T

    CD

    D)

    TD

    I:1

    4pg

    (kg

    BW

    )1

    (WH

    O)

    Inad

    ipos

    etis

    sue:

    3.6

    pg(g

    lipid

    )1

    Inbl

    ood:

    2.2

    ppt

    711

    year

    sIn

    mic

    e:do

    ses

    of5

    500

    ng(k

    gB

    W)

    1

    day

    1af

    fect

    ener

    gym

    etab

    olis

    m17

    ,119

    ,158

    Org

    anot

    ins

    (e.g

    .,T

    BT

    )T

    DI:

    1.6

    mg

    (kg

    BW

    )1

    (Wel

    fare

    Min

    istr

    yof

    Japa

    n)In

    seru

    m:2

    7nM

    Inhu

    man

    tissu

    e:3

    100

    nMFr

    om23

    to30

    days

    Inm

    ice:

    indu

    cead

    ipog

    enes

    isat

    0.05

    0.5

    mg

    (kg

    BW

    )1

    Invi

    tro:

    EC

    50:3

    10

    nMfo

    rR

    XR

    /PP

    AR

    11,2

    8

    PFC

    sIn

    door

    air

    leve

    ls:

    PFO

    S:5

    ppm

    PFO

    A:3

    .7pp

    m

    Seru

    m-l

    evel

    med

    ians

    :P

    FOS:

    19.9

    g

    liter

    1

    PFO

    A:3

    .9

    glit

    er1

    PFO

    S:5.

    4ye

    ars

    PFO

    A:3

    .8ye

    ars

    Inro

    dent

    s:P

    FOA

    pren

    atal

    expo

    sure

    effe

    cts

    ina

    rang

    eof

    0.01

    5m

    g(k

    gB

    W)

    1

    10,1

    4,40

    ,14

    1,14

    2

    BFR

    s(e

    .g.,

    PB

    DE

    )E

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    2.5 106 kg year1) used in polycarbonated plastic,in polystyrene resins, and as dental sealants.It is also used as an additive to other plas-tics such as PVC, and halogenated derivativesof BPA are widely used as flame retardants(55). Because unbound monomers remain af-ter BPA polymerization, BPA molecules canbe released from beverage and food containers,for example, from plastic baby bottles or fromtin can liners. Human exposure to BPA is thuswidespread, and unconjugated BPA moleculesare detected in human blood, tissues, and milk.In a reference study in the United States, asmany as 95% of human urine samples containeddetectable levels of BPA in a range that is pre-dicted to be biologically active (38, 57). Estro-genic properties of BPA were first described in1936 (58). Since then, experiments performedin rodents have confirmed its hormonal activ-ity, although the models and the high doses re-ported do not allow direct transposition to hu-man risks. Thus, the potential human healthrisks caused by BPA exposure remain fiercelydebated. Experimental data have been usedto evaluate long-term exposure of mammalianmodel organisms during development and inadulthood to low doses of BPA [levels that fallbelow the regulatory safety standard (59)]. Inshort, these studies point to a number of ad-verse effects in mammals that include abnormalpenile/urethra development, decreased spermcount, early sexual maturation in females, andbrain and behavioral abnormalities. As such, the

    potential impact of BPA on human health is noteasily dismissed.

    A few epidemiological and preliminary stud-ies, based on small populations, have uncov-ered associations between BPA blood levels inwomen and various ailments, including obesity,recurrent miscarriages, and sterility (6062).Additionally, higher urinary concentrations ofBPA are associated with an increased prevalenceof cardiovascular disease, diabetes, and liver en-zyme abnormalities (60). This last study high-lighted the need for regulatory action regardingBPA exposure, and Canada was the first countryto ban the use of BPA in baby bottles.

    2.4.5. Phthalates. Phthalate esters have beenused worldwide as softeners to impart flexibil-ity, pliability, and elasticity to otherwise rigidpolymers such as PVC. Produced in large quan-tities since the 1930s, nearly all groups of indus-trial consumer products contain phthalates ortraces of phthalates. These molecules are foundmostly in industrial paints and solvents but alsoin toys, personal-care products, and medicaldevices such as intravenous tubing and bloodtransfusion bags. In such devices, they can makeup 80% of the products weight (32). UnlikeBPA, phthalates are not covalently bound to thepolymer matrix, making them highly suscepti-ble to leaching. As a result, phthalates contami-nate food, particularly meat and milk products,and are found nearly everywhere in interior en-vironments. In addition, important routes ofhuman exposure include dermal uptake frompersonal-care products and from plastic medi-cal devices that come into direct contact withbiological fluids. Exposure to phthalates canoccur in the developing fetus through theplacenta-blood barrier and in postnatal stagesduring breast feeding or from mouthing toysand baby-care products. Once incorporatedinto the human body, phthalates are short-lived and are rapidly metabolized in a two-phase process (63). In phase I, diester phtha-lates are hydrolyzed into monoester phthalates,whose dosage is used for biomonitoring humanexposure. The conjugation process in phase II

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    Diethylhexylphthalate (DEHP):the most-usedphthalate; itsmetabolite, MEHP[mono(2-ethylhexyl)phthalate],interferes with severaltypes of nuclearreceptors

    leads to the urinary excretion of the conjugatedmetabolites.

    Among all the phthalates, diethylhexylphthalate (DEHP) elicits the most concern,with more than two million tons producedannually. This compound is widely used inmedical devices and in a variety of foodproducts. DEHP causes animal toxicity inmany physiological systems; however, many ofthe abnormalities that have been characterizedsince the 1940s have occurred at high DEHPdoses (32). In addition, DEHP promotes livertumor development in rodent models throughsevere peroxisomal proliferation. However,peroxisome proliferation has not been ob-served in humans, and according to a decisionof the International Agency for Research onCancer, DEHP cannot be classified as a humancarcinogen.

    Experimental studies at low doses of DEHPexposure, which appear to be most pertinent tohuman health, have demonstrated subtle repro-ductive toxicity in male rodents (64, 65). Otherreproductive outcomes include testicular dys-genesis together with permanent feminizationand demasculinization, resulting in a reducedanogenital distance (66).

    Some epidemiological studies reportedan association between cord blood levelsof mono(2-ethylhexyl)phthalate (MEHP), aDEHP metabolite, and shorter gestational ageof delivery. Indirect evidence also suggeststhat diethyl phthalate and dibutyl phthalatemay impart antiandrogenic effects in theperinatal period (reviewed in Reference 67).Maternal urine levels of metabolites of DEHP(benzylbutyl phthalate, diethyl phthalate, anddibutyl phthalate) are associated with a higherrisk of incomplete testicular descent for malehuman infants and are inversely correlatedwith the anogenital distance (68, 69). Otherdevelopmental effects of phthalate exposuremay cause damage to the pulmonary systemand may result in asthma (70).

    More recently, several studies have demon-strated a correlation between phthalates andmetabolic disorders. In short- and long-termrodent studies, dose-related deregulation of

    levels of serum insulin, blood glucose, liverglycogen, T3, T4, thyroid-stimulating hor-mone, and cortisol was observed (71, 72). Inhumans, the log-transformed concentrations ofseveral phthalate metabolites positively corre-lated with abdominal obesity and insulin resis-tance in adult males (73). These analyses sup-port the concept of environmental obesogensbut await further confirmation by longitudinalstudies.

    At first glance, this presentation of so manytypes of chemicals suspected of generatingmetabolic disruptors may seem alarming (seeTables 1 and 2). However, because many stud-ies discussed here are cross-sectional, a defini-tive causal link between metabolic disorders andEDC exposure is still hypothetical. For that rea-son, parallel studies aimed at identifying themolecular mechanisms of EDC activity with re-gard to metabolism should provide greater in-sights into the real health risks posed by thesecompounds.

    3. METABOLIC DISRUPTION:MECHANISTIC APPROACHESIn the context of endocrine disruption,metabolic disruption may result from threemain types of activity. First, hormones in gen-eral and sex steroid hormones in particular con-tribute to general body homeostasis throughdiverse metabolic regulations. Thus, a certainnumber of metabolic perturbations are simplythe result of hormonal disruption. Second, di-rect EDC activity through receptors respond-ing to xenobiotics and regulating xenobioticmetabolism may also contribute to a metabolicphenotype. Third, EDC interactions with spe-cialized metabolic receptors may serve as a pri-mary mechanism for metabolic disruption. Thisarticle presents and discusses experimental ob-servations linking EDCs with metabolic dis-ruption along these three types of activity (seeFigure 1).

    3.1. Metabolic Disruption ThroughHormone Receptors

    Hormone receptors belong to a class of clas-sic hormone receptors that recognize only one

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    or a few molecules with high affinity. Thyroidhormone (TH), mineralocorticoid, glucocorti-coid, retinoic acid, estrogen, vitamin D, pro-gesterone, and androgen receptors belong tothis class. Initial studies identified ER and ARas the targets of many EDCs, which resulted indevelopmental and reproductive effects, as wellas metabolic alterations.

    3.1.1. Metabolic disruption mediated by in-appropriate activation of the estrogen re-ceptor. ER and ER are the main media-tors of the biological effects of estrogens. Uponestrogen binding, they form homodimers thatbind to the promoters of estrogen-responsivegenes. These molecules share a similar struc-ture and bind to the same response elementbut have varying relative binding affinities forsome steroid hormones. In addition to theirwell-established roles in reproduction, ERand ER are involved in brain development andfunction of many other organs, such as skin,bone, and liver.

    Several lines of evidence link ERs tometabolism. For example, in postmenopausalwomen and ovarectomized rodents in whichestrogen is low, one observes an increase inwhite adipose tissue; estrogen replacementtherapy reverses these effects. ER but notER appears to mediate these effects, asinferred from studies using mice in which ERis knocked out: Both male and female mutantmice show increased insulin resistance andimpaired glucose tolerance (74, 75). Althoughthe underlying mechanisms remain unclearfor these observed results, it seems likely thatER activation modulates neural networkscontrolling food intake as well as acts directlyin adipose tissue (reviewed in Reference 76). Ata cellular level, preadipocytes also express ERand ER, and during development, estrogenscontribute to an increase in adipocyte number,with subsequent effects on adipocyte function(77). At the molecular level, ERs and estrogensregulate many aspects of metabolism, includingglucose transport, glycolysis, mitochondrialstructure and activity, and fatty acid oxidation(reviewed in Reference 8).

    Bisphenol A

    Adipogenesis Insulin levelsBody weight

    Phthalates Organotins Dioxins

    ARNTAhR

    PFCs

    ?

    CAR/PXR RXRPPAR RXR PPAR RXRGRGR ER ER RXRTR

    Figure 1Endocrine-disrupting chemicals (EDCs) interact with aryl hydrocarbonreceptor (AhR) and with diverse members of the nuclear receptor (NR)superfamily, which convey EDC-mediated metabolic disruption. Sensorreceptors like peroxisome proliferatoractivated receptors (PPARs) play aprominent role: PPAR activated by phthalates or organotins inducesadipogenesis in vitro, and this effect is inhibited by dioxins through AhRactivation. PPAR, which has a major role in fatty acid oxidation, limitsadipogenic activity and is activated in vivo by phthalates and polyfluoroalkylcompounds (PFCs). Estrogenic EDCs such as bisphenol A have also beeninvolved in metabolic disruption through complex interaction with hormonereceptors such as the estrogen receptors (ERs), thyroid hormone receptor(TR), and glucocorticoid receptor (GR). These receptors are important for thecontrol of adipogenesis, weight gain, and insulin levels, although theunderlying mechanisms are not yet well understood (dashed lines). Finally, eventhough the mechanisms have yet to be described (dashed lines and questionmark), the xenosensors pregnane X receptor (PXR), constitutive androstanereceptor (CAR), and AhR also play a crucial role in regulating metabolichomeostasis via direct or indirect interaction with the metabolic pathways.Other abbreviations used: ARNT, aryl hydrocarbon receptor nucleartranslocator; RXR, retinoid X receptor.

    Experimental evidence showing the effectsof estrogen-mimicking EDCs such as BPAon metabolism remains scarce and has beenrestricted to cultured cell line models. Studiesusing 3T3-L1 cells suggested that early BPAexposure may enhance adipocyte differenti-ation in a dose-dependent manner and maypermanently disrupt adipocyte-specific geneexpression and leptin synthesis (78, 79). Forinstance, the estrogenic surfactant octylphenolelevates adipocyte production of resistinthrough activation of the ER and extracellularsignalregulated kinase pathways in 3T3-L1

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    Thyroid hormonereceptor (TR): TRand TR are nuclearreceptors that areactivated by thethyroid hormones andplay an important rolein development andmetabolism regulation

    cells (80). Resistin is secreted by adipocytes andmay cause insulin resistance and predispositionto type 2 diabetes (81). These limited in vitrostudies suggest that octylphenol-induced se-cretion of resistin may contribute to metabolicdisorders. Finally, BPA may affect ER activityin the pancreas and increase insulin secretion(82). According to this report, short exposure toBPA provokes chronic hyperinsulinemia, withperturbations of glucose and insulin tolerancetests. This activity has been related to ERexpression in the pancreas, with 17-estradiolshown to increase -cell insulin content, insulingene expression, and insulin release (82).

    There are two important aspects to con-sider with respect to estrogen-like activity andmetabolic changes. The first aspect concernsnongenomic responses to estrogen mediatedby the nonclassical transmembrane receptorGPR30. GPR30 deletion in mice revealed itsmajor role in many facets of estrogen metabolicactivity (83), with phenotypes including im-paired glucose tolerance and reduction of bonegrowth. This membrane receptor can also beactivated by BPA and nonylphenol, as assessedin an in vitro cell culture model (84). Furtherstudies are thus needed to evaluate the in vivorelevance of this activation.

    The second major question concerns ex-posure to estrogenic EDCs during the criticalperiod of development. Indeed, embryos andfetuses are likely to be much more sensitiveto perturbation by endocrine-like activities.Protective mechanisms available in adultanimals, such as DNA repair mechanisms orliver detoxification and metabolism, are notfully functional in the fetus or neonate. Thus,exposure to EDCs during this period can causeadverse effects, some of which are not apparentuntil much later in life. This point is bestillustrated by prenatal exposure to the estrogenderivative diethylstilbestrol (DES), which waswidely used until the 1970s as an antimiscar-riage medication; this early exposure impairedreproduction later in life (85). Mice exposedto low DES doses during pregnancy producednormal-sized offspring but later showed anage-dependent increased body weight gain and

    altered obesity-related gene expression. Prena-tal exposure to DES also led to elevated serumlevels of leptin, adiponectin, interleukin (IL)-6,and triglycerides in mice prior to their becom-ing overweight and obese (86). With regard toEDCs, the effects of prenatal exposure to BPAare well documented. In contrast to the reducedbody weight associated with BPA exposure inadult rodents, exposure to BPA during fetallife resulted in an increase in adult body weight(87). In rats, perinatal exposure to low BPAdoses increased adipogenesis and body weightin adult females, which exhibited adipocytehypertrophy and overexpression of lipogenicgenes (88). Accordingly, high- or low-doseexposure to BPA during gestation to pubertyleads to hyperlipidemia with increased bodyand adipose tissue weight in both sexes (89).

    An epigenetic mechanism has been pro-posed to explain these transgenerational ef-fects. Epigenetic changes are inherited changesin phenotype or gene expression caused bymechanisms other than changes in the underly-ing DNA sequence. Epigenetic effects involvemodifications in the activation of certain genes.It is thus hypothesized that EDCs impact obe-sity via estrogen-driven epigenetic reprogram-ming of gene activity during development (90)(see Figure 1).

    3.1.2. Metabolic disruption through inap-propriate activation of thyroid hormone re-ceptor and glucocorticoid receptor. EDCsmay also modulate other hormone nuclear re-ceptors, particularly thyroid hormone receptor(TR) and glucocorticoid receptor (GR). MostTH activity is mediated by the TRs TR andTR, which form heterodimers with RXR tobind the promoter sequences of target genes.TR agonists relieve the repression that unli-ganded TRs may exert on some target genes,thus further inducing gene expression. In addi-tion to an important role in brain development,THs are tightly associated with metabolism.Elevated TH levels accelerate metabolism, in-crease lipolysis as well as hepatic cholesterolbiosynthesis and excretion, and provoke weight

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    Pregnane X receptor(PXR): a nuclearreceptor known as axenosensor and masterregulator ofdetoxificationpathways; known assteroid X receptor inhumans

    Constitutiveandrostane receptor(CAR): a nuclearreceptor known as axenosensor and masterregulator ofdetoxificationpathways

    AhR: arylhydrocarbon receptor

    Cytochrome P450(CYP) family: a largeand diverse group ofenzymes playing animportant role in thedetoxificationpathways. Theirsubstrates includemetabolicintermediates andxenobiotic substances

    loss. The exact opposite results are observedwith low TH levels.

    In contrast to TR, GR forms homodimersand resides in the cytosol, forming complexeswith molecular chaperones. Ligand bindingreleases the chaperones, triggers GR nucleartranslocation, and influences gene expression.Glucocorticoids acting through GRs allow anorganism to adequately respond to physical oremotional stresses by promoting gluconeogen-esis, increasing blood glucose levels, and mo-bilizing the oxidation of fatty acids. The phar-macological uses of glucocorticoids, chiefly inthe context of controlling chronic inflamma-tion, have serious metabolic side effects such asdiabetes, muscle wasting, and growth retarda-tion in children.

    EDCs also interact with these TR and GRreceptors. For instance, in differentiating 3T3-L1 cells, BPA and dicyclohexyl phthalate stim-ulate GR-mediated lipid accumulation and syn-ergize with a weak GR agonist to increaseexpression of adipocyte-specific markers (91).BPA may also act as an antagonist of the TRpathway by enhancing recruitment of the core-pressor NCoR to TR (92). In parallel, perinatalexposure of BPA increases levels of thyroxine(T4) (93). Given the important role of TH inenergy homeostasis, BPA effects on TR dur-ing development may be important in long-term body weight increase. BFRs also disruptthe TH pathway, and daily exposure of rats toPBDE over four weeks resulted in a significantincrease in lipolysis and a significant decreasein glucose oxidation, characteristics associatedwith obesity, insulin resistance, and type 2 di-abetes, although such exposure had no effecton body weight and adipocyte size. Althoughthe underlying molecular mechanisms remainto be experimentally addressed, these physio-logical effects are consistent with a change inER and TR pathways (94, 95).

    3.2. Metabolic DisruptionThrough Xenosensors

    The body is protected from the accumulationof toxic chemicals by a complex strategy that

    in part takes place in the liver, regulating theexpression of drug-metabolizing enzymes andtransporters. This adaptive response incorpo-rates at least three xenosensors: pregnane X re-ceptor (PXR), constitutive androstane receptor(CAR), and aryl hydrocarbon receptor (AhR), aswell as xenobiotic metabolism and transportersystems.

    3.2.1. Pregnane X receptor and constitutiveandrostane receptor. PXR and CAR aremembers of the NR superfamily of sensorreceptors, and although they were originallydefined as xenosensors involved in regulatingthe metabolism of xenobiotics, their contribu-tion to fatty acid, lipid, and glucose metabolismhas been only recently appreciated (96, 97).

    PXR and CAR regulate gene expression byforming heterodimers with RXR that bind toxenobiotic response sequences present in thepromoters of their target genes. However, theirmechanisms of activation differ. PXR is locatedprimarily in the nucleus and is strongly acti-vated upon ligand binding. In contrast, in theabsence of ligand, CAR is retained in the cy-toplasm through association with the cytoplas-mic CAR-retention protein (CCRP) and heat-shock protein 90 (HSP90). In the presence ofactivators, CAR dissociates from its two chap-erones and translocates into the nucleus, whereit forms heterodimers with RXR (reviewed inReference 98).

    PXR and CAR are highly expressed in theliver, where they act as master regulators ofdetoxification pathways through induction ofphase I to phase III enzymes. In the first phase,a polar group is added to hydrophobic sub-strates by hydroxylation and oxidation via thecytochrome P450 (CYP) mono-oxygenase sys-tem. CYP3A is responsible for the metabolismof up to 60% of the drugs presently on themarket (reviewed in Reference 94) and is amajor target gene of PXR, whereasphenobarbital-induced activation of CARtriggers the expression of CYP2B. Phase IIenzymes increase hydrophilicity of the com-pounds through various conjugation reactions,and phase III involves transporters that allow

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    Peroxisomeproliferatoractivated receptor(PPAR): PPAR,-/, and - arenuclear receptors thatplay a prominent roleas lipid sensors

    for removal of these compounds throughsecretion. Along these three phases, PXRand CAR have common target genes such asthose encoding glutathione-S-transferase andmultidrug resistance protein (MRP)2 and -3;these receptors also have distinct targets such asmultidrug resistance gene (MDR1) and MRP1,respectively. Thus, the combined activities ofPXR and CAR modify and eliminate nearly alltoxicants encountered by the living organism.

    With the above in mind, ligands andactivators of PXR and CAR come from twomain sources. First, endogenous ligands forhuman PXR include some bile acid derivatives,pregnanes formed from cholesterol as imme-diate precursors of progesterone, and othermetabolic products of steroids. The ligandsof CAR are less promiscuous than those ofPXR, perhaps due to the smaller size of theCAR ligand-binding pocket. Examples of CARligands include the androstane metabolites andsteroid metabolites. This situation supports thehypothesis that PXR and CAR play an impor-tant role in endocrine system regulation. Theactivity of PXR is, however, defined primarilyby its interaction with exogenous compounds,including herbal medicines and pharmaceuticaldrugs (such as rifampicin), synthetic gluco-corticoids (such as dexamethasone), or steroidhormones (DES, 17-estradiol). CAR alsoresponds to exogenous compounds such asphenobarbital, which induces CAR nucleartranslocation, or the well-characterized ligandTCPOBOP. A number of EDCs activate PXRand CAR; both may be activated by nonylphe-nol, DEHP, and MEHP. BPA and some PCBsactivate human PXR, whereas PFOA, PFOS,and the organochlorine methoxychlor canactivate CAR (99102).

    As mentioned above, PXR and CAR wereidentified chiefly as xenobiotic-metabolizingregulators; however, clinical observations re-vealed that many CAR and PXR activators af-fect lipid and glucose metabolism in patients.For instance, the known PXR activator ri-fampicin induced liver steatosis in tuberculosispatients (103), and long-term treatment withphenobarbital provoked significant changes in

    hepatic and plasma metabolite profiles (104,105). Furthermore, laboratory animal and invitro studies show a similar trend: PXR acti-vation induced a steatogenic effect in rat andmouse liver (106108), and CAR and PXR ac-tivators repressed hepatic gluconeogenic en-zymes and genes (109111). CAR was recentlydescribed as an antiobesity NR that amelio-rates diabetes and fatty liver (112, 113). Inaddition to direct effects of PXR and CARon lipid and glucose metabolism, PXR and/orCAR indirectly affect these pathways by in-terfering with other regulatory pathways andNRs (114) (see Figure 2). CAR and PXR bindother transcription factors like forkhead boxesA2 and O1, inhibiting their DNA binding (96).PXR and CAR may also compete for the DR1-binding site recognized by the NR hepatocytenuclear factor 4 (HNF4) and peroxisomeproliferatoractivated receptor (PPAR). Fi-nally, PXR and CAR can also exert an inhibitoryeffect by targeting common coactivators likePPAR coactivator 1 (PGC1), which inter-acts with many transcription factors to regulatemetabolic homeostasis (96).

    The activation of PXR and CAR by EDCsmay account for the metabolic responses notedafter exposure to these chemicals. For example,DEHP induces CAR-dependent activation ofthe nuclear receptor Rev-erb pathway, whichin turn helps to control the cellular clock andfunctions in energy metabolism (101). BecausePXR and CAR regulate several CYP familymembers involved mainly in the metabolismof steroids and other endogenous compoundslike sex steroid hormones, their EDC-mediatedactivation may alter metabolism indirectly bychanging the effective concentrations of thesehormones (see Section 3.1.1) (98). Althoughthese hypotheses are appealing, to date no stud-ies have established a clear link between EDCsand metabolic disorders via PXR and CAR.

    3.2.2. Aryl hydrocarbon receptor. AhR isa ligand-activated transcription factor thatbelongs to the basic helix-loop-helix Per-ARNT-SIM (bHLH-PASwhere Per denotesthe Drosophila melanogaster clock gene Period;

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    ARNT denotes aryl hydrocarbon receptor nu-clear translocator; and SIM denotes a neurode-velopmental regulator in flies, single-minded )family of proteins. AhR is a xenosensor that me-diates the biological response to a wide spec-trum of xenobiotics; in particular, AhR is themajor factor sensing and mediating the toxiceffects of the dioxin TCDD.

    The nonactivated AhR protein resides inthe cytosol and, upon ligand-mediated activa-tion, translocates into the nucleus, where it het-erodimerizes with the ubiquitously expressedARNT, a member of the same protein fam-ily. The AhR/ARNT complex binds to specificregulatory DNA sequences to regulate geneexpression. AhR activity may also be medi-ated by alternative ligands and by an ARNT-independent mechanism, although details ofthese mechanisms remain poorly understood(116).

    Among the targets involved in detoxifica-tion, AhR target genes include the phase Ienzyme CYP1A1 and the phase II enzymesUGT1A1 and UGT1A6. In addition, AhR maycontribute to the coordinated regulation of hu-man drug-metabolizing enzymes and conjugatetransporters by inducing PXR and CAR expres-sion (117). Endogenous molecules that bindAhR and benefit from detoxification activity arelipoxin 4 and leukotriene derivatives, as wellas the heme metabolites biliverdin and biliru-bin. Xenobiotics that activate AhR include var-ious dietary phytochemicals, some PCBs, andTCDD. Because it is very poorly metabolized,TCDD triggers sustained activation of AhR,contributing to the toxic effects of dioxin. Thesetoxic effects thereby highlight the undesiredevents that may occur through inappropriateAhR activation and reveal a subset of AhR tar-get genes unrelated to detoxification. These tar-gets include the CDK inhibitors p21CIP1 andp27Kip1 (118), which may explain the broad roleof AhR in organogenesis, embryonic develop-ment, the cell cycle, immunosuppression, andcarcinogenicity.

    Recently, AhR has been implicated as a reg-ulator of energy metabolism. Epidemiologicalstudies show an association between dioxin ex-

    EDCe DNA-binding competition

    NR2

    NR1

    f Proteasome activation

    Proteasome

    +

    NRE1 +

    a Activation or modulation

    NR1coAct

    NRE1

    b Inhibition

    NR1coRe

    NRE1

    c Squelching

    NR1

    NR2coAct

    +

    NRE1NRE2

    d Synergism or inhibition

    NR2 NR1

    NRE1

    NR2NR1

    Figure 2Endocrine-disrupting chemicals (EDCs) interfere with nuclear receptor (NR)signaling via multiple mechanisms. In this figure, NR1 and NR2 are genericnames for the NRs discussed in the text. EDCs can act as direct agonists orantagonists of NR1, taking the place of the endogenous ligand. They can directthe recruitment of coactivators (coAct) by the NR and trigger target genetranscription, although some EDCs act as modulators rather than as fullagonists by inducing the recruitment of only some of the coactivators. EDCsthat act as antagonists favor conformational changes that allow for therecruitment of corepressors (coRe) or inhibit DNA binding and target geneexpression (a,b). Moreover, EDCs can interfere by indirect mechanisms: EDCbinding to NR2 leads to disturbances of NR1 signaling via molecular cross-talksuch as competition for coactivators (c) or for DNA-binding sites (e). Otherindirect mechanisms are the binding of NR1 and NR2 to neighboringsequences, which may lead to either synergism or inhibition of the regulatoryactivity (d ) or to the EDC-mediated activation of NR2, which results in NR1degradation through proteasome activation ( f ). NRE1/NRE2, nuclearreceptor response element 1 and 2.

    posure and type 2 diabetes (25). Other stud-ies also demonstrate that high and low dosesof dioxins affect genes in an AhR-dependentmanner linked with hepatic circadian rhythm,cholesterol biosynthesis, fatty acid synthesis,glucose metabolism, and adipocyte differenti-ation (119, 120). The mechanisms by whichAhR regulates energy metabolism are not yetwell described, but various direct and indirectmechanisms including cross-talk with ER maybe involved. AhR may disrupt the ER signal-ing pathways through increased ER proteaso-mal degradation, modulating estrogen levels via

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    CYP expression, altering ER transcriptional ac-tivity via coactivator squelching, or promot-ing DNA-binding competition (121, 122) (seeFigure 2). In addition, AhR also indirectlyaffects adipogenesis through inhibition ofPPAR expression (123).

    Additional experimental and epidemiologi-cal studies are still required to assess whetherAhR-mediated responses affect metabolism inaddition to the well-known roles of Ahr in im-munity, development, and cancer.

    3.3. Metabolic Disruption ThroughPeroxisome ProliferatorActivatedReceptors

    Metabolic homeostasis requires a controlledbalance between energy storage and consump-tion; several NRs and their coregulators are in-strumental in these processes. Among these, thePPARs act as lipid sensors that cooperate indifferent organs to adapt gene expression to agiven metabolic status. PPARs are sensor recep-tors with a rather large ligand-binding domain,which can accommodate a variety of ligands,primarily lipid derivatives. In the presence ofligand, PPARs heterodimerize with RXR andbind to the PPAR response elements localizedin the promoter regions of their target genes(124).

    The PPAR family is composed of threeisotypes: PPAR, -/, and -. PPAR is ex-pressed predominantly in tissues characterizedby a high rate of fatty acid catabolism such asliver, kidney, heart, and muscle. PPAR wasfirst identified as the protein responsible forthe induction of peroxisome proliferation inrodents exposed to a variety of compoundscollectively termed peroxisome proliferators.However, humans do not undergo peroxisomeproliferation and are thereby protected fromthe consequent liver tumors observed insensitive species. PPAR plays a major role infatty acid oxidation in all species, controllinglipoprotein metabolism and limiting inflamma-tion. PPAR is ubiquitously expressed, sharespartially overlapping functions with PPAR,and also plays a role in cell differentiation and

    survival (125, 126). Finally, PPAR functionsin adipogenesis, lipid storage, and the controlof insulin sensitivity; it also participates ininflammatory responses (127).

    Plasticizers, surfactants, pesticides, anddioxins can modulate PPAR activity, althoughfairly little is known about the molecular mech-anisms and the physiological outputs involved.The specificity of this PPAR-mediated re-sponse is highlighted in a study in which200 pesticides were systematically screened fortheir peroxisome proliferation activity. Onlythree compounds were identified as havingPPAR transcriptional activity, and none pos-sessed PPAR transcriptional activity (127).Among these pesticides, diclofop-methyl andpyrethrins induced PPAR target gene expres-sion at levels similar to those induced by classicagonists in mice (128, 129).

    The phthalates are another group of well-characterized peroxisome proliferators (130).In vitro transactivation assays and intact cellu-lar systems were used to reveal that phthalatesand their metabolites bind and activate the threePPARs, among other NRs (131134). Thesestudies also determined the range of potencyand efficacy of phthalate monoesters, show-ing differences between isotypes and species.Modeling the DEHP metabolite MEHP in thePPAR ligand-binding pocket indicates thatMEHP may contact residues similar to thosedefined for the classic PPAR agonist rosigli-tazone (135). MEHP induces adipogenesis in aPPAR-dependent manner, albeit with lowerefficiency than rosiglitazone in 3T3-L1 cells(134). Accordingly, gene expression microarrayanalyses indicate that 70% of the genes are reg-ulated by either ligand, some of them to differ-ing degrees. However, 30% of the genes are ex-clusively regulated by rosiglitazone and not byMEHP, suggesting that MEHP acts as a selec-tive modulator of PPAR rather than as a fullagonist. This differential activity results fromthe different abilities of MEHP and rosiglita-zone to induce the release of corepressors suchas NCoR and the recruitment of coactivatorssuch as p300 or PGC1 (133). Taken together,these in vitro data demonstrate that MEHP is

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    proadipogenic in a cell culture model, suggest-ing that it may act as a metabolic disruptor andmay promote obesity in vivo.

    Paradoxically, in vivo experiments partiallycontradict these results (136). Adult micetreated with high or low doses of DEHP areprotected from weight gain, gaining 30% lessweight than controls. These mice possess a re-duced fat mass and a metabolic improvement,with lower levels of triglycerides in the liver andthe blood, smaller adipocytes, and enhancedglucose tolerance. These effects were not ob-served in PPAR-null mice, confirming thatin vivo DEHP activity is mediated primarilyby PPAR in the liver, leading to increasedfatty acid catabolism and induced expressionof PPAR target genes such as that encodingfibroblast growth factor 21 (FGF21) (137) orgenes controlling fatty acid -oxidation. Sur-prisingly, this phenotype is also completelyabolished in PPAR-humanized mice (mice inwhich the mouse PPAR alleles are replaced bythe human PPAR gene). These mice, whenexposed to a DEHP-containing diet, tend tobe more sensitive to diet-induced obesity thanare untreated controls (136). These observa-tions point to the possibility of species-specificEDC activity, due at least in part to evolution-ary differences in the receptors interacting withthem.

    Studies of phthalate exposure in utero haveyielded dissimilar results. Male and female off-spring of rats exposed to diisobutyl phthalateand butylparaben exhibit reduced plasma lep-tin and insulin levels, similar to the modifi-cations observed upon in utero exposure torosiglitazone (138). In contrast, a study evalu-ating the impact of in utero exposure to DEHPcould not identify parameters indicating adultmetabolic disorders (6). These differences maybe attributable to the compounds tested as wellas the specific experimental protocols. In anycase, these studies highlight the necessity to in-vestigate the risks engendered by fetal exposureto phthalates.

    The PFCs, particularly PFOA and PFOS,can also activate mouse and human PPARs intransactivation assays (139), although the in

    vivo consequences of such activity remain quitecontroversial. Adult mice exposed to high dosesof PFOA exhibit weight loss, which is abro-gated in PPAR-null mice (140). The pro-posed mechanism involves PPAR-dependentanorexigenic activity in the hypothalamus ofadult rodents (141). In contrast, Hines et al.(142) reported that PFOA has no effect on bodyweight gain when exposure occurs at the adultstage. However, developmental exposure to lowPFC levels results in increased body weightand increased serum insulin and leptin levelsat midlife (142). Again, species-specific PPARactivity was proposed because low doses ofPFOA significantly activate the function ofPPAR in wild-type mice but not in PPAR-humanized mice. Human PPAR may there-fore be less responsive to PFOA, increasingthe possibility of species-specific EDC activ-ity. More specifically, the extent to which thesePPAR activators influence metabolic home-ostasis in humans deserves more study (143).

    Several EDCs also specifically targetPPAR. Using a high-throughput method,Kanayama et al. (31) showed that among 40EDCs, organotins such as TBT and TPTOare activators of human PPAR and RXR.TBT binds to and activates the three humansubtypes of RXR as well as many permissiveheterodimeric partners such as liver X receptor(LXR), nuclear receptorrelated 1 protein(NURR1), PPAR, and PPAR, but notPPAR. Organotins bind and activate, pri-marily through RXR and not through PPAR,the PPAR:RXR heterodimer at nanomolarconcentrations. The crystal structure of theRXR ligand-binding domain bound to TBTindicates that TBT binds with high affinity toRXR, even though TBT is structurally distinctfrom above-described ligands and only partlyoccupies the RXR ligand-binding pocket(144). Consistent with the critical role playedby PPAR:RXR signaling in mammalianadipogenesis, TBT promotes adipogenesisin 3T3-L1 cells by direct transcriptionaleffects on the PPAR target genes. In uteroexposure to TBT in rodents led to alter-ations in fat structure and metabolism, with a

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    disorganization of hepatic and gonadal archi-tecture, steatosis in the liver, and an increase inlipid accumulation and mature adipocytes. Thefat massbut not the total body weightof inutero TBT-treated mice significantly increasesin adulthood, supporting the conclusion thatembryonic and chronic lifetime organotinexposure may contribute to the incidence ofobesity through disruption of the PPAR:RXRpathway (28).

    Altogether, these many examples of EDCinteraction with receptors highlight the factthat a given compound can interfere withdifferent NRs and different pathways (seeTable 1). For example, depending on the com-pound, BFRs interface with AR, ER, and pro-gesterone receptor to elicit both agonist- andantagonist-like effects (94). PBDEs bind but donot activate AhR (145); in contrast, they in-duce the expression of various CYP enzymes,in part through the activation of PXR (146,147). PBDEs are also active in TH regula-tion by disrupting peripheral TH transport andmetabolism/deactivation or by binding and ac-tivating TRs (148, 149). The final consequencesof EDCs exposure are thus due to cross-talk be-tween these pathways, rather than to a linearcausation chain (96, 114, 122, 123, 150), andare much more complex to decipher in vivo.

    4. METABOLIC DISRUPTORS:TOWARD MANY CHALLENGES

    This review emphasizes the remarkable emer-gence of EDC-related research, which hasshifted focus from endocrine disruption tometabolic disruption. Epidemiological studiesthat underscore the parallels between EDC ex-posure and obesity incidence, as well as animallaboratory studies that demonstrate the abilityof EDCs to act on metabolic transcription fac-tors, are lines of investigation that cannot becasually discounted. However, there are manydifficulties to overcome before one can fairly as-sess the risks that past, present, and future envi-ronmental chemicals engender on human andwildlife health. In this last section, we highlight

    some of the important questions that remain forresearchers and regulators.

    4.1. Monitoring Exposure Levels

    Ambient monitoring is performed by samplingair, dust, water, etc., and by measuring the lev-els of the pollutants of interest in these samples.This method is often reasonably easy and reli-able. However, ambient monitoring provides avalue valid only at the time of sampling, whichmay not reflect levels of chronic exposure; it alsodoes not take into account the efficiency withwhich living organisms breathe, ingest, or ab-sorb these compounds. In that respect, biomon-itoring is a more appropriate evaluation of thepresence of compounds or their metabolites inbiological samples, particularly in blood andurine, and ideally in tissue samples. Biomoni-toring does not identify the source of the con-tamination but provides the individual expo-sure level at a given time point. Biomonitoringassays also reflect past exposure to persistentpollutants. However, biomonitoring is invasiveand costly and cannot be proposed as a standardroutine evaluation, except for occupational ex-posure. Alternatively, biomonitoring of wildlifesamples can be more easily performed and mayserve as a good indicator of exposure to somepollutants widely found in the environment.

    4.2. Identifying the MetabolicEffective Dose

    One current issue in identifying the metaboliceffective dose concerns the so-called U-shapedor inverted U-shaped dose-response curve. Adose-response curve of this form is reportedfor BPA: Effects are observed at very low doses(from 1012 M) and at high doses (108 M), butno effects are observed at intermediate doses(109 M). These U-shaped curves suggest theexistence of two independent mechanisms forlow doses and high doses (151, 152). However,mechanistic studies are still lacking, and evi-dence for low-dose activity is not available inepidemiological studies.

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    A second complication is exposure to a mix-ture of EDCs rather than to a single EDC. Hu-mans and wildlife are exposed daily to a varietyof compounds, and it is thus likely that even ifnone of the compounds reach an effective level,the combination or mixture of chemicals maybecome effective. This scenario is supported bythe observation that various EDCs share re-ceptors, and thus additive effects should be ob-served (see Figure 1; Tables 1 and 2). Fewexperimental studies addressing this issue ex-ist, and given the vast number of EDCs, it isunclear how to monitor exposure and how touse or develop assays that capture the effects ofthese mixtures. At a practical level it is also un-clear how regulatory decisions will be amendedto account for exposure to mixtures rather thanto single compounds.

    4.3. Establishing the Link BetweenExposure and Metabolic Effects

    Metabolic alterations such as metabolic syn-drome and type 2 diabetes are complex andmultifactorial. Elevated body mass index andobesity are not diseases but rather contributeto various alterations that lead to the diseasedstate. EDC exposure is one more factor thatincreases an already long list of predisposingfactors that act in combination to increase therisk of obesity or other metabolic alterations.Such contributions can be revealed only bycomprehensive studies of large and well-characterized cohorts, such as the cohort usedfor the NHANES project (see sidebar entitledNHANES). However, these studies are cross-sectional (see sidebar entitled ObservationalStudies), due to the difficulties inherent in theevaluation of exposure, and may be subjectto unidentified confounding factors. At best,these studies can demonstrate correlations butnot causal links between exposure and effects.

    4.4. Experimental Exploration of theMetabolic Disruption Properties ofEndocrine-Disrupting Chemicals

    How can we reach the most appropriate un-derstanding of EDC biology that will help to

    define appropriate actions? Although cellularmodels are flexible and allow large numbersof conditions and doses to be tested, they arelimited and unable to factor in bioavailabil-ity of the compounds and their metabolites orthe route of exposure. Reductionist molecu-lar and cellular studies may not take into ac-count the knowledge that several EDCs inter-fere with a variety of NRs, not all of whichare expressed in the same tissue or at the sametime. Additionally, EDCs can affect several or-gans in the body with different intensities, lead-ing to a global response that may be oppositeof that observed in cell cultures. Experimen-tation in animals is therefore unavoidable, asanimals are threatened by environmental con-taminants and provide a reasonable approxi-mation of human metabolism for most com-pounds. However, two main issues must beconsidered. First, EDC-interacting receptorsdisplay species-specific activity that is well de-scribed for PPAR, PXR, and CAR (98, 136).The development of humanized mice, in whichthe gene of the receptor of interest is exchangedfor the human allele, provides new tools for thistype of investigation (136, 143). Second, issuesof dose and exposure time complicate exper-imental design (see Table 2). Mice may livefor two years, and a three-month exposure canbe considered chronic. Does this experimentalsetup accurately reflect the decades over whichhumans might be exposed?

    4.5. Exposure During Critical Periodsof Development

    The dramatic effect of DES exposure on femalebabies illustrates the critical issue of exposureduring development (see Section 3.1.1). Con-sistent with the well-known functions of clas-sic hormones in developing reproductive or-gans, the effects are easily understood whenthese hormones are disrupted or mimicked.Even disregarding transgenerational effects, themetabolic consequences of prenatal exposurethat manifest in adulthood are difficult to as-sess and to understand. As discussed above (seeSection 3.1.1), controversy surrounds many of

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    these consequences, and only systematic animalstudies may lead to a fair risk evaluation. Futureefforts should be aimed at elucidating whetherand how epigenetic imprinting is involved inthese pathologies (153).

    4.6. How Should New ChemicalsBe Regulated?

    As described in Table 1, several chemical prod-ucts are either totally banned or authorized foruse under strict conditions. Banning a persistentorganic pollutant will immediately limit expo-sure, but a number of years will pass before thechemical is entirely suppressed, and such sup-pression will occur only if large transnationalterritories ban the chemical of interest (seeTable 2). Inevitably, banned products are re-placed by others that bring other unwanted ef-fects. How do we establish the most pertinentand effective modes of risk evaluation not onlyfor the present but also for any future com-pound released to consumers?

    From the research point of view, recent yearshave witnessed many efforts to set up new tech-nologies for EDC detection in human tissues,including scenarios of low doses, nonpersistentEDCs, and the developmental period (27, 56,67). New integrative approaches combining ge-nomics, proteomics, metabolomics, systems bi-ology, and computational modeling should helpto understand the complexity of the cocktail ef-fect and its consequences when exposure occursat various life stages (101, 150, 154). In addi-tion, these approaches should help to evaluate

    the global effects of EDC interference with dif-ferent NRs and the activation of a complex bi-ological network. Before reaching this level ofunderstanding, these integrative strategies mayhelp define a signature: a composite signal ofno explanatory value but reflecting exposure tometabolic disruptors. Such a signature may helpin experimentally establishing a predictive valueto new compounds.

    From the regulatory point of view, govern-ments face the challenge of making appropri-ate decisions by balancing potential risks againstdemonstrated advantages. Help for future deci-sions will come from two complementary pro-cesses. The first process is illustrated by theEuropean Registration, Evaluation, Authorisa-tion, and Restriction of Chemicals (REACH)program, aimed at protection of human healthand the environment through systematic reg-istration, assessment, and annotation of an ex-haustive list of industry compounds. The sec-ond process encourages research through grantsubsidiaries, as illustrated by the recent financ-ing of BPA research by the National Insti-tutes of Health (NIH). These initiatives includeincentives for transparency and collaboration,both at the level of government and betweenscientists. Metabolic perturbations are only onesmall aspect of the EDC-related problems tobe solved, but what we know now may be onlythe tip of the iceberg. In the present context ofendemic metabolic disorders, with severe eco-nomic, social, and professional consequences,every action first to understand and then to con-trol risk factors is beneficial on all counts.

    SUMMARY POINTS

    1. Increasing human exposure to endocrine-disrupting chemicals (EDCs) has been asso-ciated with the development of some of the main ailments of the industrialized world,particularly metabolic disorders like obesity, diabetes, and metabolic syndrome.

    2. Among different mechanisms of action, lipophilic EDCs compounds can bind specificallyto nuclear receptors and can displace the corresponding endogenous ligands to modulatehormone-responsive pathways.

    3. Persistent organic pollutants such as organochlorine pesticides, dioxins, and polyfluo-roalkyl compounds and nonpersistent pollutants such as bisphenol A and several phtha-lates are suspected of metabolic disruption activity.

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    4. A major mechanism of EDC-mediated metabolic disruption is through EDC interactionwith nuclear receptors, including (a) sex steroid hormone receptors, (b) receptors actingas xenobiotic sensors, and (c) receptors specialized in metabolic regulations.

    5. This field is littered by controversies, in part due to the difficulties in proving or disprovingEDC activity. The major issues are the monitoring of exposure levels, the identificationof the metabolic effective dose, and the establishment of a link between (a) either expo-sure during critical periods of development or chronic exposure at very low doses and(b) metabolic effects. Finally, this area of research would benefit tremendously if com-mon methodologies of experimental EDC exposure were established. All these issuesneed further work to create a common and effective regulatory policy for environmentalchemical pollutants.

    DISCLOSURE STATEMENT

    The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

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