Distruptores Metabolicos (Articulo Referencial Para Examen)

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Endocrine Disruptors:From Endocrine to Metabolic DisruptionCristina Casals-Casas and Beatrice DesvergneCenter for Integrative Genomics, Faculty of Biology and Medicine, University of LauLausanne, 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 Physiologyis 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

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

Abstract Synthetic chemicals currently used in a variety of industrial and cultural applications are leading to widespread contamination oenvironment. Even though the intended uses of pesticides, plasters, antimicrobials, and ame retardants are benecial, effects onman health are a global concern. These so-called endocrine-disrupchemicals (EDCs) can disrupt hormonal balance and result in devemental and reproductive abnormalities. New in vitro, in vivo, anddemiological studies link human EDCexposure with obesity, metabsyndrome, and type 2 diabetes. Here we review the main chemical cpounds that may contribute to metabolic disruption. We then prestheir demonstrated or suggested mechanisms of action with respenuclear receptor signaling. Finally, we discuss the difculties of assessing the risks linked to EDC exposure, including developmexposure, problems of high- and low-dose exposure, and the comity of current chemical environments.

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EDCs: endocrine-disrupting chemicals

Metabolic syndrome:a combination of disorders 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 healthand reproduction

in 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-pliedby twofactors, theexpansioninchemical

production, which hasnowreached 400milliontons globally, and the increased pollution fromthese chemicals. As such, the impact on humanhealth through known or unknown effects of these chemicals on hormonal systems is great.

The term endocrine disruptors was rstcoined by Ana Soto and collaborators, whoidentied 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 interference with 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 linked with EDCs. Globalobesityrates have risen dra-matically over the past three decades in adults,children, and adolescents, especially in devel-oped countries.Obesityis frequently associated with metabolic disorders (including type 2 dia-betes, metabolic syndrome, cardiovascular andpulmonary complications, and liver disease) as well as other health issues such as psycholog-

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

A combination of genetic, lifestyle, and e vironmental factors likely account for the rapand signicant increase in obesity rates. Athough genetic factors may explain a portioof obesity predisposition, they alone are unab

to account for the sudden appearance and progression of the current worldwide obesity epdemic. Modern lifestyles that include excessienergy intake, lack of physical activity, sledeprivation, and more stable home temperatures appear to be major contributing factorof obesity. However, the increased incidencof metabolic diseases also correlates with sustantial changes in the chemical environmenresulting from new industrial and agriculturprocedures initiatedoverthe past 40years.Thichange in the environment has led to the hypothesis that some of the numerous environmental pollutants are EDCs, interfering with various aspects of metabolism and adding aother risk factor for obesity (4, 5). This hypothesis is supported by laboratory and anmal research as well as epidemiological studthat have shown that a variety of environmetal EDCs can inuence adipogenesis and obsity (reviewed in References 510). Such EDChave been referred to as environmental obesogens (11). However, because adverse effects EDCs may also lead to other metabolic diseasesuchasmetabolicsyndromeandtype2diabetesthis subclass of EDCs would be better referreto as metabolic disruptors (12).

1.3. A Common Molecular Mechanism for Endocrine Disruption and Metabolic Disruption Hormones function mainly through interac-tions with their cognate receptors, which canbeclassied into two large groups: (a) membranebound receptors, which respond primarilto peptide hormones such as insulin, an(b) nuclear receptors (NRs), which are activateby interaction with small lipophilic hormonesuch as sex steroid hormones. EDCs may posess multiple mechanisms of action; howeve

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Estrogen receptor(ERs): ER and are members of thnuclear receptorsuperfamily. Theyform homodimerbind to DNA Retinoid X recept(RXR): a membethe nuclear receptsuperfamily and amajor partner of onuclear receptorsas PPAR, PXR, aCAR, with whichforms heterodime

Persistent organicpollutants: chem

that persist in theenvironment andbioaccumulate wirisks of adverse eto human health aenvironment

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), thereby disrupting 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 tospecic 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 of the complexities of metabolic homeostasis anddevelopment. The ability of EDCs to interact with 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 rst section discusses the chemical com-pounds that are presently considered to be major 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 metabolicdisruption.The last sectionhighlights the main challenges that scientistsand regulators face in this eld.

2. A MYRIAD OF ENDOCRINE-DISRUPTINGCHEMICALSEDCs 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 theworld (1317). Persistent organicpollutants are prevalent among environmen-

tal contaminants because they are resistant tocommonmodesofchemical,biological, or pho-tolytic degradation.Moreover, many EDCs canbe stored for years in animal and human fatmass. However, other EDCs that are rapidly degraded 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-goriesof chemicals with suspected metabolism-disrupting activity are presented below (see Tables 1 and 2). For more detailed informa-tion, the interestedreadermayrefer to in-depthreviews focusedon specic chemical categories,as discussed below.

2.1. PesticidesPesticides are any substance or mixture of sub-stances intended forpreventing, 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 association with breast cancer is suspected but not yet

www.annualreviews.org Pollutants and Metabolic Disruption 137


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NHANES

The National Health and Nutrition Examination Survey (NHANES) is the American food consumption database pro-gram conducted by the National Center for Health Statistics,Centers for Disease Control and Prevention. This program was

designed to collect data and to assess the health and nutritionalstatus of adults and children in the United States. The programbegan in 1960, but in 1999 NHANES was changed to include thetesting of blood and urine for an extensive number of chemicalsand to monitor roughly 5,000 to 10,000 nationally representativepersons per year. All NHANES surveys are cross-sectional andcontain a core set of physical examinations, clinical and labora-tory tests, andpersonal interviews. Information about diseaseandhealthstatus,diet, sociodemographics, occupation, andeducationis collected. In addition, tests are conducted for a varietyof mate-rials, such as micronutrients, disease markers, and environmentalpollutants. NHANESs partnership with the EnvironmentalProtection Agency has also allowed for the implementation of longitudinal studies of many important environmental inu-ences on health [NHANES I Epidemiologic Follow-Up Study (NHEFS)]. NHANES and NHEFS data are public and availablefor researchers at http://www.cdc.gov/nchs/nhanes.htm .

PVC: polyvinylchloride

demonstrated by epidemiological studies (19). A well-documented case study in the UnitedKingdom listed 127 pesticides identied ashaving endocrine-disrupting properties (16).Despite confounding issues stemming fromthe multifactorial causes of disease and thechallenges in monitoring pesticide exposure,this study underscores the link between med-ical problems and pesticide exposure (16). With respect to metabolic disorders, a largenumber of epidemiological studies have alsolinked pesticide exposure with obesity, dia-betes, insulin resistance, and metabolic syn-drome (9, 20). For example, an association wasdiscovered between prenatal exposure to theDDT breakdown product dichlorodiphenyl-dichloroethylene (DDE) and increased body mass index in adult women (21). Similarly,cord blood levels of the OCP hexachloroben-zene correlated with a two- to threefold-higherrisk of an elevated body mass index and obe-sity in children (22). Another study used the

National Health and Nutrition ExaminationSurvey (NHANES) database and carried oua cross-sectional analysis of 1,721 adults (sNHANES and Observational Studies sidebars); the study reported a positive assocition between diabetes and the levels of 19 dferent persistent pollutants (including OCPs

measured in serum (21). Other epidemiological studies nd a signicant association btween pesticide exposure [mostly OCPs sucas heptachlore epoxide, oxychlordane, or hexachlorocyclohexane ( -HCH)] and higherincidences of metabolic syndrome, insulin rsistance, and diabetes (23, 24). A higher prevlence of diabetes is also associated with DDexposure (25).

2.2. DioxinsDioxins consist of a group of organochlrines that include the polychlorinated dibenzodioxins (PCDDs), the polychlorinated dibenzofurans (PCDFs), and the polychlorinatebiphenyls (PCBs) and other related compounds. Dioxins can be produced from natural sources such as volcanoes and foreres but are created mostly by human ativity as by-products in organochloride production, in incineration of chlorine-containingsubstances such as polyvinyl chloride (PVCand in bleached paper production. The PCDD2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)is the most toxic of all dioxins. This dioxin wa major contaminant in the Seveso catastrophand in the Vietnam War (Agent Orange); it wasalso used as a poison in the attempted assasnation of Viktor Yushchenko (17).

Dioxins are fat soluble and readily climb tfood chain via their bioaccumulation in fat tisues. They are neither readily metabolized noexcreted, and TCDD has a half-life of approximately 8 years in humans. Several epidemilogical studies have evaluated the toxic effects TCDDandothersdioxins on thegeneral popu-lation as well as heavilyexposed subgroups suas Vietnam War veterans (reviewed in Refeences 17 and 26). These studies demonstrate cause and effect between dioxin exposure, w



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PFCs: polyuorocompounds

an increase in cancers, nervous system degen-eration, immune damage, thyroid disease, andreproductiveandsexualdevelopmentdisorders. With respect to metabolism, exploration of theNHANES database indicated that PCDDs andPCDFs are weakly associated with metabolicdisorders, whereas PCBs are strongly associ-

ated with type 2 diabetes (27). Several cross-sectional investigations further supported thesecorrelations (reviewed in Reference 25).

2.3. OrganotinsOrganotins, including tributyltin chloride(TBT) andbis(triphenyltin) oxide (TPTO), arepersistent organic pollutants that have been widelyused as agricultural fungicides, as rodentrepellents, as molluscicides, and in antifoulingpaints for ships and shing nets. Organotincompounds such as PVC are also used to stabi-lize plastics.

TBT and TPTO provide one of the clear-est examples of environmental endocrine dis-ruption: Exposure of marine gastropods to very lowconcentrationsof thesecompounds inducesan irreversible sexual abnormality in femalestermed imposex, resulting in impaired repro-ductive tness and possibly sterility (28). Con-cerns over the toxicity of these compounds ledto a worldwide restriction and a ban on marineuses. Currently, human exposure may comefrom dietary sources, such as sh and shell-sh, or through contaminated drinking waterandfood.However,noepidemiologicaldata areavailableconcerninghuman exposure, although TBT has been reported to have modest adverseeffects on mammalian male and female repro-ductive tracts (29, 30). Nonetheless, recent ex-perimental studies revealed proadipogenic ac-tivity of TBT and TPTO (11, 31).

2.4. PlasticsOwing to their variety, robustness, and ex-tremely low costs, plastics are fundamental inmodernlife,publichealth, andmedicine; plasticproduction exceeded 300 million tons in 2010(32). After more than ve decadesof debate and

OBSERVATIONAL STUDIES

Different types of observational studies are detailed http://www.vetmed.wsu.edu/courses-jmgay/glossclinstudy.htm . A summary is presented below.

Clinical studies aimed at evaluating the effects of EDC ex

sure rely mainly on observational studies, which interpret expiments of nature and are exposed to large confounding biasHowever, such studies provide preliminary evidence to be uas a basis for hypotheses.

Cross-sectional studies examine the relationship between deases and other factors (such as EDC levels) at one point in tin a denedpopulation. Cross-sectional studies lack anyinformtionon timingof exposure andinclude only prevalentcases.Thcan suggest a link between a disease and the factor of interes

In longitudinal studies, or cohort studies, a panel of indivials is interviewed repeatedly over a period of time. This allow

prospective and analytical study of a group in which somedividuals have had, currently have, or will have the exposof interest to determine the association between that exposuandan outcome. Cohort studiesare stronger than cross-sectionaand case-control studies when well executed, but they are mexpensive.

Case-control studies are a retrospective comparison of tproportion of cases with a potential risk factor to the propotion of controls (individuals without the disease) with the sarisk factor. Due to the potential for many forms of bias in tstudy type, case-control studies provide relatively weak empirevidence, even when properly executed.

research, controversy still surrounds the risksthat plastics may cause in humans, particularly with respect to endocrine-disrupting proper-ties. Adverse effects can stem from the variouscomponents of plastics, the additives used, ora combination of both. Laboratory animal andepidemiological studies have studied the effectsof several of these substances on human health. A few examples are provided below.

2.4.1. Polyuoroalkyl compounds. Polyu-oroalkyl compounds (PFCs) are synthetic u-orinated organic compounds used in a widerange of industrial applications and consumerproducts, including paper, leather, textile coat-ings, and re-ghting foam, and in the polymer



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BFRs: brominatedame retardants

industry. Among them, peruorooctane sul-fonate (PFOS) and peruorooctanoate (PFOA)are widely detected in the environment. PFCsare classied as persistent organic pollutants,even though they are not stored in fat tissue butinstead form chemical adducts with liver andserum proteins. Laboratory rodents exposed to

PFCs exhibit developmental effects such as re-duced birthweightandincreased neonatalmor-tality (3335). In addition to hormonal pertur-bations with decreased testosterone levels andincreased estradiol levels in adult rats (36), re-ductions in serum cholesterol and/or triglyc-eride in mice and rats exposed to high doses of PFOS and PFOA (37) suggest that these chem-icals disturb normal lipid metabolism.

Inverse relationships were observed be-tween PFOS and PFOA concentrations in cordblood and birth weight, ponderal index, andhead circumference in children (38; reviewedin Reference 15). Numerous studies have eval-uated the possible associations of blood PFClevelswith metabolicparameters; themost con-sistent result is the positive association betweenPFC exposure and increased cholesterol, par-ticularly high-density lipoprotein (HDL) (3944). The same reports discounted any associa-tion with metabolic diseases such as type 2 dia-betes andmetabolic syndrome (3944) andsug-gested a complex positive correlation of PFClevels with hyperglycemia but an inverse corre-lation with metabolic syndrome in adolescents(45). Most of these studies are cross-sectionaland as such fail to provide a causal link butrather draw attention to the potential effects of PFCs on human physiology.

2.4.2. Brominated ame retardants. Bromi-nated ame retardants (BFRs), particularly polybrominated diphenyl ethers (PBDEs), areadditives used as ame retardants in a greatnumber of consumer products such as houseelectronic equipment, clothing, and furniture. Although these compounds have decreased reincidences, they are highly prevalent, ubiq-uitous, and persistent pollutants. The mainsources of human exposure come from indoorenvironments, diet, and occupational exposure

(13, 46, 47). Despite their benecial effectthese chemicals are also thought to adverseaffect human health through endocrine disruption and developmental neurotoxicity (48). Iaddition, increased incidences of hepatocellular carcinoma and thyroid adenoma have beeobserved in rodents, albeit with relatively hig

exposure doses (49). Taken together, these observations have led to the recent ban of PBDEin several American states and in the EuropeaUnion,where a ban onall BFR use isbeing contemplated. Meanwhile, PBDEs are still presenin environmental samples and are detected imilk, serum, and adipose tissue in animals anhumans.

Published studies addressing the consequences of human BRFexposure remainscarceand the effects of BFR exposure on sex sterohormone systems are still poorly understoodOne study demonstrated a correlation between PBDEs in breast milk and congenitacryptorchidism, although confounding factormay have been present (50). Only a few epdemiological studies have addressed the posible impacts of these persistent pollutants ometabolic parameters in humans. The mostelling study revealed that, among six dferent BFRs, PBDE-153 and the polybrominated biphenyl PBB-153 showed an inverteU-shaped association with type 2 diabetes anmetabolic syndrome (51). Clearly, more studies are needed to clarify the possible extent BFR-related damage.

2.4.3. Alkylphenols. Alkylphenols such as n-nonylphenol and 4-n-octylphenol are surfactants widely used in detergents, emulsierantistatic agents, demulsiers, and solubilizeand are found commonly in wastewater (52 They are also used as additives to plastics suas PVC and polystyrene, from which they caleach. Alkylphenols are capable of initiatiproliferation in breast tumor cells in the laboratory (53), consistent with their capacities foestrogenic and antiandrogenic activity (54, 5andreferencestherein).However,giventhelowenvironmental concentrations and the currenregulation of alkylphenol use in the Europea



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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 food

products. DEHP causes animal toxicity inmany physiological systems; however, many of the 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 classied 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 correlated with 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, livglycogen, T3, T4, thyroid-stimulating hor-mone, and cortisol was observed (71, 72). humans, the log-transformed concentrations ofseveral phthalate metabolites positively corrlated with abdominal obesity and insulin resitance in adult males (73). These analyses su

port the concept of environmental obesogenbut await further conrmation by longitudinastudies.

At rst glance, this presentation of so mantypes of chemicals suspected of generatimetabolic disruptors may seem alarming (se Tables 1 and 2). However, because many studies discussed here are cross-sectional, a dentivecausal link between metabolicdisordersanEDCexposure is still hypothetical. Forthat reason, parallel studies aimed at identifying thmolecularmechanisms of EDCactivity withregard to metabolism should provide greater insights into the real health risks posed by thecompounds.

3. METABOLIC DISRUPTION: MECHANISTIC APPROACHESIn the context of endocrine disruptionmetabolic disruption may result from thremain types of activity. First, hormones in general andsexsteroidhormones in particular contribute to general body homeostasis througdiverse metabolic regulations. Thus, a certainumber of metabolic perturbations are simplthe result of hormonal disruption. Second, direct EDC activity through receptors responding to xenobiotics and regulating xenobiotmetabolism may also contribute to a metabolphenotype. Third, EDC interactions with spe-cialized metabolic receptors may serve as a pmarymechanismformetabolicdisruption.Thiarticle presents and discusses experimental oservations linking EDCs with metabolic diruption along these three types of activity (sFigure 1 ).

3.1. Metabolic Disruption Through Hormone ReceptorsHormone receptors belong to a class of clasic hormone receptors that recognize only on



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

as 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 afnities forsome steroid hormones. In addition to their well-established roles in reproduction, ERandER areinvolved inbraindevelopmentandfunction of many other organs, such as skin,bone, and liver.

Several lines of evidence link ERs tometabolism. For example, in postmenopausal women and ovarectomized rodents in whichestrogen is low, one observes an increase in white 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 directly in 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

PFC

?

CAR/PXR

RXRPPAR RXR PPAR RGRGR 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 prominent 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 polyuoroacompounds (PFCs). Estrogenic EDCs such as bisphenol A have also beeinvolved in metabolic disruption through complex interaction with hormoreceptors such as the estrogen receptors (ERs), thyroid hormone receptor(TR), and glucocorticoid receptor (GR). These receptors are important focontrol of adipogenesis, weight gain, and insulin levels, although theunderlying mechanisms are not yet well understood (dashed lines ). Finally,though the mechanisms have yet to be described (dashed lines and questionmark), the xenosensors pregnane X receptor (PXR), constitutive androstareceptor (CAR), and AhR also play a crucial role in regulating metabolichomeostasis via direct or indirect interaction with the metabolic pathwayOther abbreviations used: ARNT, aryl hydrocarbon receptor nucleartranslocator; RXR, retinoid X receptor.

Experimental evidence showing the effectsof estrogen-mimicking EDCs such as BPA on metabolism remains scarce and has beenrestricted to cultured cell line models. Studiesusing 3T3-L1 cells suggested that early BPA exposure may enhance adipocyte differenti-ation in a dose-dependent manner and may permanently disrupt adipocyte-specic 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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Pregnane X recep(PXR): a nuclearreceptor known a xenosensor and mregulator of detoxicationpathways; knownsteroid X receptohumans

Constitutiveandrostane recept(CAR): a nucleareceptor known a xenosensor and mregulator of detoxicationpathways

AhR: aryl

hydrocarbon receCytochrome P450(CYP) family: a and diverse groupenzymes playing important role in detoxicationpathways. Theirsubstrates includemetabolicintermediates and xenobiotic substa

loss. The exact opposite results are observed with low TH levels.

In contrast to TR, GR forms homodimersand resides in the cytosol, forming complexes with molecular chaperones. Ligand bindingreleases the chaperones, triggers GR nucleartranslocation, and inuences 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, chiey inthe context of controlling chronic inamma-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 andsyn-ergize with a weak GR agonist to increaseexpression of adipocyte-specic 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 signicantincrease in lipolysis and a signicant decreasein glucose oxidation, characteristics associated with 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 Disruption Through 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 hydrocarbonreceptor (AhR),as well as xenobiotic metabolism and transporter

systems.3.2.1. Pregnane X receptor and constitutiveandrostane receptor. PXR and CAR aremembers of the NR superfamily of sensorreceptors, and although they were originally dened 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 by forming heterodimers with RXR that bind to xenobiotic response sequences present in thepromotersof their target genes.However, theirmechanisms of activation differ. PXR is locatedprimarily in the nucleus and is strongly activated 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 of activators, 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 of detoxication pathways through induction of phase I to phase III enzymes. In the rst 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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CYPexpression,altering ER transcriptional ac-tivity via coactivator squelching, or promot-ing DNA-binding competition (121, 122) (seeFigure 2 ). In addition, AhR also indirectly affects adipogenesis through inhibition of PPAR expression (123).

Additional experimental and epidemiologi-

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

3.3. Metabolic Disruption Through Peroxisome ProliferatorActivatedReceptors Metabolic homeostasis requires a controlledbalance between energy storage and consump-tion; several NRs and their coregulators are in-strumental in these processes.Amongthese, thePPARs act as lipid sensors that cooperate indifferent organs to adapt gene expression to agivenmetabolicstatus. PPARsaresensorrecep-tors with a rather large ligand-binding domain, which can accommodate a variety of ligands,primarily lipid derivatives. In the presence of ligand, 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 wasrst identied 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 inamma-tion. PPAR is ubiquitously expressed, sharespartially overlapping functions with PPAR ,and also plays a role in cell differentiation and

survival (125, 126). Finally, PPAR functionin adipogenesis, lipid storage, and the controof insulin sensitivity; it also participates inammatory responses (127).

Plasticizers, surfactants, pesticides, andioxins can modulate PPAR activity, althougfairly little is known about the molecular mech

anisms and the physiological outputs involve The specicity of this PPAR-mediated rsponse is highlighted in a study in whi200 pesticides were systematically screened ftheir peroxisome proliferation activity. Onlthree compounds were identied as havinPPAR transcriptional activity, and none possessed PPAR transcriptional activity (127 Among these pesticides, diclofop-methyl anpyrethrins induced PPAR target gene expression at levels similar to those induced by clasagonists in mice (128, 129).

The phthalates are another group of wellcharacterized peroxisome proliferators (130In vitro transactivation assays and intact celllar systems were used to reveal that phthalatandtheirmetabolitesbindandactivatethethreePPARs, among other NRs (131134). Thesstudies also determined the range of potencand efcacy of phthalate monoesters, showing differences between isotypes and specie Modeling the DEHP metabolite MEHP in thePPAR ligand-binding pocket indicates tha MEHP may contact residues similar to thosdened for the classic PPAR agonist rosiglitazone (135). MEHP induces adipogenesis inPPAR -dependent manner, albeit with loweefciency than rosiglitazone in 3T3-L1 cel(134). Accordingly, gene expression microarraanalyses indicate that 70% of the genes are regulated by either ligand, some of them to diffeing degrees. However, 30% of the genes are exclusively regulated by rosiglitazone and not b MEHP, suggesting that MEHP acts as a selective modulator of PPAR rather than as a fulagonist. This differential activity results fromthe different abilities of MEHP and rosiglitazone to induce the release of corepressors sucas NCoR and the recruitment of coactivatorsuch as p300 or PGC1 (133). Taken togetherthese in vitro data demonstrate that MEHP i



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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 partially contradict these results (136). Adult micetreated with high or low doses of DEHP areprotected from weight gain, gaining 30% less

weight than controls. These mice possess a re-duced fat mass and a metabolic improvement, withlower levels of triglycerides in the liverandthe blood, smaller adipocytes, and enhancedglucose tolerance. These effects were not ob-served in PPAR -null mice, conrming thatin vivo DEHP activity is mediated primarily by PPAR in the liver, leading to increasedfatty acid catabolism and induced expressionof PPAR target genes such as that encodingbroblast growth factor 21 (FGF21) (137) orgenes controlling fatty acid -oxidation. Sur-prisingly, this phenotype is also completely abolished in PPAR -humanized mice (mice in which themouse PPAR allelesare replaced by the 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-specicEDC activity, due at least in part to evolution-ary differences in the receptors interacting withthem.

Studies of phthalate exposure in utero have yielded 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 modi-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 may be attributable to the compounds tested as wellas the specic experimental protocols. In any case, 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 exposedto 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 of adult rodents (141). In contrast, Hines et al.

(142) reported that PFOA has noeffect onbody weight gain when exposure occurs at the adultstage.However, developmentalexposure to lowPFC levels results in increased body weightand increased serum insulin and leptin levelsat midlife (142).Again, species-specic PPARactivity was proposed because low doses of PFOA signicantly activate the function of PPAR in wild-type mice but not in PPAR -humanized mice. Human PPAR may there-fore be less responsive to PFOA, increasingthe possibility of species-specic EDC activ-ity. More specically, the extent to which thesePPAR activators inuence metabolic home-ostasis in humans deserves more study (143).

Several EDCs also specically 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 afnity toRXR, even though TBT is structurally distinctfrom above-described ligands and only partly occupies 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 signicantly increasesin adulthood, supporting the conclusion thatembryonic and chronic lifetime organotin

exposure may contribute to the incidence of obesity 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 (see Table 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 nal 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 ability of EDCs to act on metabolic transcription fac-tors, are lines of investigation that cannot becasually discounted. However, there are many difculties to overcome beforeonecanfairlyas-sess the risks that past, present, and future envi-ronmental chemicals engender on human and wildlife health. In this last section, we highlight

some of the importantquestions that remainforresearchers and regulators.

4.1. Monitoring Exposure Levels Ambient monitoring is performed by samplinair, dust, water, etc., and by measuring the levels of the pollutants of interest in these sample This method is often reasonably easy and reable. However, ambient monitoring provides value valid only at the time of sampling, whimaynotreectlevelsofchronicexposure;italsdoes not take into account the efciency wi which living organisms breathe, ingest, or asorb these compounds. In that respect, biomon-itoring is a more appropriate evaluation of thpresence of compounds or their metabolites ibiological samples, particularly in blood an

urine, and ideally in tissue samples. Biomontoring does not identify the source of the contamination but provides the individual exposure level at a given time point. Biomonitorinassays also reect past exposure to persistepollutants. However, biomonitoring is invasivand costly and cannot be proposed as a standarroutine evaluation, except for occupational exposure. Alternatively, biomonitoring of wildlifsamples can be more easily performed and mserve as a good indicator of exposure to som

pollutants widely found in the environment.

4.2. Identifying the MetabolicEffective DoseOne current issue in identifying the metabolieffective dose concerns the so-called U-shapeor inverted U-shaped dose-response curve. dose-response curve of this form is reportefor BPA: Effects are observed at very low dos(from 10 12 M) and at high doses (10 8 M), buno effects are observed at intermediate dos(10 9 M). These U-shaped curves suggest thexistence of two independent mechanisms folow doses and high doses (151, 152). Howevmechanistic studies are still lacking, and evdence for low-dose activity is not availableepidemiological 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 variety of compounds, and it is thus likely that even if none of the compounds reach an effective level,the combination or mixture of chemicals may become effective. This scenario is supported by

the 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 of these 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 Between Exposure 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 the

risk of obesity or other metabolic alterations.Such contributions can be revealed only by comprehensive 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 difculties inherent in theevaluation of exposure, and may be subjectto unidentied confounding factors. At best,these studies can demonstrate correlations but

not causal links between exposure and effects.

4.4. Experimental Exploration of the Metabolic Disruption Properties of Endocrine-Disrupting ChemicalsHow can we reach the most appropriate un-derstanding of EDC biology that will help to

dene appropriate actions? Although cellularmodels are exible 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 withdifferent 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-specic activity that is well de-scribed for PPAR , PXR, and CAR (98, 136). The development of humanized mice, in whichthe gene of the receptorof 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 reect the decades over whichhumans might be exposed?

4.5. Exposure During Critical Periodsof Development The dramatic effect of DESexposure 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.Evendisregarding transgenerational effects, themetabolic consequences of prenatal exposurethat manifest in adulthood are difcult to as-sess and to understand. As discussed above (seeSection 3.1.1), controversy surrounds many of



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these consequences, andonly systematicanimalstudies 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? Asdescribed in Table 1 , several chemical prod-ucts are either totally banned or authorized foruseunderstrictconditions.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 (see Table 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 only for the present but also for any future com-pound released to consumers?

Fromtheresearchpointofview,recentyearshave 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). Newintegrative approaches combiningge-nomics, proteomics, metabolomics, systems bi-ology, andcomputational modelingshouldhelpto understand the complexity of the cocktail ef-fect andits consequenceswhen exposure occursat various life stages (101, 150, 154). In addi-tion, these approaches should help to evaluate

the global effects of EDC interference with different NRs and the activation of a complex bological network. Before reaching this level understanding, these integrative strategies mahelp dene a signature: a composite signal no explanatory value but reecting exposure metabolicdisruptors. Such a signaturemayhel

inexperimentally establishinga predictivevaluto new compounds.From the regulatory point of view, govern

ments face the challenge of making appropratedecisionsby balancingpotentialrisksagaindemonstrated advantages. Help for future decisions will come from two complementary prcesses. The rst process is illustrated by thEuropean Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACHprogram, aimed at protection of human healthand the environment through systematic registration, assessment, and annotation of an exhaustive list of industry compounds. The secondprocess encourages research through gransubsidiaries, as illustrated by the recent naning of BPA research by the National Institutes of Health(NIH).These initiatives includeincentives for transparency and collaborationboth at the level of government and betweescientists. Metabolic perturbations areonly onsmall aspect of the EDC-related problems tbe solved, but what we know now may be onthe tip of the iceberg. In the present context oendemic metabolic disorders, with severe ecnomic, social, and professional consequenceevery actionrst to understand andthen to con-trol risk factors is benecial 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. Amongdifferentmechanisms of action, lipophilic EDCs compoundscanbind specically to nuclear receptors andcan displace the corresponding endogenous ligands to modulatehormone-responsive pathways.

3. Persistent organic pollutants such as organochlorine pesticides, dioxins, and polyuo-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 interaction with nuclear receptors, including (a) sex steroid hormone receptors, (b) receptors actingas xenobiotic sensors, and (c ) receptors specialized in metabolic regulations.

5. Thiseldislitteredbycontroversies,inpartduetothedifcultiesinprovingordisprovingEDC activity. The major issues are the monitoring of exposure levels, the identicationof 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 benet 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 afliations, memberships, funding, or nancial holdings thatmight be perceived as affecting the objectivity of this review.

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