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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. 73:135–62

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

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

This article’s 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 5–10). 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): ERα and ERβ

are 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 (13–17). 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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Tab

le1

ED

Cs

desc

ribe

das

met

abol

icdi

srup

tors

and

thei

ref

fect

son

the

met

abol

ism

a

ED

Cs

Typ

eor

sour

ceL

egal

stat

usN

Rs

Invi

tro/

anim

alst

udie

s

Hum

anep

idem

iolo

gica

lst

udie

sD

evel

opm

enta

lex

posu

rest

udie

sR

efer

ence

sO

rgan

ochl

orin

es(e

.g.,

DD

T)

Pes

ticid

esan

dpl

astic

izer

s19

70s:

DD

Tba

nned

inm

ost

deve

lope

dco

untr

ies

2000

s:re

stri

cted

byth

eSt

ockh

olm

Con

vent

ion

ER

α,A

RA

ssoc

iate

dw

ithM

etS

and

diab

etes

Ass

ocia

ted

with

child

ren

bein

gov

erw

eigh

t(hu

man

s)

22,2

4,25

Dio

xins

(e.g

.,P

CB

,TC

DD

)E

nvir

onm

enta

lpo

lluta

nts

info

od

2000

s:P

CB

bann

edan

dot

her

diox

ins

rest

rict

edby

the

Stoc

khol

mC

onve

ntio

n

Via

AhR

:P

PA

Rγ

,E

Rs

Adi

poge

nesi

sin

hibi

tion

Ass

ocia

ted

with

Met

S,ob

esity

,an

ddi

abet

es

123

Org

anot

ins

(e.g

.,T

BT

,T

PT

O)

Env

iron

men

tal

pollu

tant

sin

food

Ban

ned

wor

ldw

ide

byth

eIn

tern

atio

nalM

ariti

me

Org

aniz

atio

n

RX

R:

PP

AR

γ

Adi

poge

nesi

sin

duct

ion

Con

trol

ofad

ipog

enes

isdi

srup

tion

(mic

e)

28,3

1,14

4

PFC

s(e

.g.,

PFO

A,P

FOS)

Pla

stic

izer

s20

09:r

estr

icte

dby

the

Stoc

khol

mC

onve

ntio

nan

dth

eE

U

ER

s,A

R,

PP

AR

sW

eigh

tlos

s,an

orex

igen

icef

fect

Ass

ocia

ted

with

incr

ease

dch

oles

tero

lle

vels

Wei

ghtg

ain

and

incr

ease

dse

rum

insu

linan

dle

ptin

leve

ls(m

ice)

38,4

0,14

0–14

2

BFR

s(e

.g.,

PB

DE

)Fl

ame

reta

rdan

tsP

BD

Eba

nned

inth

eE

Uan

dso

me

U.S

.sta

tes

2009

:som

eB

FRs

bann

edby

the

Stoc

khol

mC

onve

ntio

n

PX

R,E

Rs,

TR

Lip

olys

isin

crea

se,

gluc

ose

oxid

atio

nde

crea

se

Ass

ocia

ted

with

Met

San

ddi

abet

es

95,1

22,1

55

Alk

ylph

enol

s(e

.g.,

octy

lphe

nol)

Surf

acta

nts

Res

tric

ted

for

som

eus

esin

the

EU

ER

s,A

R,

CA

RR

esis

tinex

pres

sion

upre

gula

tion

80

BP

AP

last

iciz

ers

2009

:Can

ada

beco

mes

the

first

coun

try

toba

nB

PA

inba

bybo

ttle

s;W

HO

begi

nsas

sess

ing

BP

Asa

fety

ER

s,A

R,

TR

,GR

Adi

poge

nesi

sin

duct

ion,

insu

linin

crea

se

Ass

ocia

ted

with

diab

etes

and

liver

abno

rmal

ities

Incr

ease

dbo

dyw

eigh

t(m

ice

and

rats

)

60,8

2,85

,15

6

Pht

hala

tes

(e.g

.,D

EH

P,D

BP

,D

EP

)

Pla

stic

izer

sR

estr

icte

din

child

ren’

sto

ysin

the

EU

(199

9)an

dth

eU

nite

dSt

ates

(200

9)20

10:A

ustr

alia

bans

prod

ucts

with

>1%

ofD

EH

P

PP

AR

s,C

AR

/PX

R,

GR

Adi

poge

nesi

sin

duct

ion

ince

lls,

body

wei

ght

decr

ease

inm

ice

Ass

ocia

ted

with

obes

ityan

din

sulin

resi

stan

ce

DiB

P:r

educ

edpl

asm

ain

sulin

and

lept

inle

vels

inm

ice

DE

HP

:no

effe

ct(m

ice)

6,9,

73,

133,

136,

138

a Abb

revi

atio

nsus

ed:A

hr,a

rylh

ydro

carb

onre

cept

or;A

R,a

ndro

gen

rece

ptor

;BFR

,bro

min

ated

flam

ere

tard

ant;

BP

A,b

isph

enol

A;C

AR

,con

stitu

tive

andr

osta

nere

cept

or;D

BP

,dib

utyl

phth

alat

e;D

DT

,dic

hlor

odip

heny

ltric

hlor

oeth

ane;

DE

HP

,die

thyl

hexy

lpht

hala

te;D

EP

,die

thyl

phth

alat

e;E

DC

,end

ocri

ne-d

isru

ptin

gch

emic

al;E

R,e

stro

gen

rece

ptor

;EU

,Eur

opea

nU

nion

;G

R,g

luco

cort

icoi

dre

cept

or;M

etS,

met

abol

icsy

ndro

me;

NR

,nuc

lear

rece

ptor

;PB

DE

,pol

ybro

min

ated

diph

enyl

ethe

r;P

CB

,pol

ychl

orin

ated

biph

enyl

;PFC

,pol

yfluo

roal

kylc

ompo

und;

PFO

A,p

erflu

oroo

ctan

oate

;PFO

S,pe

rfluo

rooc

tane

sulfo

nate

;PP

AR

,per

oxis

ome

prol

ifera

tor–

activ

ated

rece

ptor

;PX

R,p

regn

ane

Xre

cept

or;R

XR

,ret

inoi

dX

rece

ptor

;TB

T,t

ribu

tylti

nch

lori

de;T

CD

D,2

,3,7

,8-t

etra

chlo

rodi

benz

o-p-

diox

in;T

PT

O,b

is(t

riph

enyl

tin)o

xide

;TR

,thy

roid

horm

one

rece

ptor

;WH

O:W

orld

Hea

lthO

rgan

izat

ion.


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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

<5

to>

15,0

00m

g(k

gB

W)−

15

year

sIn

cells

:20

μM

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

7–11

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

γ

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

μg

liter

−1

PFO

A:3

.9μ

glit

er−1

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

xpos

ure

thro

ugh

diet

:37

–97

ngda

y−1

Exp

osur

eth

roug

hho

use

dust

:Adu

lts:1

6.7

ngda

y−1 ;

child

ren:

191.

3ng

day−

1

Mea

nle

vels

inad

ipos

etis

sue:

Eur

ope

and

Asi

a:<

5ng

(glip

id)−

1

Nor

thA

mer

ica:

>20

0ng

(glip

id)−

1

Infe

tall

iver

:ran

geof

4–98

.5ng

(glip

id)−

1(in

the

Uni

ted

Stat

es)

Inbr

east

milk

:ran

geof

1.57

–73.

9ng

(glip

id)−

1(w

orld

wid

e)

Inse

rum

:fro

mw

eeks

tom

onth

sIn

fat:

seve

ral

year

s

Inra

ts:e

xpos

ure

to14

mg

(kg

BW

)−1

day−

1fo

rfo

urw

eeks

alte

rslip

olys

isan

dgl

ucos

eox

ydat

ion

13,6

7,95

Alk

ylph

enol

sN

P’s

TD

I:7.

5m

gda

y−1

(Ger

man

y)In

urin

e:ra

nge

of0.

4–13

.9ng

ml−

1

Inad

ipos

etis

sue:

med

ian

leve

lof

57ng

g−1

(Spa

in)

NP

inbl

ood:

2–3

hIn

vitr

o:lo

wes

teffe

ctco

ncen

trat

ions

inth

e10

–100

0-nM

rang

e52

,55,

56

BP

AT

DI:

<50

μg

(kg

BW

)−1

day−

1(U

.S.E

nvir

onm

enta

lP

rote

ctio

nA

genc

y)

Ran

geof

0.1–

10ng

ml−

1in

bloo

d,ur

ine,

fat,

and

feta

ltis

sue

6h

Invi

tro:

low

este

ffect

conc

entr

atio

nsin

the

0.1–

1-nM

rang

eIn

mic

e:w

eigh

tinc

reas

eco

rrel

ated

with

inut

ero

expo

sure

to2.

4–50

0μ

g(k

gB

W)−

1da

y−1

55,6

7,89

,15

6

Pht

hala

tes

DB

P’s

TD

I:10

mg

(kg

BW

)−1

day−

1(E

urop

ean

Food

Safe

tyA

utho

rity

)

Ran

geof

pren

atal

phth

alat

em

etab

olite

mea

nle

vels

inur

ine

ofm

othe

rs:2

.54–

816

μg

liter

−1

Mon

oest

ers

ofD

EH

Pin

child

ren’

sur

ine:

91.3

μg

liter

−1(N

HA

NE

S)

From

hour

sto

days

Ince

lls:5

0-μ

MD

EH

P,D

BP

,and

met

abol

ites

Inm

ice:

DE

HP

:1,0

00m

gkg

−1

day−

1 ;D

BP

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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 wasdesigned 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, and personal interviews. Information about disease andhealth status, diet, sociodemographics, occupation, and educationis collected. In addition, tests are conducted for a variety of mate-rials, such as micronutrients, disease markers, and environmentalpollutants. NHANES’s partnership with the EnvironmentalProtection Agency has also allowed for the implementation oflongitudinal studies of many important environmental influ-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 identified 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 bodymass 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 outa cross-sectional analysis of 1,721 adults (seeNHANES and Observational Studies side-bars); the study reported a positive associa-tion between diabetes and the levels of 19 dif-ferent persistent pollutants (including OCPs)measured in serum (21). Other epidemiolog-ical studies find a significant association be-tween pesticide exposure [mostly OCPs suchas heptachlore epoxide, oxychlordane, or β-hexachlorocyclohexane (β-HCH)] and higherincidences of metabolic syndrome, insulin re-sistance, and diabetes (23, 24). A higher preva-lence of diabetes is also associated with DDEexposure (25).

2.2. Dioxins

Dioxins consist of a group of organochlo-rines that include the polychlorinated dibenzo-dioxins (PCDDs), the polychlorinated diben-zofurans (PCDFs), and the polychlorinatedbiphenyls (PCBs) and other related com-pounds. Dioxins can be produced from nat-ural sources such as volcanoes and forestfires but are created mostly by human ac-tivity as by-products in organochloride pro-duction, in incineration of chlorine-containingsubstances such as polyvinyl chloride (PVC),and in bleached paper production. The PCDD2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)is the most toxic of all dioxins. This dioxin wasa major contaminant in the Seveso catastropheand in the Vietnam War (Agent Orange); it wasalso used as a poison in the attempted assassi-nation of Viktor Yushchenko (17).

Dioxins are fat soluble and readily climb thefood chain via their bioaccumulation in fat tis-sues. They are neither readily metabolized norexcreted, and TCDD has a half-life of approx-imately 8 years in humans. Several epidemio-logical studies have evaluated the toxic effects ofTCDD and others dioxins on the general popu-lation as well as heavily exposed subgroups suchas Vietnam War veterans (reviewed in Refer-ences 17 and 26). These studies demonstrate acause and effect between dioxin exposure, with


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PFCs: polyfluoroalkylcompounds

an increase in cancers, nervous system degen-eration, immune damage, thyroid disease, andreproductive and sexual development disorders.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. Organotins

Organotins, including tributyltin chloride(TBT) and bis(triphenyltin) oxide (TPTO), arepersistent organic pollutants that have beenwidely used as agricultural fungicides, as rodentrepellents, as molluscicides, and in antifoulingpaints for ships and fishing 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 verylow concentrations of these compounds inducesan irreversible sexual abnormality in femalestermed imposex, resulting in impaired repro-ductive fitness 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 fish and shell-fish, or through contaminated drinking waterand food. However, no epidemiological data areavailable concerning human exposure, althoughTBT 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. Plastics

Owing to their variety, robustness, and ex-tremely low costs, plastics are fundamental inmodern life, public health, and medicine; plasticproduction exceeded 300 million tons in 2010(32). After more than five decades of debate and

OBSERVATIONAL STUDIES

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

Clinical studies aimed at evaluating the effects of EDC expo-sure rely mainly on observational studies, which interpret exper-iments of nature and are exposed to large confounding biases.However, such studies provide preliminary evidence to be usedas a basis for hypotheses.

Cross-sectional studies examine the relationship between dis-eases and other factors (such as EDC levels) at one point in timein a defined population. Cross-sectional studies lack any informa-tion on timing of exposure and include only prevalent cases. Theycan suggest a link between a disease and the factor of interest.

In longitudinal studies, or cohort studies, a panel of individu-als is interviewed repeatedly over a period of time. This allows aprospective and analytical study of a group in which some in-dividuals have had, currently have, or will have the exposureof interest to determine the association between that exposureand an outcome. Cohort studies are stronger than cross-sectionaland case-control studies when well executed, but they are moreexpensive.

Case-control studies are a retrospective comparison of theproportion of cases with a potential risk factor to the propor-tion of controls (individuals without the disease) with the samerisk factor. Due to the potential for many forms of bias in thisstudy type, case-control studies provide relatively weak empiricalevidence, even when properly executed.

research, controversy still surrounds the risksthat plastics may cause in humans, particularlywith 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. Polyfluoroalkyl compounds. Polyflu-oroalkyl compounds (PFCs) are synthetic flu-orinated organic compounds used in a widerange of industrial applications and consumerproducts, including paper, leather, textile coat-ings, and fire-fighting foam, and in the polymer


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BFRs: brominatedflame retardants

industry. Among them, perfluorooctane sul-fonate (PFOS) and perfluorooctanoate (PFOA)are widely detected in the environment. PFCsare classified as persistent organic pollutants,even though they are not stored in fat tissue butinstead form chemical adducts with liver andserum proteins. Laboratory rodents exposed toPFCs exhibit developmental effects such as re-duced birth weight and increased neonatal mor-tality (33–35). 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 ofPFOS 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 PFClevels with metabolic parameters; the most con-sistent result is the positive association betweenPFC exposure and increased cholesterol, par-ticularly high-density lipoprotein (HDL) (39–44). The same reports discounted any associa-tion with metabolic diseases such as type 2 dia-betes and metabolic syndrome (39–44) and sug-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 ofPFCs on human physiology.

2.4.2. Brominated flame retardants. Bromi-nated flame retardants (BFRs), particularlypolybrominated diphenyl ethers (PBDEs), areadditives used as flame retardants in a greatnumber of consumer products such as houseelectronic equipment, clothing, and furniture.Although these compounds have decreased fireincidences, 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 beneficial effects,these chemicals are also thought to adverselyaffect human health through endocrine disrup-tion and developmental neurotoxicity (48). Inaddition, increased incidences of hepatocellu-lar carcinoma and thyroid adenoma have beenobserved in rodents, albeit with relatively highexposure doses (49). Taken together, these ob-servations have led to the recent ban of PBDEsin several American states and in the EuropeanUnion, where a ban on all BFR use is being con-templated. Meanwhile, PBDEs are still presentin environmental samples and are detected inmilk, serum, and adipose tissue in animals andhumans.

Published studies addressing the conse-quences of human BRF exposure remain scarce,and the effects of BFR exposure on sex steroidhormone systems are still poorly understood.One study demonstrated a correlation be-tween PBDEs in breast milk and congenitalcryptorchidism, although confounding factorsmay have been present (50). Only a few epi-demiological studies have addressed the pos-sible impacts of these persistent pollutants onmetabolic parameters in humans. The mosttelling study revealed that, among six dif-ferent BFRs, PBDE-153 and the polybromi-nated biphenyl PBB-153 showed an invertedU-shaped association with type 2 diabetes andmetabolic syndrome (51). Clearly, more stud-ies are needed to clarify the possible extent ofBFR-related damage.

2.4.3. Alkylphenols. Alkylphenols such as 4-n-nonylphenol and 4-n-octylphenol are sur-factants widely used in detergents, emulsifiers,antistatic agents, demulsifiers, and solubilizersand are found commonly in wastewater (52).They are also used as additives to plastics suchas PVC and polystyrene, from which they canleach. Alkylphenols are capable of initiatingproliferation in breast tumor cells in the lab-oratory (53), consistent with their capacities forestrogenic and antiandrogenic activity (54, 55,and references therein). However, given the lowenvironmental concentrations and the currentregulation of alkylphenol use in the European


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Bisphenol A (BPA):a high-volume-production plasticizerthat is an estrogenmimic and is detectedin 95% of humanurine samples

Union [Directive 2003/53/EC (2003)], someauthors argue that alkylphenols do not pose ahealth risk. Human exposure was recently eval-uated in a population of women in southernSpain; nonylphenol was detected in 100% ofthe adipose tissue samples tested. In this study,body mass index was associated with nonylphe-nol levels and emerged as a determinant of ex-posure (56). More studies with larger study pop-ulations are thus required to evaluate the risksstill posed by these chemicals.

2.4.4. Bisphenol A. Bisphenol A (BPA) is ahigh-volume-production monomer (>2.5 ×106 kg year−1) 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 (60–62).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 product’s 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. ERα and ERβ 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, ERα

and ERβ 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. ERα but notERβ appears to mediate these effects, asinferred from studies using mice in which ERα

is 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 thatERα activation modulates neural networkscontrolling food intake as well as acts directlyin adipose tissue (reviewed in Reference 76). Ata cellular level, preadipocytes also express ERα

and ERβ, 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

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CAR/PXR RXRPPARγ RXR PPARα 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 proliferator–activated receptors (PPARs) play aprominent role: PPARγ activated by phthalates or organotins inducesadipogenesis in vitro, and this effect is inhibited by dioxins through AhRactivation. PPARα, 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 extracellularsignal–regulated kinase pathways in 3T3-L1


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Thyroid hormonereceptor (TR): TRα

and TRβ 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 ERα 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 ERα

expression in the pancreas, with 17β-estradiolshown to increase β-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 TRα andTRβ, 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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Peroxisomeproliferator–activated receptor(PPAR): PPARα,-β/δ, and -γ 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, 17β-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 (99–102).

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 (106–108), and CAR and PXR ac-tivators repressed hepatic gluconeogenic en-zymes and genes (109–111). 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 4α (HNF4α) and peroxisomeproliferator–activated receptor (PPAR)α. Fi-nally, PXR and CAR can also exert an inhibitoryeffect by targeting common coactivators likePPARγ coactivator 1α (PGC1α), 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-erbα 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-PAS—where 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 ofPPARγ 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 Proliferator–ActivatedReceptors

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: PPARα, -β/δ, and -γ. PPARα is ex-pressed predominantly in tissues characterizedby a high rate of fatty acid catabolism such asliver, kidney, heart, and muscle. PPARα 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. PPARα plays a major role infatty acid oxidation in all species, controllinglipoprotein metabolism and limiting inflamma-tion. PPARβ is ubiquitously expressed, sharespartially overlapping functions with PPARα,and also plays a role in cell differentiation and

survival (125, 126). Finally, PPARγ 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 havingPPARα transcriptional activity, and none pos-sessed PPARγ transcriptional activity (127).Among these pesticides, diclofop-methyl andpyrethrins induced PPARα 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 (131–134). Thesestudies also determined the range of potencyand efficacy of phthalate monoesters, show-ing differences between isotypes and species.Modeling the DEHP metabolite MEHP in thePPARγ ligand-binding pocket indicates thatMEHP may contact residues similar to thosedefined for the classic PPARγ agonist rosigli-tazone (135). MEHP induces adipogenesis in aPPARγ-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 PPARγ 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 PGC1α (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 PPARα-null mice, confirming thatin vivo DEHP activity is mediated primarilyby PPARα in the liver, leading to increasedfatty acid catabolism and induced expressionof PPARα target genes such as that encodingfibroblast growth factor 21 (FGF21) (137) orgenes controlling fatty acid β-oxidation. Sur-prisingly, this phenotype is also completelyabolished in PPARα-humanized mice (mice inwhich the mouse PPARα alleles are replaced bythe human PPARα 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 PPARα-null mice (140). The pro-posed mechanism involves PPARα-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 PPARα

activity was proposed because low doses ofPFOA significantly activate the function ofPPARα in wild-type mice but not in PPARα-humanized mice. Human PPARα 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 targetPPARγ. Using a high-throughput method,Kanayama et al. (31) showed that among 40EDCs, organotins such as TBT and TPTOare activators of human PPARγ 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 receptor–related 1 protein(NURR1), PPARβ, and PPARγ, but notPPARα. Organotins bind and activate, pri-marily through RXR and not through PPARγ,the PPARγ:RXR heterodimer at nanomolarconcentrations. The crystal structure of theRXRα 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 RXRα ligand-binding pocket(144). Consistent with the critical role playedby PPARγ:RXR signaling in mammalianadipogenesis, TBT promotes adipogenesisin 3T3-L1 cells by direct transcriptionaleffects on the PPARγ 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 mass—but not the total body weight—of 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 PPARγ: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 10−12 M) and at high doses (10−8 M), butno effects are observed at intermediate doses(10−9 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 PPARα, 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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PH73-FrontMatter ARI 14 January 2011 10:0

Annual Review ofPhysiology

Volume 73, 2011Contents

PERSPECTIVES, David Julius, Editor

A Long Affair with Renal TubulesGerhard H. Giebisch � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor

Heart Valve Structure and Function in Development and DiseaseRobert B. Hinton and Katherine E. Yutzey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �29

Myocardial Remodeling: Cellular and Extracellular Events and TargetsJennifer A. Dixon and Francis G. Spinale � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �47

ECOLOGICAL, EVOLUTIONARY, AND COMPARATIVE PHYSIOLOGY,Martin E. Feder, Section Editor

Ecological Physiology of Diet and Digestive SystemsWilliam H. Karasov, Carlos Martınez del Rio, and Enrique Caviedes-Vidal � � � � � � � � � � � � �69

Effects of Oxygen on Growth and Size: Synthesis of Molecular,Organismal, and Evolutionary Studies with Drosophila melanogasterJon F. Harrison and Gabriel G. Haddad � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �95

LEA Proteins During Water Stress: Not Just for Plants AnymoreSteven C. Hand, Michael A. Menze, Mehmet Toner, Leaf Boswell,

and Daniel Moore � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 115

ENDOCRINOLOGY, Holly A. Ingraham, Section Editor

Endocrine Disruptors: From Endocrine to Metabolic DisruptionCristina Casals-Casas and Beatrice Desvergne � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 135

Endometriosis: The Role of NeuroangiogenesisAlbert Asante and Robert N. Taylor � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 163

Zebrafish in Endocrine Systems: Recent Advances and Implications forHuman DiseaseHeiko Lohr and Matthias Hammerschmidt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 183

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GASTROINTESTINAL PHYSIOLOGY, James M. Anderson, Section Editor

Mesenchymal Cells of the Intestinal Lamina PropriaD.W. Powell, I.V. Pinchuk, J.I. Saada, Xin Chen, and R.C. Mifflin � � � � � � � � � � � � � � � � � � � � 213

Niemann-Pick C1-Like 1 (NPC1L1) Protein in Intestinal and HepaticCholesterol TransportLin Jia, Jenna L. Betters, and Liqing Yu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 239

Regulation of Electroneutral NaCl Absorption by the Small IntestineAkira Kato and Michael F. Romero � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 261

Tight Junction Pore and Leak Pathways: A Dynamic DuoLe Shen, Christopher R. Weber, David R. Raleigh, Dan Yu, and Jerrold R. Turner � � � 283

NEUROPHYSIOLOGY, Roger Nicoll, Section Editor

How the Genetics of Deafness Illuminates Auditory PhysiologyGuy P. Richardson, Jacques Boutet de Monvel, and Christine Petit � � � � � � � � � � � � � � � � � � � � � � 311

RENAL AND ELECTROLYTE PHYSIOLOGY, Gerhard H. Giebisch, Section Editor

Mechanisms Underlying Rapid Aldosterone Effects in the KidneyWarren Thomas and Brian J. Harvey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 335

Regulation of Renal NaCl Transport by Nitric Oxide, Endothelin,and ATP: Clinical ImplicationsJeffrey L. Garvin, Marcela Herrera, and Pablo A. Ortiz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 359

Renin Release: Sites, Mechanisms, and ControlArmin Kurtz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 377

Terminal Differentiation in Epithelia: The Role of Integrinsin Hensin PolymerizationQais Al-Awqati � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 401

RESPIRATORY PHYSIOLOGY, Richard C. Boucher, Jr., Section Editor

Epithelial-Mesenchymal Interactions in Pulmonary FibrosisHarold A. Chapman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 413

Interaction of Cigarette Exposure and Airway EpithelialCell Gene ExpressionJerome S. Brody and Katrina Steiling � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 437

The Lung: The Natural Boundary Between Nature and NurtureMax A. Seibold and David A. Schwartz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 457

viii Contents

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Role of Chitin and Chitinase/Chitinase-Like Proteins in Inflammation,Tissue Remodeling, and InjuryChun Geun Lee, Carla A. Da Silva, Charles S. Dela Cruz, Farida Ahangari,

Bing Ma, Min-Jong Kang, Chuan-Hua He, Seyedtaghi Takyar,and Jack A. Elias � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 479

SPECIAL TOPIC, THROMBOSIS, Charles T. Esmon, Special Topic Editor

The Link Between Vascular Features and ThrombosisCharles T. Esmon and Naomi L. Esmon � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 503

Role of Tissue Factor in Venous ThrombosisDavid A. Manly, Jeremiah Boles, and Nigel Mackman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 515

Venous Valvular Stasis–Associated Hypoxia and Thrombosis: What Isthe Link?Edwin G. Bovill and Albert van der Vliet � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 527

Indexes

Cumulative Index of Contributing Authors, Volumes 69–73 � � � � � � � � � � � � � � � � � � � � � � � � � � � 547

Cumulative Index of Chapter Titles, Volumes 69–73 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 550

Errata

An online log of corrections to Annual Review of Physiology articles may be found athttp://physiol.annualreviews.org/errata.shtml

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