enviromental chemical exposure and human epigenetics

7/27/2019 Enviromental Chemical Exposure and Human Epigenetics

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Table1Effectsofenvironm

entalchemicalsonepigeneticchanges

Environmental

chemicals

Ep

igeneticchanges

In

vitro/in

vivo

Tissue/spe

cies

Exampleofd

iseasespotentially

associatedw

iththeobserved

changesine

pigeneticchanges

Arsenic

DNAmethylation

Globalhypomethylation

Invitro

HumanHaCaTkeratinocytes,80

humanprostateepithelialcellline

RWPE-1,8

1,82

TRL1

215ratliver

epithelialcellline,8

3

V79-Cl3

Chinesehamsterce

lls226

Variouscancers227230

and

schizophrenia231


Invivo

129/SvJmice,84

fisher344Rat,86

homozygousTg.AC

mice,87

gold-

fish,2

32

humanPBL

233


and

schizophrenia231


andc-Ha-ras

hypomethylation

Invivo

C57BL/6Jmice85


and

schizophrenia231

Global

hypermethylation

Invivo

HumanPBL88,89

Colorectalcancer,234236

renalcell

carcinoma,23

7

acutelymphoblastic

leukaemia238

andbladder

urothelialcellcarcinoma239

DAP

Khypermethylation

Invitro

Humanuroepithelial

SV-HUC-1

cells90


P16

hypermethylation

Invitro

Humanmyelomacell

lineU26691

Variouscancers241,248,250,252257

DBC

1,

FAM83A,

ZSCAN12and

C1QTNF6

hypermethylation

Invitro

HumanUROtsacells92

Bladdercancer

,258

breastcancer259

andmaligna

ntlymphoprolifera-

tiveneoplasms260

P53

hypermethylation

Invitro

Humanlungadenoca

rcinomaA549

cells93

Breastcancer261

and

hepatoblasto

ma262

C-m

ychypomethylation

Invitro

TRL1215ratliverepithelialcells94

Gastriccancer,263,264

colon

cancer,263liv

ercancer,207,265,266

kidneycancer207

andbladder

cancer267

C-m

ycandc-Ha-ras

hypomethylation

Invitro

Syrianhamsterembryocells95

Gastriccancer,263,264

colon

cancer,263liv

ercancer,207,265,266

kidneycancer207

andbladder

cancer267

P16

andRASSF1

hypermethylation

Invivo

A/Jmice96


257,268,269


andER-alpha

hypomethylation

Invivo

C3Hmice97

Variouscancers97,227230

and

schizophrenia231

P53

andP16

hypermethylation

Invivo

HumanPBL98


257,261,262

DAP

Khypermethylation

Invivo

Humanbladder,kidn

eyand

ureter99


(continued)

ENVIRONMENTAL EPIGENETICS 81


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Table1Continued

Environmental

chemicals

Epigeneticchanges

In

vitro/in

vivo

Tissue/species

Exampleofdiseasespotentially

associatedw

iththeobserved

changesinepigeneticchanges

RASS

F1AandPRSS3

hy

permethylation

Invivo

Humanbladder100

Lungcanceran

dprostate

cancer268,269

P16hypermethylation

Invivo

HumanPBL270

Variouscancers

241,248,250,252257

P53hypermethylation

Invivo

Humanbasalcellcarc

inoma102

Breastcancer26

1

and

hepatoblastom

a262

Both

hypomethylation

an

dhypermethyla-

tio

nofVHL

Invitro

Humankidneycells27

1

Renalcellcarcinoma271

Hist

onemodification

#H3

acetylation

Invitro

UROtsaandURO-ASS

Ccells92

Renalcellcarcinomas272

#H4K16acetylation

Invitro

UROtsacells104

Bladdercancer273

"H3K14acetylation

Invitro

NB4cells105

Diabeticnephro

pathy274

"H3S10

ph

osphorylation

"H3

phosphorylation

Invitro

WI-38humandiploid

fibroblast

cells106

Diabeticnephro

pathy274

"H3K9acetylation

Invitro

HepG2hepatocarcinom

acells107

Diabeticnephro

pathy274

#H3,H4,H2a,H2b

ac

etylation#H3and

H4methylation

Invitro

Drosophilamelanogastertissue

culturecelllineKC161103

Heartdisease27

5

andtraumatic

braininjury2

76

"H2bmethylation

"H3K36trimethylation

Invitro

Humanlungcarcinom

aA549

cells110

Diabeticnephro

pathy,274

multiple

myeloma277

andprostate

cancer278

#H3K36dimethylation

"H3K4dimethylation

"H3K9dimethylation

Invitro

Humanlungcarcinom

aA549

cells110,279

Prostatecancer,2

78

kidneycancer,278

lungcancer,2

80

HCC281

and

AML282

#H3K27trimethylation

"H3K4trimethylation

"H2AXphosphorylation

Invitro

RPMI7951melanoma

cells112

Ataxiatelangiectasia283

#H3K18acetylation

Invitro

1470.2celllinederivedfrom

the

mouseadenocarcino

maparent

line284

Prostatecancer278

andcolon

cancer285

#H3R17methylation

miR

NAs

"miR-222,

#miR-210

Invitro

TK6cellline100

Variouscancers

286290

andAD291

#miR-19a

Invitro

T24cellline115

Variouscancers

292300

(continued)

82 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY


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Table1Continued

Environmental

chemicals

Epig

eneticchanges

In

vitro/invivo

Tissue/species

Exampleofdis

easespotentially

associatedwiththeobserved


Nickel

DNA

methylation

ATF-1,

HIF-1,gptandRb

hyp

ermethylation

Invitro

G12cellline116,117

Variouscancers3

01306

P16hypermethylation

Invivo

Mousehistiocytomas119

Variouscancers2

41,248,250,252257

Histo

nemodification

"H3K9methylation

Invitro

Humanlungcarcinoma

A549

cells123,307

Heartdisease275

andtraumatic

braininjury276

#Aca

tallfourcore

hist

ones

"H3K9dimethylation

Invitro

Humanlungcarcinoma

A549

cells,122,124

G12

cells,116,123,126,128,2791

HAEo-cell

line,120,121

human(HAE)andrat

(NRK)cells,125

Chine

sehamster

cellline127

Lungcancer,308

heartdisease,2

75

chronicglomer

ulardisease309

and

traumaticbraininjury276

"H2a,H2b

ubiquitylation

#H3K4methylation

#H3K4acetylation

#H2a,H2b,H3,H4

acetylation

#H4K5,H4K8,H4K12,

H4K

16acetylation

Invivo

Humanlungcarcinoma

A549

cells130

Ataxiatelangiectasia310

#H2A,H2B,H3,H4

acetylation(especially

inH

2BK12and

H2B

K20)

Invitro

Humanairwayepithelia

l1HAEo-

(HAE)cellline131

Heartdisease275

andtraumatic

braininjury276

"H3p

hosphorylation

Invitro

Humanlungcarcinoma

A549

cells132

Diabeticnephrop

athy274

Cadmium

DNA

methylation

GlobalDNA

hyp

omethylation

Invitro

K562cell133

Colorectalcancer

,234236

renalcell

carcinoma,2

37

acutelymphoblastic

leukaemia,2

38

bladderurothelial

cellcarcinoma239

InitiallyinducesDNA

hyp

omethylation,

prolongedexposure

resu

ltsinDNA

hyp

ermethylation

Invitro

TRL1215ratlivercells1

34

Notapplicable

miRN

As

#miR-146a

Invivo

HumanPBL137

Variouscancers3

11313

(continued)



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Table1Continued

Environmental

chemicals

Epig

eneticchanges

In

vitro/invivo

Tissue/species

Exampleofdis

easespotentially

associatedwiththeobserved


Chromium

DNA

methylation

P16andhMLH1

hyp

ermethylation

Invivo

Humanlung143,144

Variouscancers24

1,248,250,252257,314316

Gpthypermethylation

Invitro

G12cellline317

Notapplicable

Histo

nemodification

#H3S-10

pho

sphorylation

Invitro

Humanlungcarcinoma

A549

cells279

Type2diabetes,2

74

heartdisease275

andtraumatic

braininjury276

#H3K4trimethylation

#H3a

ndH4acetylation

"Di

methylationand

trim

ethylationof

H3K

9andH3K4

#H3K27trimethylation

and

H3R2

dim

ethylation

Aluminum

miRN

As

"miR-146a

Invitro

HNcells149

AD,3

18,319

cardiac

hypertrophy320

andvariousca

ncers321328

"miR-9,-128,-125b

Invitro

HNcells329

AD,3

30

neurodegeneration331

and

variouscancers332335

Mercury

DNA

methylation


Invivo

Braintissuesinpolarb

ear139

Neurologicaldiso

rders336,337

and

variouscancer338

Rnd2hypermethylation

Invitro

Mouseembryonicstem

cells140

neuronalmigrationdefect339

Lead

DNA

methylation


Invivo

HumanPBL,1

41

newbor

numbilical

cordbloodsamples14

2

Variouscancers2

27230

and

schizophrenia2

31

Pesticides

DNA

methylation

P53hypermethylation

Invitro

HumanlungadenocarcinomaA549

cells93

Breastcancer261

and

hepatoblastoma262

AlterDNAmethylation

int

hegerm

line

Invivo

Rattestis154156

Potentialeffects

intheoffspring

Hypom

ethylationof

c-junandc-myc

Invivo

Mouseliver158,159

Gastriccancer,26

3,264

colon

cancer,263

liver

cancer,207,265,266

kidneycancer2

07

andbladder

cancer267


(Alu)

Invivo

HumanPBL161,162

Variouscancers2

27230

and

schizophrenia2

31

(continued)



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Table1Continued

Environmental

chemicals

Epigeneticchanges

In

vitro/in

vivo

Tissue/spec

ies

Exampleofdiseasespotentially

associatedw

iththeobserved


BisphenolA

DNA

methylation

Hypomethylationofthe

Ag

outigeneand

Ca

bpIAP

Invivo

Mouseembryo192

Micewithhypo

methylationofthe

Agoutigeneareobese,diabetic

andexhibitincreasedcancer

rates361,362

Hypomethylationofthe

ho

meoboxgene

Ho

xa10

Invivo

CD-1mice194

Notapplicable

Hypermethylationof

LA

MP3.

Invitro

Breastepithelialcells1

95

Breastcancer19

5

miR

NAs

"miR-146a

Invitro

3Aplacentalcells196

Cardiachypertrophy,320

AD318,319

andvariouscancers321328

Dioxin

DNA

methylation

Igf2hypomethylation

Invivo

Ratliver198

RussellSilversyndrome363365

and

variouscance

rs366370

AlterationsinDNA

methylationatmul-

tip

legenomicregions

Invivo

Splenocyteofmice199

Notapplicable

miR

NAs

"miR-191

Invivo

Ratliver200

Breastcancer,342

colorectal

cancer321,371

andgastriccancer372

RDX

miR

NAs

"let-7,miR-15,-16,-26,

-181#miR-10b

Invivo

Mousebrainandliver

202

Variouscancers

325,373380

"miR-206,-30,-195

Invivo

Mousebrainandliver

202

Variouscancers

342,381385

DES

miR

NAs

#miR-9-3

Invitro

Breastepithelialcells2

05

Breastcancer20

5

Drinking

water

DNA

methylation

Glob

alhypomethylation

c-m

yc

hy

pomethylation

Invivo

Miceliver207,208

Gastriccancer,2

63,264

colon

cancer,263

livercancer,207,265,266

kidneycancer207

andbladder

cancer267

PBL,peripheralbloodleucocytes;HCC,hepatocellularcarcinoma;AML,a

cutemyeloidleukaemia;AD,Alzheimersdisease;HNcells,humanneuralcells;RDX,hexahydro-1,3,5-

trinitro-1,3,5-triazine;DES,diethylstilbestrol.



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adjacent genes.13,14 Global hypomethylation is asso-ciated with genomic instability and an increased num-ber of mutational events.1518 There are approximately1.4 million Alu repetitive elements (sequences con-taining a recognition site for the restriction enzyme

AluI)19 and a half a million long interspersed nucleo-tide (LINE-1) elements in the human genome that are

normally heavily methylated.20 More than one-thirdof DNA methylation occurs in repetitive elements.20

Because of their high representation throughout thegenome, LINE-1 and Alu have been used as globalsurrogate markers for estimating the genomic DNAmethylation level in cancer tissues,2022 althoughrecent data show lack of correlation with globalmethylation in normal tissues, such as peripheralblood.23 Other types of abnormalities that can beinduced by environmental pollutants are hyper- orhypo-methylation of specific genes or regions, poten-tially associated with aberrant gene transcription.2427

DNA methylation alterations that directly affectgene expression often occur in the CpG sites located

in the promoter regions of the genes. Recent evidencehas shown that differentially methylated sites in vari-ous cancer tissues are enriched in sequences, termedCpG island shores, up to 2 kb distant from the tran-scription start site.28 However, to date, gene-specificDNA methylation alterations induced by environmen-tal exposures have been mostly investigated in genepromoter regions. CpG island shores are clearly

worthy of further investigation in relation to environ-mental exposures, but whether they hold such im-portance in a non-cancer setting remains to bedetermined.

Histone modifications

In humans, protection and packaging of the geneticmaterial are largely performed by histone proteins,

which also offer a mechanism for regulating DNAtranscription, replication and repair.29 Histonesare nuclear globular proteins that can be covalentlymodified by acetylation (Ac), methylation, phosphor-

ylation, glycosylation, sumoylation, ubiquitinationand adenosine diphosphate (ADP) ribosylation,30,31

thus influencing chromatin structure and gene ex-pression.32,33 The most common histone modificationsthat have been shown to be modified by environmen-tal chemicals are Ac and methylation of lysine resi-dues in the amino terminal of histone 3 (H3) and H4.

Histone Ac, with only a single acetyl group added toeach amino acid residue usually, increases gene tran-scriptional activity;3437 whereas histone methylation(Me), found as mono (Me), di-methyl (Me2), andtri-methyl (Me3) group states38 can inhibit or in-crease gene expression depending on the amino acidposition that is modified.3941

miRNAs

miRNAs are short single-stranded RNAs of appro-ximately 2024 nucleotides in length that are

transcribed from DNA but not translated into pro-teins. miRNAs negatively regulate expression oftarget genes at the post-transcriptional level by bind-ing to 30-untranslated regions of target mRNAs.42

Each mature miRNA is partially complementary tomultiple target mRNAs and directs the RNA-inducedsilencing complex (RISC) to identify the target

mRNAs for inactivation.43 miRNAs are initially tran-scribed as longer primary transcripts (pri-miRNAs)and processed first by the RNase enzyme complex,and then by Dicer, leading to incorporation of a singlestrand into the RISC. miRNAs guide RISC to interact

with mRNAs and determine post-transcriptional re-pression. miRNAs are involved in the regulation ofgene expression through the targeting of mRNAsduring cell proliferation, apoptosis, control of stemcell self renewal, differentiation, metabolism, develop-ment and tumour metastasis.44,45 Compared with othermechanisms involved in gene expression, miRNAs actdirectly before protein synthesis and may be more dir-ectly involved in fine-tuning of gene expression or

quantitative regulation.46,47 Moreover, miRNAs alsoplay key roles in modifying chromatin structure andparticipating in the maintenance of genome stability.48

miRNAs can regulate various physiological and patho-logical processes, such as cell growth, differentiation,proliferation, apoptosis and metabolism.42,49 More than10 000 miRNAs have been reported in animals, plantsand viruses by using computational and experimentalmethods in miRNA-related public databases. The aber-rant expression of miRNAs has been linked to varioushuman diseases, including Alzheimers disease, cardiachypertrophy, altered heart repolarization, lymphomas,leukaemias, and cancer at several sites.5066

Environmental pollutants andepigenetic alterationsMetals

Heavy metals are widespread environmental contam-inants and have been associated with a number ofdiseases, such as cancer, cardiovascular diseases,neurological disorders and autoimmune diseases.67,68

In recent years, there has been an increasing appreci-ation of the roles of molecular factors in the aetiologyof heavy metal-associated diseases.6971 Several stu-dies showed that metals act as catalysts in the oxida-

tive deterioration of biological macromolecules.72

Metal ions induce reactive oxygen species (ROS),and thus lead to the generation of free radicals.72,73

ROS accumulation can affect epigenetic factors.7479

Growing data have linked epigenetic alterations withheavy metal exposure.

Arsenic

Evidence has been rapidly increasing that exposureto arsenic (As) alters DNA methylation both globallyand in the promoter regions of certain genes.



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This finding suggested that gene silencing mediatedby histone deacetylation may play a critical role innickel-induced cell transformation.129 In addition,nickel has also been shown to induce a loss of histonemethylation in vivo and decreased activity of histoneH3K9 demethylase in vitro.123 Nickel also suppresseshistone H4 acetylation in vitro in both yeast and mam-

malian cells.130,131 Nickel can induce H3 phosphoryl-ation, specifically in serine 10 (H3S10) via activationof the c-jun N-terminal kinase/stress-activated proteinkinase pathway.132

Cadmium

Cadmium (Cd) has been shown to alter global DNAmethylation.133 Takiguchi et al.134 demonstrated thatCd inhibits DNMTs and initially induces global DNAhypomethylation in vitro (TRL1215 rat liver cells).However, prolonged exposure was shown to lead toDNA hypermethylation and enhanced DNMTs activityin the same experiment.134 Cd can also decrease

DNA methylation in proto-oncogenes and promoteoncogenes expression that can result in cellproliferation.133,134

Transcriptional and post-transcriptional gene regu-lation is critical in responses to Cd exposure, in

which miRNAs may play an important role.135,136

Bollati et al.137 have recently demonstrated thatincreased expression of miR-146a in peripheral bloodleucocytes from steel workers was related to inhal-ation of Cd-rich air particles. miRNA-146a expres-sion is regulated by the transcription factornuclear factor-kappa B, which represents an import-ant causal link between inflammation andcarcinogenesis.138

Other metals

Mercury (Hg) is widely present in various envir-onmental media and foods at levels that can ad-

versely affect humans and animals. Exposure to Hghas been associated with brain tissue DNA hypo-methylation in the polar bear.139 Arai et al.140 havestudied the effects of Hg on DNA methylation statusin mouse embryonic stem cells. After 48 or 96 h ofexposure to the chemical, they observed hypermethy-lation of Rnd2 gene in Hg-treated mouse embryonicstem cells.

Lead is among the most prevalent toxic environmen-tal metals, and has substantial oxidative properties.

Long-term exposure to lead was shown to alter epi-genetic marks. In the Normative Aging Study, LINE-1methylation levels were examined in association withpatella and tibia lead levels, measured by K-X-Rayfluorescence. Patella lead levels were associated withreduced LINE-1 DNA methylation. The association be-tween lead exposure and LINE-1 DNA methylationmay have implications for the mechanisms of actionof lead on health outcomes, and also suggests thatchanges in DNA methylation may represent a bio-marker of past lead exposure.141 In addition, Pilsner

et al.142 characterized genomic DNA methylation inthe lower brain stem region from 47 polar bearshunted in central East Greenland between 1999 and2001. They have reported an inverse association be-tween cumulative lead measures and genomic DNAmethylation level.

Hexavalent chromium [Cr(VI)] is a mutagen and

carcinogen that has been linked to lung cancer andother adverse health effects in occupational studies.Kondo et al.143 found p16 and hMLH1 hypermethyla-tion in lung cancer patients with past chromateexposure.144 In vitro experiments on cells exposedto binary mixtures of benzo[a]pyrene (B[a]P) andchromium have shown that B[a]P activates Cyp1A1transcriptional responses mediated by the aryl hydro-carbon receptor (AhR), whereas chromium repressesB[a]P-inducible AhR-mediated gene expression145,146

by inducing cross-links of histone deacetylase 1DNAmethyltransferase 1 (HDAC1DNMT1) complexes tothe Cyp1A1 promoter chromatin and inhibit histonemarks, including phosphorylation of histone H3Ser-10, trimethylation of H3 Lys-4 and various acetyl-ation marks in histones H3 and H4. HDAC1 andDNMT1 inhibitors or depletion of HDAC1 or DNMT1

with siRNAs blocked the chromium-induced tran-scriptional repression by decreasing the interactionof these proteins with the Cyp1A1 promoter andallowing histone acetylation to proceed. By inhibitingCyp1A1 expression, chromium stimulate the forma-tion of B[a]P DNA adducts. These findings maylink histone modifications to chromium-associateddevelopmental and carcinogenic outcomes.147

Chromate exposure of human lung A549 cells hasbeen shown to increase the global levels of di- and

tri-methylated histone H3 lysine 9 (H3K9) and lysine4 (H3K4), but decrease tri-methylated histone H3lysine 27 (H3K27) and di-methylated histone H3 ar-ginine 2 (H3R2). Most interestingly, H3K9 dimethyla-tion was enriched in the human MLH1 gene promoterfollowing chromate exposure, and this was correlated

with decreased MLH1 mRNA expression. Chromateexposure increased the protein as well as mRNAlevels of G9a, a histone methyltransferase that specif-ically methylates H3K9. This Cr(VI)-induced increasein G9a may account for the global elevation of H3K9dimethylation. Furthermore, supplementation withascorbate, the primary reductant of Cr(VI) and alsoan essential cofactor for the histone demethylase ac-

tivity, partially reversed the H3K9 dimethylationinduced by chromate. These results suggest thatCr(VI) may target histone methyltransferases anddemethylases, which in turn affect both global andgene promoter-specific histone methylation, leadingto the silencing of specific tumour suppressorgenes.148

Recent investigations have demonstrated that alu-minum exposure can alter the expression of anumber of miRNAs. miR-146a in human neural cells

was up-regulated after treatment with aluminium



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sulphate. Up-regulation of miR-146a corresponded tothe decreased expression of complement factor H, arepressor of inflammation.149 In addition, a study onaluminium-sulphate-treated human neural cells inprimary culture has shown increased expression of aset of miRNAs, including miR-9, miR-125b andmiR-128.150 The same miRNAs were also found to

be up-regulated in brain cells of Alzheimer patients,suggesting that aluminum exposure may induce gen-otoxicity via miRNA-related regulatory elements.150

Pesticides

Growing evidence suggests that epigenetic eventscan be induced by pesticide exposures.28,151153

Animal models have shown that exposure to somepesticides, such as vinclozolin and methoxyclor, in-duces heritable alterations of DNA methylationin male germline associated with testis dysfunc-tion,154156 or affects ovarian function via alteredmethylation patterns.157 Decreased methylation in

the promoter regions of c-jun and c-myc and increasedlevels of their mRNAs and proteins were foundin livers of mice exposed to dichloro- and trichloro-acetic acid.158,159 Dichlorvos has been demonstratedto induce DNA methylation in multiple tissues inan animal toxicity study.160 DNA methylation in re-petitive elements in blood DNA was inversely asso-ciated with increased levels of plasma pesticideresidues and other persistent organic pollutantsin an Arctic population,161 a finding later confirmedin a similar study in a Korean population.162 Whetheraberrant DNA methylation represents the link be-tween pesticides and risks of pesticide-related disease,including the excess of cancer risk observed in

some epidemiology studies,

163168

remains to bedetermined.Dieldrin, a widely used organochlorine pesticide, has

been shown to increase acetylation of core histonesH3 and H4 in a time-dependent manner. Histoneacetylation was induced within 10 min of dieldrin ex-posure, suggesting that histone hyperacetylation is anearly event in dieldrin-induced diseases. Treatment

with anacardic acid, a histone acetyltransferaseinhibitor, decreased dieldrin-induced histone acetyl-ation.169 Dieldrin was further shown to induce his-tone hyperacetylation in the striatum and substantianigra in mouse models, suggesting the roles forhistone hyperacetylation in dieldrin-induced dopa-

minergic neuronal degeneration.170

Air pollution

Exposure to particulate matter (PM) of ambient airpollution has been associated with increased morbid-ity and mortality related to cardiovascular and re-spiratory diseases.171,172 Black carbon, a componentof PM derived from vehicular traffic, has beenlinked to decreased DNA methylation in LINE-1 re-petitive elements in 1097 blood DNA samples of

elderly men in the Boston area. Additional evidencefor PM effects on DNA methylation stemmed from aninvestigation of workers in a steel plant with

well-characterized exposure to PM with diameters of


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poly (ADP-ribose) polymerases-1 (PARP-1), a geneinvolved in DNA repair.188

Bisphenol A

Bisphenol A (BPA) is an endocrine disruptor withpotential reproductive effects, as well as a weakcarcinogen associated with increased cancer risk inadult life through fetal exposures.189,190 BPA is

widely used as an industrial plasticizer in epoxyresins for food and beverage containers, baby bottlesand dental composites.191 Dolinoy et al.192 reportedthat periconceptional exposure to BPA shiftedthe coat colour distribution of the viable yellowagouti (Avy) mouse offspring toward yellow bydecreasing CpG methylation in an intracisternal Aparticle (IAP) retrotransposon upstream of the

Agouti gene.193 In this animal model, the yellow-coat phenotype is associated with increased cancerrates, as well as with obesity and insulin resistance.In the same set of experiments, maternal dietary sup-

plementation, with either methyl donors like folicacid or the phytoestrogen genistein, blunted theeffect of BPA on IAP methylation and prevented thecoat colour change caused by BPA exposure.192 Inpregnant CD-1 mice treated with BPA, Bromeret al.194 found decreased methylation and increasedexpression of the homeobox gene Hoxa10, which con-trols uterine organogenesis. In breast epithelial cellstreated with low-dose BPA, gene expression profilingidentified 170 genes with expression changes in re-sponse to BPA, of which expression of lysosomal-associated membrane protein 3 (LAMP3) was shownto be silenced due to DNA hypermethylation in itspromoter.195

In a recent study by Avissar-Whiting et al.,

196

anelevated expression of miR-146a was observed inBPA-treated placental cell lines and miR-146a expres-sion was associated with slower cell proliferationand higher sensitivity to the bleomycin-inducedDNA damage.

Dioxin

Dioxin is a compound that has been classified as ahuman carcinogen by the International Agency forResearch on Cancer. As dioxin is only a weak muta-gen, extensive research has been conducted to identifypotential mechanisms contributing to carcinogenesis.One proposed pathway to carcinogenesis is related to

the powerful dioxin-induced activation of microsomalenzymes, such as CYP1B1, that might activateother procarcinogen compounds to active carcinogen.The capability of dioxin to induce CYP1B1 has beenrecently shown in vitro to depend on the methylationstate of the CYP1B1 promoter.197 Also, dioxin wasshown to reduce the DNA methylation level of Igf2in rat liver.198 Recently, alterations in DNA methyla-tion at multiple genomic regions were identified insplenocytes of mice treated with dioxin, a finding

potentially related to dioxin immunotoxicity.199 In axenograft mouse model of hepatocellular carcinoma,Elyakim et al.200 have also found that dioxinup-regulated miR-191. In the same study, inhibitionof miR-191 inhibited apoptosis and decreased cell pro-liferation, suggesting that increased miR-191 expres-sion may contribute to determine dioxin-induced

carcinogenicity.

Hexahydro-1,3,5-trinitro-1,3,5-triazine(RDX, also known as hexogen or cyclonite)

Hexahydro-1,3,5-trinitro-1,3,5-triazine (commonlyknown as RDX, the British code name for RoyalDemolition Explosive) is an explosive polynitramineand common ammunition constituent used in mili-tary and civil activities. Although most of this envir-onmental pollutant is found in soils, RDX and itsmetabolites are also found in water sources.201

Exposure to RDX and its metabolites could causeneurotoxicity, immunotoxicity and cancers.202 Zhang

et al.202

have recently evaluated the effects of RDX onmiRNA expression in mouse brain and liver. In thisstudy, out of 113 miRNAs, 10 were up-regulated and3 were down-regulated. Most of the miRNAs thatshowed altered expression, including let-7, miR-17-92, miR-10b, miR-15, miR-16, miR-26 and miR-181, were found to regulate toxicant-metabolizingenzymes, as well as genes related to carcinogenesisand neurotoxicity.202

Diethylstilbestrol

Diethylstilbestrol (DES) is a synthetic oestrogen thatwas used to prevent miscarriages in pregnant womenbetween the 1940s and the 1960s.203 A moderate in-crease in breast cancer risk has been shown both indaughters of women who were treated with DESduring pregnancy, as well as in their daughters.204

Hsu et al.205 have demonstrated that the expressionof 82 miRNAs (9.1% of the 898 miRNAs evaluated)

were altered in breast epithelial cells when exposed toDES. In particular, the suppression of miR-9-3 expres-sion was accompanied by promoter hypermethylationof the miR-9-3 coding gene in DES-treated epithelialcells.205

Chemicals in drinking water

Chlorination by-products are formed as a result of the

water chlorination for anti-fouling purposes. Variouschlorination by-products in drinking water, such astriethyltin,206 chloroform207 and trihalomethanes,208

have been questioned for potential adverse healtheffects.209 These chemicals have been shown toinduce certain epigenetic changes. Rats that werechronically intoxicated with triethyltin in drinking

water showed development of cerebral oedema aswell as an increase of phosphatidylethanolamine-N-methyltransferase activities. This increased



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methylation might be a compensatory mechanism forcounteracting the membrane damages induced bytriethyltin.206 Chloroform, dichloroacetic acid (DCA)and trichloroacetic acid (TCA), three liver and kidneycarcinogens, are by-products of chlorine disinfectionfound in drinking water.210,211 Mice treated withDCA, TCA and chloroform show global hypomethyla-

tion and increased expression of c-myc, a proto-oncogene involved in liver and kidney tumours.207

Trihalomethanes (chloroform, bromodichloro-methane, chlorodibromomethane and bromoform) areregulated organic contaminants in chlorinated drink-ing water. In female B6C3F1 mouse liver, trihalo-methanes demonstrated carcinogenic activity.Chloroform and bromodichloromethane decreased thelevel of 5-methylcytosine in hepatic DNA. Methylationin the promoter region of the c-myc gene was reducedby the trihalomethanes, consistent with their carcino-genic activity.208

Environmental epigenomics:challenges and opportunitiesfor epidemiologic studiesThe studies reviewed in this article have demonstratedthe potential effects of environmental pollutants onthe epigenome. Several of the epigenomic changesobserved in response to environmental exposuresmight be mechanistically associated with susceptibil-ity to diseases (Table 1). Further studies of epigeneticmechanisms in disease pathogenesis, including therole of epigenetics in the developmental origins ofhealth and disease, their relationships with environ-

mental exposures and the pathways associated withthe disease phenotype may help develop preventiveand therapeutic strategies.

Epigenetics and developmental originsof health and disease

During embryogenesis, epigenetic patterns changedynamically to adapt embryos to be fit for furtherdifferentiation.7 Two waves of epigenetic reprogram-ming, which take place at the zygote stage and duringprimordial germ cells formation, accompany mamma-lian development.212

Experiments on mice carrying the Avy have demon-strated that embryo life is a window of exquisite sen-

sitivity to the environment. In viable yellow (Avy/a)mice, transcription originating in a IAP retrotrans-poson inserted upstream of the agouti gene (A)causes ectopic expression of agouti protein, result-ing in yellow fur, obesity, diabetes and increasedsusceptibility to tumours.213 BPA is a high-production-volume chemical used in the manufactureof polycarbonate plastic. In utero or neonatal expos-ure to BPA is associated with higher body weight,increased breast and prostate cancer and alteredreproductive function.

Additional experimental studies have suggested epi-genetic mechanisms as potential intermediates forthe effects of prenatal exposures to pesticides suchas vinclozolin and methoxyclor,154 as well as of other conditions such as nutritional supplies ofmethyl donors.192 Evidence has also been accumulat-ing in humans. Investigations of candidate loci among

individuals prenatally exposed to poor nutritionduring the Dutch famine in 194445 indicate that epi-genetic changes induced by prenatal exposures maybe common in humans, although they appear to berelatively small and greatly dependent on the timingof the exposure during gestation.214,215 Based on find-ings of changes in DNA methylation in subjectsexposed to the Dutch famine, Heijmans et al.216

have suggested that the epigenome may representa molecular archive of the prenatal environment,

via which the in-utero environment may produce ser-ious ramifications on health and disease later in life.Terry et al.217 found that prenatal exposure to cigar-ette smoke was associated with increased overallblood DNA methylation level in adulthood. Otherexamples include decreased LINE-1 and Sat 2 methy-lation level in adults and children prenatally exposedto smoking,218 and global DNA hypomethyla-tion in newborns with utero exposures of maternalsmoking.219 In addition to these DNA methylationchanges, Maccani et al.220 have recently observedthat miR-16, miR-21 and miR-146a were down-regulated in cigarette smoke-exposed placentas com-pared to controls.

Additional well-conducted epigenetic studies arenow warranted to generate a catalogue of regionsthat are sensitive to the prenatal environment and

may reflect developmental influences on humandisease.

Can we develop epigenomic biosensors ofpast exposures?

An important property of epigenomic signatures isthat, because they can be propagated through cell div-ision even in cells with high turnover, they can persisteven after the exposure is removed. In addition, asdiscussed above, an individuals epigenome may alsoreflect his/her prenatal environmental exposure ex-perience. Thus, epigenomic profiling of individualsexposed to environmental pollutants might provide

biosensors or molecular archives of ones past oreven prenatal environmental exposures. Using epige-nomics, exposure assessment might be brought to re-search investigations and preventive settings whererepeated collections of exposure data might be un-feasible or exceedingly expensive. Further research isneeded to establish how rapid are the changesinduced by environmental pollutants, as well as

whether they accumulate in response to repeated orcontinuous exposure and how long they persist afterthe exposure is removed.



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What are suitable study designs andapproaches for environmental epigenomics?

The field of environmental epigenetics has evolvedrapidly in the past several years. As research applica-tions grow, investigators will be facing several diffi-culties and challenges. Some studies have producedinconsistent results on same pollutants. Several fac-

tors may contribute to the inconsistencies. Epigeneticalterations are tissue specific.221 It is conceivable thatthe same environmental pollutant may produce differ-ent epigenetic changes in different tissues, and even

within the same tissue on different cell types. Largerstudies with well-defined exposure information thatallows examining epigenetic changes across differenttissues are needed. Different study design, small sam-ple size and different laboratory methods may also bemajor causes for the inconsistency. Replicating resultsand identifying the sources of variability across stu-dies is a major challenge for epigenetic investigations.Because epigenetic markers change over time, diseaseoutcomes are prone to reverse causation, i.e. an asso-

ciation between a disease and an epigenetic markermay be determined by an influence of the disease onthe epigenetic patterns, rather than vice versa.222

Although epigenetic alterations that were found tobe induced by or associated with environmental pol-lutants were also found in various diseases, almost nostudy has examined the sequence of exposures, epi-genetic alterations and diseases.

Longitudinal studies with prospective collection ofobjective measures of exposure, biospecimens for epi-genetic analyses and preclinical and clinical diseaseoutcomes are needed to appropriately establish caus-ality. Existing prospective epidemiology investigationsmight provide resources for mapping epigenomic

changes in response to specific chemicals. However,cohort studies in which biospecimens have been pre-

viously collected for genetic or biochemical studiesmight pose several challenges. Most studies have col-lected biospecimens, such as blood, urine or buccalcells, which might not necessarily participate in theaetiology of the disease of interest. Methods of collec-tion and processing (e.g. whole blood vs buffy coat)might modify the cell types stored, thus potentiallyimpacting on epigenetic marks. In addition, high-coverage methods providing high-dimensional dataon DNA methylation, histone modifications andmiRNA expression are increasingly used in humaninvestigations.

Albeit epigenetic mechanisms have propertiesthat make them ideal molecular intermediates of en-

vironmental effects, the proportion of the effects ofany individual environmental exposure that mightbe mediated through epigenetic mechanisms isstill undetermined. Epidemiology and statisticalapproaches, including well-designed prospectivestudies and advanced statistical methods for causalinference are urgently needed. Similarly to genomicstudies,223 epidemiological causal reasoning in

epigenomics should include careful consideration ofknowledge, data, methods and techniques from mul-tiple disciplines.

The potential interactions between differentforms of epigenetic modification

Most studies in environmental epigenetics have sep-arately evaluated only one of the types of the epigen-etic marks, i.e. DNA methylation, histonemodifications or miRNA expression. However, epigen-etic marks are related by an intricate series of inter-actions that may generate a self-reinforcing cycle ofepigenetic events directed to control gene expres-sion.224 For instance, histone deacetylation andmethylation at specific amino acid residues con-tribute to the establishment of DNA methylation pat-terns. miRNA expression is controlled by DNAmethylation in miRNA encoding genes, and, in turn,miRNAs have been shown to modify DNA methyla-tion.225 Future studies that include comprehensive

investigations of multiple epigenetic mechanismsmight help elucidate the timing and participation ofDNA methylation, histone modifications and miRNAsto determine environmental effects on diseasedevelopment.

Can epigenomics be used for prevention?

One major objective of epidemiology investigations isto provide the groundwork for future preventive inter-

ventions. Numerous clinical and preclinical studiesshowed that most of the epigenetic changes are re-

versible, which offers novel insights to develop newpreventive and therapeutic strategies that might takeadvantage of molecules that modify the activities ofepigenetic enzymes, such as DNMTs and HDACs, as

well as of the growing field of RNAi therapeutics.Drugs have been designed and developed that pro-duce functional effects, such as histone acetylationand DNA hypomethylation that might be used to re-store the normal transcription level of genes. Futureepidemiology studies have a unique opportunity toevaluate whether the effects of environmental expos-ures on the epigenome are mitigated by positivechanges in lifestyles, or worsened by the interaction

with other risk factors. Future epigenomic researchmay provide information for developing preventivestrategies, including exposure reduction, as well aspharmacological, dietary or lifestyle interventions.

FundingOur work is partially supported by grants from theHSPH-NIEHS Center for Environmental Health NewInvestigator Fund (P30ES000002) and NIH award1RC1ES018461-01.

Conflict of interest: None declared.



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KEY MESSAGES

Rapidly growing evidence has linked environmental pollutants with epigenetic variations, includingchanges in DNA methylation, histone modifications and microRNAs.

Some of such epigenetic changes have been associated with various diseases.

Further studies of epigenetic mechanisms in disease pathogenesis, their relationships with environ-mental exposures and related pathways are needed for the development of preventive and therapeuticstrategies.

Future epidemiology studies on environmental pollutants and epigenome face several challenges.

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