Environmental Stressors Induced Epigenetic Marker Modifications: an Overview
Environmental chemical stressors as epigenome modifiers: A new horizon in assessment of toxicological effects
HeqingShen 1,*, F. L. Martin2 Yanhua Su 3
1Key Laboratory of Urban Environment and Health, Institute of Urban Environment, ChineseAcademy of Sciences, Xiamen 361021, PR China;
2Centre for Biophotonics, Lancaster Environment Centre, LancasterUniversity, LancasterLA1 4YQ, UK;
3Department of Preventive Medicine, School of Public Health of XiamenUniversity, Xiamen 361005, PR China
*Corresponding author:(email: )
Table S1 Effects of environment factors on histone modification and chromatin remodelling
Chemical / Model / Histone modification and chromatin remodelling / Note / ReferenceNi / Chinese hamster transgenic gpt1 cells / global H4ac↓ / gpt silencing / [27]
global H3K9me & H3K9me2↑ / DNA↑, gtp long-term silencing
Human airway epithelial cells / H2Aac, H2Bac, H3ac & H4ac↓ / K12 & K20 changed more than K5 & K15 in H2B / [28]
Rat kidney tubular epithelial cells
Human lung bronchoepithelial A549 cells / H2Aac, H2Bac, H3ac & H4ac↓; H3K9me2, H2Aub & H2Bub↑ / Minimum cytotoxicity / [29]
Human hepatoma Hep3B cells
Mouse epidermal JB6 C141 cells
Chinese hamster transgenic gpt+/- cells
Peripheral blood mononuclear cells / global H3K4me3↑, H3K9ac↓, H3K9me2↓ / Ni in urine / [98]
Ni/As/Fe / Steel worker blood leukocytes / H3K9ac↑, H3K4me2↑ / H3K4me2 is more sensitive / [99]
MeHg / Mice GD7-PB7 exposure / H3K27me3↑& H3ac↓ / Promoter IV of BDNF gene in hippocampus of the foetus mice / [33]
Fluoxetine / MeHg treated mice GD7-PB8 exposure / H3K27me3→& H3ac↑
Cr / Mouse hepatoma Hepa-1 cells / blocking B[a]P-dependent HDAC-1 release; preventing p300 binding to chromatin; CYP1A1↓ / [30]
B[a]P / HeLa cells / H3K4Me3↑& H3K9Ac↑of LINE1 / DNMT1gene LINE1 promoter CpG↓ / [84]
B[a]P / Mouse hepatoma Hepa-1c1c7 cells / H3S10ph↑, H3K4me3↑, H3ac↑, H4ac↑ / CYP1A1↑ / [32]
Cr/B[a]P / Mouse hepatoma Hepa-1c1c7 cells / cross-link HDAC1-DNMT1 complexes in CYP1A1 gene promoter chromatin
AsIII / Human lung carcinima A549 cells / H3K4me3↑, H3K9me2↑, H3K27me3↓, H3K36me3↑, H3K36me2↓ / H3K9me2↑with ↑G9a of HMT / [100]
Selenite / Human prostate cancer LNCaP cells / H3K9ac↑, H3K9me↓ / HDAC↓ / [83]
TCDD / MCF-7 cells / H3K9ac↑, H3K14ac↑, H3K4me3↑, H4ac↑of CYP1B1 gene / AHR, p300, PCAF to enhancer / [101]
NP / Circulating myeloid dendritic cells / H3ac↑, H4Ac↑, H3K4me3↑of TNFA locus / ↑MTC [MLL & WDR5] / [102]
Phenols / sf9 cells / ER-α & ER-β mediated HAT↑; equol, genistein, AglyMax, daidzein (no affect on ER-α), 17β-estradiol (impact ER-α stronger than ER-β) / [64]
ac: acetylation; As: arsenic; Avy: viable yellow agouti; B[a]P: benzo[a]pyrene; BDNF: brain-derived neurotrophic factor; Cr: chromium; DMR: differentially methylated region; DNMT: DNA methyltransferase; Fe: iron; GD: gestational day; GSTP: glutathione-S-transferase π; HAT: histone acetyltransferase; HDAC: histone deacetylase; HMT: histone methyltransferase; IFG: insulin-like growth factor; MeHg: methylmercury; MBD: methyl-CpG binding protein; me: methylation; MLL: mixed-lineage leukemia; MTC: methyltranferase complex; Ni: nickel; NP: nonylphenol; PCAF: p300/cAMP response element-binding protein binding protein-associated factor; AHR: aryl hydrocarbon receptor; PB: postnatal day; ph: phosphorylation; SAH: S-adenosyl homocysteine; SAM: S-adenosyl methionine; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TNFA: tumor necrosis factor-α gene; ub: ubiquitination; WDR5: tryptophan-aspartic acid repeat domain 5
Table S2. Effects of environment factors on global DNA and gene promoter methylation
Chemical / Model / Global DNA or gene promoter methylation / Note / ReferencePM / Human blood / LINE1↓, Alu→ / Black carbon of the traffic tracer / [103]
PM2.5 / Human blood / LINE1↓, Alu→
PM10 / Human blood / LINE1↓, Alu↓ / Long-term exposure / [71]
PM10 / Human blood / iNOS↓ / Nitric oxide synthase (iNOS); post-exposure
SiO2 / Human HaCaT cells / DNA↓ / DNMT1, DNMT3A↓& MBD2↓; nanoparticles exposure / [104]
Pu / Human lung adenocarcinoma / RASSF1A↓, p16↑ / Ras effector homolog1 gene & CDKN2A; radiation exposure / [36]
Pb / Cord blood / Alu↓ / Pb in mid-tibial shaft / [105]
LINE-1↓ / Pb in patella
Pb / Human male blood / LINE-1↓ / Pb in patella / [89]
As / Human blood / p53↑, p16↑ / p53 in exposed people & As induced skin cancer patients;p16 at high level only / [39]
As / Human HaCaT keratinocyte / DNA↓ / HPLC analysis / [37]
POPs / Human blood (Greenlandic Inuit) / Alu↓ / p,p´-DDT, p,p´-DDE, β-hexachlorocyclohexane, oxychlordane, α-chlordane, mirex, total PCBs, and total POPs in plasma / [88]
POPs / Human blood (Koreans) / Alu↓, LINE-1→ / oxychlordane, trans-nonachlor, p,p'-DDE / [87]
MD1 / Pregnant mice / Agouti↑ / agouti long terminal repeat; methyl donor (MD) 1 change offspring phenotype / [75]
MD2 / Mice / germ-line exposure affect somatic Avy epigenetic state when the allele is paternally contributed / [76]
MD / Pregnant mice / Avy↑ / Metastable epiallele in the offspring / [77]
MD / Female mice / AxinFu ↑ / Murine metastable epiallele axin fused; before and during pregnancy exposure / [78]
Se / Fisher-344 rat / DNA↓ / DNA of colonic; Se deficiency/Se and folate interacted with one-carbon metabolism / [56]
BPA / Avy mouse / Agouti, CabpIAP↓ / Offspring intracisternal A particle retrotransposon upstream of Agouti gene and CabpIAPmetastable epiallele / [47]
Folic acid / Folic acid negated BPA effect in offspring
Genistein / Agouti↑ / Decreasing ectopic Agouti expression from embryonic to adulthood & protecting offspring from obesity; genistein negated BPA effect in offspring / [60]
Genistein / C57BL/6J line male mice / 8-wk-old exposure and prostate DNA hypermethylation at CpG islands of specific mouse genes↑ / [59]
EGCG / Human oesophageal cancer KYSE510 cell / p16INK4a↑, retinoic acid receptor β gene↑, O6-methylguanine methyltransferase gene↑, human mutL homologue genes↑((-)-epigallocatechin-3-O-gallate (EGCG)) / [61]
BPA / SD rat / PBE4D4↓ / 5'-flanking CpG island of PBE4D4 gene expression against ageing induced hypermethylation and gene silence in normal prostate; transient exposure in PB1, 3, 5 / [46]
Oestradiol
Cr / Lung cancer / p16INK4a↑ / >15 years exposure / [31]
DBP / Male Wistar rat liver / c-myc↓ / Protooncogene / [106]
DBP & BzBP / MCF7 cell / ER-α↓ / [50]
DEHP / Pregnant mice / DNA↑ / Offspring tests at GD19 and PB21 / [53]
Polyphenols / Human breast cancer cell lines (MCF-7 MDA-MB-231) / DNA↓ / EGCG inhibition of DNMT directly or catechin, epicatechin, quercetin, fisetin and myricetin via S-adenosyl-L-homocysteine pathway / [62]
DES / Neonatal femal mouse / LF↓ / Neonatal (PB 1-5) response of the upstream CpG-464 of oestrogen response element of LF promoter in uterus / [107]
CD-1 mice (PB1-5) / c-fos exon-4↓ / Uterine tissues c-fos expression in PB17-60 / [43]
C57BL/6 male mice (PB1-5) / 7 loci↓& 1 locus↑ / 4 of 7↓lociwithin CpG island not associated with (diethylstilbestrol) DES-induced reproductive organ abnormalities and oestrogen-response genes in epididymis / [45]
CSE / A549 lung cancer cell / synuclein-γ↓ / DNMT3B (not expressed in normal lung tissue)↓; synuclein-γ gene is prometastatic oncogene; cigarette smoke extract (CSE) / [65]
Alcohol / Human sperm / CpG#7 of H19 DMRs↓ / H19 DMRs located -2 kb upstream of H19 gene on chromosome 11p15.5 & CpG#7 within CTCF zinc finger insulator protein binding site 6 / [69]
CpG#4 of IGDMRs↓ / IGDMR is located -15 kb upstream of GTL2 and -85 kb downstream of DLK1 on chromosome 14q32
MeHg / Pregnant mice (GD7-PB7) / BDNF↑ / BDNF gene in hippocampus / [33]
PAH / Human cord blood white cell / 5'-CpG of ACSL3↑ / ACSL3: Acyl-CoA-synthetase long-chain family member 3; PAH of airborne / [66]
Urine As / Peripheral blood leukocyte / DNA↑ / When plasma folate 9 nmol/L (3H-methyl incorporation assay) / [40]
Folate / DNA↑ / 3H-methyl incorporation assay; plasma folate / [40]
Cd / Fisher 344 rat TRL1215 liver cell / Initially DNMTs↓and DNA↓, but prolonged exposure DNMTs↑and DNA↑ / [35]
Cd / Hepatic nuclei of rat (+/- choline and folate feeding) / DNMTs↓via binding Zn finger domain; not essential for catalytic activity but the alteration of site specificity and increasing de novo methylation for Cd exposure / [34]
Zn
B[a]P / HeLa cells / LINE1 promoter CpG↓ / DNMT1↓; LINE1 H3K4Me3 & H3K9Ac↑ / [84]
Cigarette smoke / Induced mice lung tumour cell line / DAPK↑ / Cigarette smoke-treated female B6C3F1 / [67]
NNK / 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treated female A/J
Vinyl carbamate / Vinyl carbamate treated female C3A
Methylene chloride / Methylene chloride treated female B6C3F1
ADOC / Induced mice lung tumour cell lines / DAPK↓ / 5-Aza-2'-deoxycytidine (ADOC) returned the silenced gene into activation
Chloroform / Female B6C3F1 mice hepatic / DNA↓, c-myc↓ / c-myc is a protooncogene, DNA measured by HPLC / [108]
BDCM / Bromodichloromethane (BDCM)
CDBM / c-myc↓ / Chlorodibromomethane (CDBM)
Bromoform
Phenobarbital / Male mice B6C3F1 or C57BL/6 / B6C3F1 mice liver DNA↓, C57BL/6 mice liver DNA→ / [109]
CMD / B6C3F1 and C57BL/6 mice liver DNA↓(CDM: choline-devoid/methionine deficient diet)
Peroxisome proliferators / Male B6C3F1 mice liver / c-myc↓; treated by 2,4-dichlorophenoxyacetic acid, dibutyl phthalate (DBP), gemfibrozil, Wy / [110]
Wy / Female B6C3F1 mice liver / c-myc gene↓ / SAM and SAH→, DNMTs↑ / [111]
Wy/methionine / Methioine reversed Wy (4-chloro-6-[2,3-xylidino]-2-pyrimidinylthioacetic acid) changed c-myc methylation
DCA/methionine / Female B6C3F1 mice liver / Methionine prevented the DNA hypomethylation caused by dichloroacetic acid (DCA) / [112]
DCA,TCA / Female B6C3F1 mice liver / DNA↓ / TCA: trichloroacetic acid / [113]
DCA,TCA / Female B6C3F1 mice liver / IGF-II↓ / Upstream of DMR-2 of IGF-II; N-methyl-N-nitrosourea initiated liver tumors / [116]
DBA / Female B6C3F1 mice liver / c-myc IGF-II↓ / Dibromoacetic acid (DBA) cause peroxisome proliferation / [115]
TCE, DCA, TCA / Female B6C3F1 mice liver / c-jun c-myc↓ / Protooncogene genes; methionine prevented trichloroethylene (TCE), DCA, and TCA induced methylation / [116]
DCA, TCA / Female B6C3F1 mice liver / c-jun c-myc↓ / DNMTs activity was increased in tumours initiated by N-methyl-N-nitrosourea while decreased in surrounding non-involved liver / [117]
DCA, TCA / Male B6C3F1 mice kidney / DNA c-myc↓ / The change not be observed in female and it is prevented by methionine / [52]
DBA, BDCM / Male B6C3F1 mice and male Fischer 344 rat kidney / DNA↓ / In kidney / [52]
TCDD / Mouse pre-implantation embryos / IGF-II↑ / H19/IGF-II imprint control region at one cell to blastocyst stage / [49]
PFOA / Human liver cell L02 / GSTP↑ / [118]
PFOS / SD rat PB21 liver / DNALINE-1↓, GSTP↑ / DNA & LINE-1↓from 2.0 mg/kg/d group; GSTP↑from 0.6 mg/kg/d group via pathway Keap1-Nrf2/MafK; GD2 - 21 exposure / [119]
Se / Human prostate cancer cell line LnCaP / DNA↓ / With DNMT1↓and DNMT3A↓ / [83]
Se / Human prostate cancer cell line LnCaP / GSTP1, APCCSR1↓ / The silenced GSTP1, adenomatous polyposis coli (APC) gene and cellular stress response 1 (CSR1) gene re-expressed / [83]
Green tea / Human gastric carcinoma tissue specimens / CDX2BMP2↓ / Homeobox transcription factor (CDX2) , bone morphogenetic protein 2(BMP2) and p16 methylation status revealed significant interrelationship / [63]
ADOC: 5-Aza-2'-deoxycytidine; Avy: viable yellow agouti; B[a]P: benzo[a]pyrene; BDCM: Bromodichloromethane; BDNF: Brain-derived neurotrophic factor; BPA: bisphenol A; BzBP: Benzyl Butyl Phthalate; CabpIAP: CDK5 activator-binding protein; CDBM: Chlorodibromomethane; CMD: choline-devoid/methionine deficient diet; CSE: cigarette smoke extract; DAPK: death-associated protein-kinase; DBA: dibromoacetic acid; DBP: dibutyl phthalate; DCA: dichloroacetic acid; DES: diethylstilbestrol; DEHP: di-(2-ethylhexyl) phthalate; DMR: differentially methylated region; DNMT: DNA methyltransferase; EGCG: (-)-epigallocatechin-3-O-gallate; GD: gestational day; GSTP: glutathione-S-transferase π；HAT: histone acetyltransferase; HDAC: histone deacetylase; HMT: histone methyltransferase; IFG: insulin-like growth factor; LF: lactoferrin; MBD: methyl-CpG binding protein; MD: methyl donor; MeHg: methylmercury; NNK: 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone; PAH: polycyclic aromatic hydrocarbon; PB: postnatal day;PBE4D4: phosphodiesterase type 4 variant; PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonic acid; PM: particulate matter; POP: persistent organic pollutant; Pu: plutonium; Pb: lead; SAH: S-adenosyl homocysteine; SAM: S-adenosyl methionine; ub: ubiquitination; Se: selenium; SiO2: silicon dioxide; TCA: trichloroacetic acid; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCE: trichloroethylene; Zn: zinc
Table S3. Effects of environment factors on the alteration of micro-RNA profile
Chemical / Model / Micro-RNA (miR) / Note / ReferencePM1,10 / Human blood leukocyte / miR-222,-21 ↑ / Post-exposure to metal-rich particle material: PM / [73]
Pb in PM / miR-222 ↑
Pb, Cd in PM / miR-146a ↓
Cigarette smoke / Lung of rat / let-7, miR-10, -26, -30, -34, -99, -122, -123, -124, -125, -140, -145, -146, -191, -192, -219, -222, -223↓ / Down-regulated miRs involved stress response, apoptosis, proliferation, angiogenesis, and expression of genes / [68]
miR-294 ↑ / miR-294 is inhibitor of transcriptional repressor genes
Diesel exhaust particles / Human airway epithelial cell / miR-31, -26b, -96, -27a, -135b -374a↓ / Associated with inflammatory responses pathways and a strong tumorigenic disease signature / [72]
miR-513c, -513b, -513a-5p, -923, -494 -338-5p↑
Nonylphenol / MCF-7 HepG2 / let-7c, miR-16, -195, -200b, -200c, -205 -589 / Human breast cancer cell MCF-7 & human hepatocellular carcinoma HepG2; related to metabolism, immune response, apoptosis cell differentiation / [48]
Tamoxifen / Fisher 344 rat / 17-92 cluster, miR106a, -34↑in liver / Regulation oncogenes that involved cell cycle rugulators, chromatin modifiers, and expression regulators / [58]
Vinclozolin / Mice testicular Sertoli cell / 11 miR expression alteration including murine specific mmu-miR-21, 22, 30c, 92, 155 and 378 and the highly conserved miR-92, -289, -494, -23a -493 / [42]
Cd: cadmium; Pb: lead; PM: particulate matter