ABSTRACT- Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Out of all these environmental chemicals, effects of air pollution is responsible for death of 3.3 million people prematurely worldwide - a figure that could double by 2050 if emissions continue to rise at the current rate. Increasing number of evidences has linked environmental pollutants with epigenetic variations, including changes in DNA methylation status, histone modifications and other factors like incorporation of miRNAs, nucleosome remodeling, etc. These entire mechanisms are likely to play important roles in disease aetiology, and their modifications, thus providing further understanding of disease aetiology, as well as biomarkers for these exposures to environmental chemicals and/or prediction of the risk for the disease. In this, we had tried to summarize the different epigenetic alterations related to environmental chemical exposures, and propose the probable mechanisms of action behind such epigenetic changes. We will also focus onopportunities, challenges and further directions for future epidemiology research in environmental epigenomics. Further studies are needed in this regard to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. Moreover, there are several reports of epigenetic modifications arising from environmental chemical exposures, but most have not been directly linked to disease endpoints.
Key-words- Environmental chemicals, Epigenetics, Disease susceptibility

INTRODUCTION- Being a part of our daily life, chemicals in the day to day use may also cause different diseases through various mechanisms. Environmental pollutants results inapproximately 13 million deaths approximately every year and as much as 24% of the diseases are estimated to be caused by environmental exposures that can be prevented (Pru¨ss-U¨stu¨n Annette, 2006).Out of all these environmental chemicals, effects of air pollution is responsible for death of 3.3 million people prematurely worldwide - a figure that could double by 2050 if emissions continue to rise at the current rate (Lelieveld et al., 2015).
Growing evidence suggests that environmental pollutants may cause diseases via epigenetic mechanism-regulated gene expression changes (Tang et al., 2007; Bezeket al., 2008). Continuous exposure to many chemicals, including through air, water, food or other media and products resulting in various diseases and health impacts are well assessed, however very little is known about the mechanism at the epigenetic level. This review has tried to summarize the effect of different environmental chemical exposures on epigenetics of various diseases studied till now (Table 1).

Epigenetics-Linking Factor between Environment and different diseases- Epigenetics defined as heritable changes in gene function occuring without a change in the nucleotide sequence (Bird, 2007). These changes in phenotypic traits occur due to variety of mechanisms (Fradin and Bougneres, 2011). An Epigenetic factor that regulates gene expression mostly includes DNA methylations, histone modifications, and expression of microRNAs (miRNAs) (Reik et al., 2001; Grewal and Moazed, 2003). An epigenetic mechanism that modifies chromatin structure can be classified into four main categories: DNA methylation, covalent histone modifications, and non-covalent mechanisms like incorporation of histone variants and nucleosome remodeling and non-coding RNAs including microRNAs (miRNAs).

Epigenetic Changes due to environmental chemical exposures- Changes in these epigenetic factors have been shown to be induced by the exposure to various environmental chemicals linked with different diseases (Baccarelli et al., 2009; Heightman et al., 2011; Wright, 2011).Entire list of such epigenetic changes as described by Hou, Zhang, Wang and Baccarelli due to different environmental factors like pollution, chemicals, pesticides, etc are enlisted in Table 1. Various epigenetic mechanisms responsible for it are described below as follows-

DNA Methylation- Out of all, DNA methylation is the mostthoroughly studied epigenetic modification in mammals, playing an important role in regulating gene expression and chromatin architecture, in association with histone modifications and other chromatin associated proteins. DNA methylation mainly occurs by the covalent modification of cytosine residues in CpG dinucleotides in mammals. In human genome, CpG dinucleotides are not evenly distributed across the human genome but are instead concentrated in ‘CpG islands’ and regions of large repetitive sequences (e.g. centromeric repeats, retrotransposon elements, rDNA etc.) (Bird, 2002; Takai et al., 2002).
During development and in differentiated tissues, most of the CpG sites in the genome are methylated, but the mostof the CpG islands usually remain unmethylated also (Suzuki et al., 2008). However, some CpG island promoters get methylated during development, resulting in long-term transcriptional silencing (Bird, 2002). DNA methylation uses various mechanisms to heritably silence genes and non-coding genomic regions. DNA methylation can lead to gene silencing by either preventing or promoting the recruitment of regulatory proteins to DNA (Prendergastet al., 1991; Wattet al., 1988) or can also mediate gene repression through interactions with histone deacetylases (HDACs) (Jones et al., 1998; Nan et al., 1998).
Recent studies have suggested that DNA methylation is also important for the regulation of non- CpG island promoters (Futscheret al., 2002; Hattoriet al., 2004). In order to fully understand the global role of DNA methylation in normal tissue,it is essential to elucidate the role of non-CpG island methylation, as CpG islands has been found to occupy only approximately of 60% of human gene promoters(Wang et al., 2004).

Covalent Histone Modifications- Histone proteins consist of the nucleosome core, havinga globular C-terminal domain and N-terminal tail (Luger et al., 1997). The N-terminal tails of histones can undergo a variety of posttranslational covalent modifications like methylation, acetylation, ubiquitylation, sumoylation and phosphorylation on specific amino acid residues, resulting in the regulation of key cellular processes such as transcription, replication and repair (Kouzarides, 2007). These modifications are proposed to store the epigenetic memory inside a cell in the form of a ‘histone code’ that determines the structure and activity of different chromatin regions (Jenuweinet al., 2001). Histone modifications take place by either changing the chromatin accessibility or by recruitment of non-histone effector proteins. The mechanism of inheritance of the histone code, however, is still not fully understood.

Nucleosome Remodelling and Histone Variants- Non-covalent mechanism of nucleosome remodeling and presence of specialized histone variants, sometimes also plays an important role in regulation of chromatin structure and gene activity. Nucleosomes regulate gene expression by altering the accessibility of regulatory DNA sequences to transcription factorsin addition to its function as DNA packaging within a cell (Jiang et al., 2009). Nucleosome free regions (NFRs) present at the 5’ and 3’ends of genes provide the sites for assembly and disassembly of the transcription machinery (Yuan et al., 2005). The nucleosome loss directly upstream of the transcription start site is strongly correlated with gene activation (Shivaswamy et al., 2008; Lin et al., 2007). Moreover, the presence of an NFR at gene promoters with basal level of transcription is related with the ability for rapid activation upon stimulation (Gal-Yam et al., 2006). In contrast, shutting off of the transcription start site within the NFR by a nucleosome is associated with gene repression (Schones et al., 2008). NFR modulation is achieved by ATP-dependent chromatin-remodeling complexes, which modifies the accessibility of DNA regulatory sitesthrough both sliding and ejection of nucleosomes (Smith et al., 2005). The interaction between nucleosome remodeling machinery, DNA methylation and histone modifications plays a vital role in establishing global gene expression patterns and chromatin design (Harikrishnan et al., 2005; Wysocka et al., 2006).

Non-coding RNA like miRNAs- miRNAs are small, approximately 22 nucleotides, non-coding RNAs that regulate gene expression through posttranscriptional silencing of target genes. Sequence-specific base pairing of miRNAs with 3’untranslated regions of target mRNA within the RNA-induced silencing complex results in degradation of target messenger RNA or inhibition of translation (He et al., 2004). miRNAs are expressed in a tissue-specific manner and control a wide array of biological processes including cell proliferation, apoptosis and differentiation. The list of miRNAs identified in the human genome and their potential target genes is growing rapidly, demonstrating their extensive role in maintaining global gene expression patterns (Zhang et al., 2007).
Like normal genes, the expression of miRNAs can be regulated by epigenetic mechanisms (Saito et al., 2006). In addition, miRNAs can also modulate epigenetic regulatory mechanisms inside a cell by targeting enzymes responsible for DNA methylation (DNMT3A and DNMT3B) and histone modifications (EZH2) (Fabbriet al., 2007; Friedman et al., 2009). Such interaction among the various components of the epigenetic machinery re-emphasizes the integrated nature of epigenetic mechanisms involved in the maintenance of global gene expression patterns.

Table 1: Effect of Environmental Chemicals on epigenetic changes of various diseases

Environmental Chemicals	Epigenetic Changes	Details of study	Diseases studied	References
Air Pollution	DNA methylation- Global hypomethylation	Human PBL(In vivo)	Various cancers and Schizophrenia	Baccarelli et al.,2009; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	iNOS hypomethylation	Human PBL(In vivo)	Lung cancer	Tarantini et al.,2009; Pereira et al.,2007
	Global hypermethylation	C57BL/CBA mice sperm(In vivo)	Colorectal cancer renal cell carcinoma, acute lymphoblastic leukaemia and bladder urothelial cell carcinoma	Yauk et al.,2008; Cheetham et al.,2008; Alemayehu et al. Norrie et al.,2002; Minardi et al.,2009; Schafer et al.,2010; Owen et al.,2010
	Hypermethylation of IFNg and hypomethylation of IL4	CD4+T-Lymphocytes(In vivo)	Asthma	Liu et al.,2008
	Histone modification - Increased H3K4 dimethylation and H3K9 acetylation	Human PBL(In vivo)	Diabetic nephropathy	Cantone et al.,2011; Sayyed et al.,2010
	Global hypomethylation (Alu, LINE-1)	Human buffy coat(In vivo)	Various cancers and schizophrenia	Klein et al.,2002; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	miRNAs- Increased miR-222	Human PBL(In vivo)	Various cancers	Klein et al.,2002; Felli et al.,2005; le Sage et al.,2007; Garofalo et al.,2009
	Increased miR-21	Human PBL(In vivo)	Various cancers	Klein et al.,2002; Connolly etal.,2008; Chan et al.,2005; Iorio et al.,2005; Frankel et al.,2008; Zhu et al.,2007; Schetter et al.,2008; Bloomston et al.,2007; Meng et al.,2007
Aluminium	miRNAs- Increased miR-146a	HN cells(In vitro)	AD, cardiac hypertrophy and various cancers	Pogue et al.,2009; Lukiw et al.,2008; Pogue et al., 2009; Cheng et al.,2007; Volinia et al.,2006; Taganov et al.,2006; Bhaumik et al.,2008; Shen et al.,2008; Calin et al.,2005; Xu et al.,2008; Yanaihara et al.,2006; Kozaki et al.,2008
	Increased miR-9, miR-128, miR-125b	HN cells(In vitro)	AD, neurodegeneration and various cancers	Lukiw et al.,2007; Saba et al.,2008; Roehle et al.,2008; Wang et al.,2008; Tan et al.,2010; Veerla et al.,2009
Arsenic	DNA methylation- Global hypomethylation	Human HaCaT keratinocytes, human prostate epithelial cell line RWPE-1, TRL 1215 rat liver epithelial cell line, V79-Cl3 Chinese hamster cells(In vitro)	Various cancers and schizophrenia	Reichard et al.,2007; Benbrahim-Tallaa et al.,2005; Coppin et al.,2008; Zhao et al.,1997; Sciandrello et al.,2004; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
		129/SvJ mice,84 fisher 344 Rat,86 homozygous Tg.AC mice,87 goldfish,232 human PBL233(In vivo)	Various cancers and schizophrenia	Chen et al.,2004; Uthus et al.,2005; Xie et al.,2004; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	Global hypomethylation and c-Ha-ras hypomethylation	C57BL/6J mice(In vivo)	Various cancers and schizophrenia	Okoji et al., 2002; Smith et al., 2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	Global hypermethylation	Human PBL(In vivo)	Colorectal cancer, renal cell carcinoma, acute lymphoblastic leukaemia and bladder urothelial cell carcinoma	Majumdar et al.,2010; Pilsner et al.,2007; Cheetham et al.,2008; Alemayehu et al.,2008; Norrie et al.,2002; Minardi et al.,2009; Schafer et al.,2010; Owen et al.,2010;
	DAPK hypermethylation	SV-HUC-1 cells(In vitro)	Various cancers	Chai et al.,2007; Qian et al.,2010; Laytragoon-Lewin et al.,2010; Paluszczak et al.,2011; Hafner et al.,2011; Li et al.,2011; Ben Ayed-Guerfali et al.,2011; Sugita et al.,2011; Zhang et al.,2011; Hu et al.,2010; Van der Auwera et al.,2010; Zhang et al.,2011; Peng et al.,2010
	P16 hypermethylation	Human myeloma cell line U266(In vitro)	Various cancers	Lewin et al.,2010; Hu et al.,2010; Zhang et al.,2011; Malhotra et al.,2010; Poetsch et al.,2011; Lin et al.,2012; Wang et al.,2011; Zainuddin et al.,2011; Shaw et al.,2010
	DBC1, FAM83A, ZSCAN12 and C1QTNF6	Human UROtsa cells(In vitro)	Bladder cancer, breast cancer and malignant	Jensenet al.,2008; Serizawa et al.,2011; Hill et al.,2010;
	hypermethylation		lymphoproliferative neoplasms	Gronbaek et al.,2008
	P53 hypermethylation	Human lung adenocarcinoma A549 cells(In vitro)	Breast cancer and hepatoblastoma	Mass et al.,1997; Radpour et al.,2010; Hanafusa et al.,2005
	C-myc hypomethylation	TRL 1215 rat liver epithelial cells(In vitro)	cancer, liver cancer, kidney cancer and bladder cancer	Chen et al.,2001; Pereira et al.,2001; Luo et al.,2010; Fang et al.,1996; Tsujiuchi et al.,1999; Shen et al.,1997; Del et al.,1989
	C-myc and c-Ha-ras hypomethylation	Syrian hamster embryo cells (In vitro)	Gastric cancer, colon cancer, liver cancer, kidney cancer and bladder cancer	Takahashi et al.,2002; Pereira et al.,2001; Luo et al.,2010; Fang et al.,1996; Tsujiuchi et al.,1999; Shen et al.,1997; Del et al.,1989
	P16 and RASSF1 hypermethylation	A/J mice (In vivo)	Various cancers	Cui et al.,2006; Laytragoon-Lewin et al.,2010; Hu et al.,2010; Zhang et al.,2011; Malhotra et al.,2010; Poetsch et al.,2011; Lin et al.,2012; Wang et al.,2011; Zainuddin et al.,2011; Shaw et al.,2010; Rabiau et al.,2009; Buckingham et al.,2010
	Global hypomethylation and ER-alpha hypomethylation	C3H mice (In vivo)	Various cancersand schizophrenia	Waalkes et al.,2004; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,200
	P53 and P16 hypermethylation	Human PBL (In vivo)	Various cancers	Chanda et al.,2006; Laytragoon- Lewin et al.,2010; Hu et al.,2010; Zhang et al.,2011; Malhotra et al.,2010; Poetsch et al.,2011; Lin et al.,2012; Wang et al.,2011; Zainuddin et al.,2011; Shaw et al.,2010; Radpour et al.,2010; Hanafusa et al.,2005
	DAPK hypermethylation	Human bladder, kidney and ureter (In vivo)	Various cancers	Chen et al.,2007; Qian et al.,2010; Laytragoon-Lewin et al.,2010; Paluszczak et al.,2011; Hafner et al.,2011; Li et al.,2011; Ben Ayed-Guerfali et al.,2011; Sugita et al.,2011; Zhang et al.,2011; Hu et al.,2010; Van der Auwera et al.,2010; Zhang et al.,2011; Peng et al.,2010
	RASSF1A and PRSS3 hypermethylation	Human bladder (In vivo)	Lung cancer and prostate cancer	Marsit et al.,2006; Rabiau et al.,2009; Buckingham et al.,2010
	P16 hypermethylation	Human PBL (In vivo)	Various cancers	Zhang et al.,2007; Laytragoon Lewin et al.,2010; Hu et al.,2010; Zhang et al.,2011; Malhotra et al.,2010; Poetsch et al.,2011; Lin et al.,2012; Wang et al.,2011; Zainuddin et al.,2011; Shaw et al.,2010
	P53 hypermethylation	Human basal cell carcinoma(In vivo)	Breast cancer and hepatoblastoma	Boonchai et al.,2000; Radpour et al.,2010; Hanafusa et al.,2005
	Both hypomethylation and hypermethylation of VHL	Human kidney cells (In vitro)	Renal cell carcinoma	Zhong et al.,2001
	Histone modification- Decreased H3 acetylation	UROtsa and URO-ASSC cells(In vitro)	Renal cell carcinomas	Jensen et al.,2008; Kanao et al.,2008
	Decreased H4K16 acetylation	UROtsa cells (In vitro)	Bladder cancer	Jo et al.,2009
	Increased H3K14 acetylation Increased H3S10 phosphorylation	NB4 cells (In vitro)	Diabetic nephropathy	Li et al.,2002; Sayyed et al.,2010
	Increased H3 phosphorylation	WI-38 human diploid fibroblast cells(In vitro)	Diabetic nephropathy	Li et al.,2003; Sayyed et al.,2010
	Increased H3K9 acetylation	HepG2 hepatocarcinoma cells(In vitro)	Diabetic nephropathy	Ramirez et al.,2008; Sayyed et al.,2010
	Decreased H3, H4, H2a, H2b acetylation Decreased H3 and H4 methylation Increased H2b methylation	Drosophila melanogaster tissue culture cell line KC161(In vitro)	Heart disease and traumatic brain injury	Arrigo et al.,1983; Gaikwad et al.,2010; Gao et al.,2006
	Increased H3K36 trimethylation Decreased H3K36 dimethylation Increased H3K4 dimethylation	Human lung carcinoma A549 cells(In vitro)	Diabetic nephropathy, multiple myeloma and prostate cancer	Zhou et al.,2008; Sayyed et al.,2010; Zhao et al.,2010; Seligson et al.,2009
	Increased H3K9 dimethylation Decreased H3K27 trimethylation Increased H3K4 trimethylation	Human lung carcinoma A549 cells(In vitro)	Prostate cancer, kidney cancer, lung cancer, HCC and AML	Zhou et al.,2008; Seligson et al.,2009; Arita et al.,2009; Chen et al.,2010; Yao et al.,2010; Paul et al.,2010
	Increased H2AX phosphorylation Decreased H3K18 acetylation Decreased H3R17 methylation	RPMI7951 melanoma cells(In vitro) 1470.2 cell line derived from the mouse a denocarcinoma parent line(In vitro)	Ataxia telangiectasia Prostate cancerand colon cancer	Zykova et al.,2006; Porcedda et al.,2008 Barr et al.,2009; Seligson et al.,2009; Ashktorab et al.,2009
	miRNAs- Increased miR-222, Decreased miR-210	TK6 cell line(In vitro)	Various cancersand AD	Marsit et al.,2006; Felli et al.,2005; le Sage et al.,2007; Garofalo et al.,2009; Mi et al.,2007; Saumet et al.,2009; Hebert et al.,2008
	Decreased miR-19a	T24 cell line(In vitro)	Various cancers	Cao et al.,2011; Takakura et al.,2008; Calin et al.,2004; Arndt et al.,2009; Bandres et al.,2006; Malzkorn et al.,2010; Hebert et al.,2007; Budhu et al.,2008; Connolly et al.,2008; Hayashita et al.,2005
Benzene	DNA methylation- Global hypomethylation (Alu, LINE-1)	Human PBL (In vivo)	Various cancers and schizophrenia	Baccarelli et al.,2009; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	P15 hypermethylation and melanoma antigen-1 (MAGE-1) hypomethylation	Human PBL (In vivo)	Psoriasis and various cancers	Kim et al.,2007; Bassil et al.,2007; Koutros et al.,2010; Waggoner et al.,2011; Bollati et al.,2007; Zhang et al.,2009; Furonaka et al.,2004; Lindberg et al.,2008; Kim et al.,2009; Shimamoto et al.2005; Chen et al.,2002; Gallardo et al.,2004; El-Shakankiry et al.,2006; Matsuno et al.,2005; Wemmert et al.,2009; Berg et al.,2007; Wong et al.,2003
	Global DNA hypomethylation	Human lymphoblastoid cell line TK6(In vitro)	Various cancers and schizophrenia	Ji et al.,2010; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	Hypermethylation of poly (ADP-ribose) polymerases- 1 (PARP-1)	Lymphoblastoid cell line F32(In vitro)	Various cancers	Gao et al.,2010
Bisphenol A	DNA methylation- Hypomethylation of the Agouti gene and CabpIAP	Mouse embryo(In vivo)	Mice with hypomethylation of the Agouti gene are obese, diabetic and exhibit increased cancer rates	Dolinoy et al.,2007; Morgan et al.,2010; Xiang et al.,2010
	Hypomethylation of the homeobox gene Hoxa10	CD-1 mice (In vivo)	Not applicable	Bromer et al.,2010;
	Hypermethylation of LAMP3.	Breast epithelial cells (In vitro)	Breast cancer	Weng et al.,2010;
	miRNAs- Increased miR-146a	3A placental cells (In vitro)	Cardiac hypertrophy, AD and various cancers	Whiting et al.,2010; Lukiw et al.,2008; Pogue et al.,2009; Cheng et al.,2007; Volinia et al.,2006; Taganov et al.,2006; Bhaumik et al.,2008; Shen et al.,2008; Calin et al.,2005; Xu et al.,2008; Yanaihara et al.,2006; Kozaki et al.,2008;
Cadmium	DNA methylation- Global DNA hypomethylation	K562 cell(In vitro)	Colorectal cancer, renal cell carcinoma, acute lymphoblastic leukaemia,bladder urothelial cell carcinoma	Huang et al.,2008; Cheetham et al.,2008; Alemayehu et al.,2008; Norrie et al.,2002; Minardi et al.,2009; Schafer et al.,2010; Owen et al.,2010
	Initially induces DNA hypomethylation, prolonged exposure results in DNA hypermethylation	TRL1215 rat liver cells (In vitro)	Not applicable	Takiguchi et al.,2003;
	miRNAs- Decreased miR-146a	Human PBL(In vivo)	Various cancers	Bollati et al.,2010; Gramantieri et al.,2007; Jazdzewski et al.,2008; Lin et al.,2008
Chromium	DNA methylation- P16 and hMLH1 hypermethylation	Human lung(In vivo)	Various cancers	Kondo et al.,2006; Takahashi et al.,2005; Laytragoon-Lewin et al.,2010; Hu et al.,2010; Zhang et al.,2011; Malhotra et al.,2010; Poetsch et al.,2011; Lin et al.,2012; Wang et al.,2011; Zainuddin et al.,2011; Shaw et al.,2010; Gonzalez- Ramirez et al.,2011; Vasavi et al.,2010; Ling et al.,2010
	Gpt hyperme,thylation	G12 cell line (In vitro)	Not applicable	Klein et al.,2002
	Histone modification- Decreased H3S-10 Phosphorylation	Human lung carcinoma A549 cells (In vitro)	Type 2 diabetes, heart disease and traumatic brain injury	Arita et al.,2009; Sayyed et al.,2010; Gaikwad et al.,2010; Gao et al.,2006
	Decreased H3K4 trimethylation
	Decreased H3 and H4 acetylation
	Increased Dimethylation and trimethylation of H3K9 and H3K4
	Decreased H3K27trimethylation and H3R2 dimethylation
DES	miRNAs- Decreased miR-9-3	Breast epithelial cells (In vitro)	Breast cancer	Hsu et al.,2009
Dioxin	DNA methylation- Igf2 hypomethylation	Rat liver (In vivo)	Russell–Silver syndrome and various cancers	Wang et al.,2007; Gucev et al.,2009; Zeschnigk et al.,2008; Chopra et al.,2010; Dammann et al.,2010; Baba et al.,2010; Li et al.,2009; Cui et al.,2002; Ito et al.,2008
	Alterations in DNA methylation at multiple genomic regions	Splenocyte of mice (In vivo)	Not applicable	McClure et al.,2011
Drinking Water	DNA methylation- Global hypomethylation c-myc hypomethylation	Mice liver (In vivo)	Gastric cancer, colon cancer, liver cancer, kidney cancer and bladder cancer	al.,2000; Luoet al.,2010; Fang et al.,1996; Tsujiuchi et al.,1999; Shen et al.,1997; Del et al.,1989
Lead	DNA methylation- Global hypomethylation	Human PBL, newborn umbilical cord blood samples(In vivo)	Various cancersand schizophrenia	Wright et al.,2010; Pilsner et al.,2009; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
Mercury	DNA methylation- Global hypomethylation	Brain tissues in polar bear(In vivo)	Neurological disorders and various cancer	Pilsner et al.,2010; Mill et al.,2008; Wang et al.,2008; Esteller et al.,2008
	Rnd2 hypermethylation	Mouse embryonic stem cells(In vitro)	Neuronal migration defect	Arai et al.,2011; Heng et al.,2008
Nickel	DNA methylation- ATF-1, HIF-1, gpt and Rb hypermethylation	G12 cell line(In vitro)	Various cancers	Lee et al.,1995; Chim et al.,2003; Stirzaker et al.,1997; Chen et al.,2004; Zhao et al.,2010; Zhao et al.,2003; Li et al.,1998
	P16 hypermethylation	Mouse histiocytomas(In vivo)	Various cancers	Govindarajan et al.,2002; Laytragoon-Lewin et al.,2010; Hu et al.,2010; Zhang et al.,2011; Malhotra et al.,2010; Poetsch et al.,2011; Lin et al.,2012; Wang et al.,2011; Zainuddin et al.,2011; Shaw et al.,2010
	Histone modification- Increased H3K9 methylation Decreased Acetylation at all four core histones	Human lung carcinoma A549 cells(In vitro)	Heart disease and traumatic brain injury	Chen et al.,2006; Ke et al.,2006; Gaikwad et al.,2010; Gao et al.,2006
	dimethylation Increased H2a, H2b ubiquitylation Decreased H3K4 methylation Decreased H3K4 acetylation Decreased H2a, H2b, H3, H4 acetylation	Human lung carcinoma A549 cells,G12 cells, 1HAEo- cell line, human (HAE) and rat (NRK) cells, Chinese hamster cell line (In vitro)	Lung cancer, heart disease, chronic glomerular disease and traumatic brain injury	Lee et al.,1995; Karaczyn et al.,2005; Karaczyn et al.,2006; Broday et al.,2000; Chen et al.,2006; Ke et al.,2006; Klein et al.,1997; Yan et al.,2003; Arita et al.,2009; Gaikwad et al.,2010; Gao et al.,2006; Chen et al.,2010; Lefevre et al.,2010
	DecreasedH4K5, H4K8, H4K12, H4K16 acetylation	Human lung carcinoma A549 cells (In vivo)	Ataxia telangiectasia	Broday et al.,2000; Kumar et al.,2011
	DecreasedH2A, H2B, H3, H4 acetylation (especially in H2BK12 and H2BK20)	Human airway epithelial 1HAEo(HAE) cell line (In vitro)	Heart disease and traumatic brain injury	Golebiowski et al.,2005; Gaikwad et al.,2010; Gao et al.,2006;
	Increased H3 phosphorylation	Human lung carcinoma A549 cells (In vitro)	Diabetic nephropathy	Ke et al., 2008; Sayyed et al., 2010
Pesticides	DNA methylation- P53 hypermethylation	Human lung adenocarcinoma A549 cells (In vitro)	Breast cancer and hepatoblastoma	Mass et al.,1997; Radpour et al.,2010; Hanafusa et al.,2005
	Alter DNA methylation in the germ line	Rat testis (In vivo)	Potential effects in the offspring	Anway et al.,2005; Guerrero-Bosagn et al.,2010; Anway et al.,2006
	Hypomethylation of c-jun and c-myc	Mouse liver (In vivo)	Gastric cancer, colon cancer, liver cancer, kidney cancer and bladder	Tao et al.,2000; Pereira et al.,2001; Luo et al.,2010; Fang et al.,1996; Tsujiuchi et al.,1999; Shen et al.,1997 Del et al.,1989
	Global hypomethylation (Alu)	Human PBL(In vivo)	Various cancersand schizophrenia	Rusiecki et al.,2008; Kim et al.,2010; Smith et al.,2007; Roman-Gomez et al.,2006; Deng et al.,2006; Brothman et al.,2005; Shimabukuro et al.,2007
	Both hypomethylation and hypermethylation of VHL	Human kidney cells (In vitro)	Renal cell carcinoma	Zhong et al.,2001
	Histone modification- Increased Ac of H3 and H4	Immortalized rat mesencephalic/ dopaminergic cells (N27 cells)(In vitro and in vivo)	Parkinson’s disease	Song et al.,2010
RDX	miRNAs- Increased let-7, miR-15, miR-16, miR-26, miR-181 Decreased miR-10b	Mouse brain and liver (In vivo)	Various cancers	Zhang et al.,2009; Calin et al.,2005; Calin et al.,2002; Cimmino et al.,2005; Ambs et al.,2008; Roccaro et al.,2009; Johnson et al.,2005; Lee et al.,2007; Yanaihara et al.,2006; Sampson et al.,2007
	Increased miR-206, miR-30, miR-195	Mouse brain and liver (In vivo)	Various cancers	Zhang et al.,2009; Iorio et al.,2005; Adams et al.,2007; Roccaro et al.,2009; Dixon- McIver et al.,2008; van Rooij et al.,2006; Sayed et al.,2007

PBL: Peripheral blood leucocytes; HCC: Hepatocellular carcinoma; AML: Acute myeloid leukaemia; AD: Alzheimer’s disease; HN cells:
Human neural cells; RDX: Hexahydro-1,3,5-trinitro-1,3,5-triazine; DES: Diethylstilbestrol.

Suitable study designs, approaches, challenges and opportunities for Environmental Epigenomics Studies- The rapid growth of environmental epigenetics field in the past several years has led the investigators to face different difficulties and challenges as well. Few studies had produced uneven results on same environmental chemicals that may be because of several factors. The fact that these tissue specific epigenetic alterations (Minard et al., 2009) is likely to be acceptable because same environmental chemical might produce different epigenetic changes in different tissues, and even it can change within the same tissue on different cell types. Difference in study design, laboratory methods and small sample size may also be major causes for these inconsistencies in epigenetic changes. Replication of results and identification of the sources of variability across studies is one of the major challenges for epigenetic investigations. There relationship between a disease and an epigenetic marker can be determined by an effect of disease on the epigenetic patterns, instead of vice versa (Reltonet al., 2010), since epigenetic markers change over time. The epigenetic alterations that were found to be induced by or associated with environmental pollutants were also found in various diseases. Earlier prospective epidemiological studies might be helpful for mapping epigenomic changes in response to specific chemicals. Methods of collection and processing can modify the cell types stored, thus potentially having its effect on epigenetic marks. In addition to this, high through put methods providing good quality data on DNA methylation, histone modifications and miRNA expression are gradually used these days in human investigations. The share of the effects of any particular environmental exposure that can mediate through epigenetic mechanisms is still undetermined, though epigenetic mechanisms are ideal molecular intermediates of environmental effects. Statistical approaches, including well-designed prospective studies and advanced statistical methods are urgently needed for causal inference in this regard. The epidemiological causal reasoning in epigenomics should include careful consideration of knowledge, data, methods and techniques from several disciplines similar to genomic studies (Geneletti et al., 2011).

Epigenomics: Can it be used for prevention of various diseases- One of the main objectives behind these epidemiology investigations is to look for future preventive interventions. Various clinical and preclinical studies has already showed that most of the epigenetic changes are reversible, which offers novel insights to develop new preventive and therapeutic strategies in this field that can make use of molecules that alter the activities of epigenetic enzymes, such as DNA Methyl Transferases (DNMTs) and Histone Deacetylases (HDACs). Drugs have already been designed and developed in this regard that produce functional effects like histone acetylation and DNA hypomethylation that can be used to restore the normal gene transcription. Future epidemiology studies and epigenomic research to evaluate the effects of environmental exposures on the epigenome may provide information for developing preventive strategies, including exposure reduction, along with pharmacological, dietary or lifestyle interventions as well.

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