Environmental Impact on DNA Methylation in the Germline: State of the Art and Gaps of Knowledge

Table 1

Selected epidemiological studies on the effects of environmental chemical exposures on human DNA methylation.

Exposure (chemical)	Study population	Target tissue	Target DNA region	Method	DNA methylation changes	Reference
Metals
Arsenic (As)	294 adults, India	PBL	Global	Methyl acceptance assay	Hypermethylation	[45]
	64 adults, India	PBL	Global	Methyl acceptance assay	Hypermethylation	[46]
	320 adults, Bangladesh	PBL	Global	Methyl acceptance assay	Hypermethylation	[47]
	96 adults, India	PBL	p16, p53	Bisulfite methyl specific PCR	Hypermethylation	[48]
	202 women, Argentina	PBL	p16, MLH1, and LINE-1	Bisulfite PCR pyrosequencing	Hypermethylation at p16 and MLH1	[51]
	163 patients with arseniasis and 110 controls, China	PBL	p16	Bisulfite methyl specific PCR	Hypermethylation	[49]
	16 individuals of which 8 were with arsenicosis, Mexico	PBL	Epigenome-wide	Arrays	Differential methylation patterns	[50]
	10 individuals with skin lesions and 10 controls, Bangladesh	PBL	Epigenome-wide	Arrays	6 differentially methylated sites including RHBDF1	[53]
	38 patients with urothelial carcinoma, Taiwan	Tumor biopsies	DAPK	Bisulfite PCR sequencing	Hypermethylation	[52]
	28 patients with urothelial carcinoma, Taiwan	Tumor biopsies	Epigenome-wide	Arrays	Hypermethylation in CTNNA2, KLK7, NPY2R, ZNF132, and KCNK17	[54]
	113 mother-child pairs, Bangladesh	PBL (maternal and umbilical cord samples)	p16, p53, LINE-1, and Alu	Bisulfite PCR pyrosequencing	Hypermethylation at p16 and LINE-1	[55]
	113 mother-child pairs, Bangladesh	PBL (maternal and umbilical cord samples)	Global; LINE-1, Alu	Methyl incorporation assay; bisulfite PCR pyrosequencing; LUMA (Luminometric Methylation Assay)	Hypermethylation (sex-dependent)	[57]
	71 newborns, Thailand	PBL (cord blood)	Global; LINE-1; p53	Global: total 5-mC by HPLC-MS; LINE-1: COBRA; p53: methylation-specific restriction endonuclease digestion	Hypermethylation at p53	[58]
	44 newborns, Bangladesh	PBL	Epigenome-wide	Arrays	Differential methylation in thousands of sites	[56]
	134 infants, USA	PBL	Epigenome-wide	Arrays	Hypermethylation at several loci	[59]
	newborns, Mexico	PBL	Epigenome-wide	Arrays	Differential methylation in thousands of sites	[60]
Chromium (Cr)	115 workers  and 60 controls, China	PBL	Global	ELISA	Hypomethylation	[61]
Mercury (Hg)	131 dental professionals, USA	Buccal mucosa	LINE-1, DNMT1, SEPW1, and SEPP1	Bisulfite PCR pyrosequencing	Hypomethylation at SEPP1 in males	[63]
Lead (Pb)	517 elderly men, USA	PBL	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypomethylation at LINE-1	[64]
	9 exposed individuals	PBL	p16	Methylation-specific PCR and thermal denaturation	Hypermethylation	[65]
Cadmium (Cd)	202 women, Argentina	PBL	LINE-1, p16, and MLH1	Bisulfite PCR pyrosequencing	Hypomethylation at LINE-1	[66]
	17 mother-child pairs, USA	PBL (maternal and newborn)	Epigenome-wide	Arrays	Differential methylation at subsets of genes	[68]
Selenium (Se)	286 adults, Bangladesh	PBL	Global	Methyl acceptance assay	Hypomethylation	[67]
Hg, Pb, and Cd	43 women undergoing IVF, USA	PBL	Epigenome-wide	Arrays	Hg: hypermethylation at GSTM1; Pb: hypomethylation at COL1A2	[62]
Air pollution; (including PM; and PAH)	48 adult nonsmokers, Belgium	PBL	Global	HPLC	Hypomethylation	[70]
	718 elderly individuals, USA	PBL	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypomethylation at LINE-1	[71]
	706 elderly individuals, USA	PBL	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypomethylation	[72]
	777 elderly individuals, USA	PBL	F3, IFN-γ, IL-6, TLR-2, and ICAM-1	Bisulfite PCR pyrosequencing	F3, ICAM-1, and TLR-2 hypomethylation; IFN-γ and IL-6 hypermethylation	[73]
	776 elderly individuals, USA	PBL	F3, ICAM-1, IFN-γ, IL-6, TLR-2, CRAT, GCR, iNOS, and OGG1	Bisulfite PCR pyrosequencing	Differential methylation at TLR2, GCR, TLR2, F3, and IL6	[74]
	63 steel workers, Italy	PBL	LINE-1, Alu, iNOS; p16, p53, hTERT, and APC, RASSF1A	Bisulfite PCR pyrosequencing	Hypomethylation at iNOS, p53, and RASSF1A; hypermethylation at APC, p16	[81–83]
	49 nonsmoking coke-oven workers and 43 controls, Poland	PBL	p16, p53, IL-6, HIC1, LINE-1, and Alu	Bisulfite PCR pyrosequencing	Hypermethylation at LINE-1, Alu, and IL-6; hypomethylation at p53	[84]
	60 truck drivers and 60 controls, China	PBL	Tandem repeats Satα, NBL2, and D4Z4	Bisulfite PCR pyrosequencing	Hypomethylation at Satα and NBL2	[85]
	120 male workers, Italy and China	PBL	LINE-1 subfamilies (L1HS, L1PA5, L1PA2, and L1Ta); Alu subfamilies (AluSx, AluYb8, and AluYd6); HERV subfamilies (MLT1D, ERV1, and ERV9)	Bisulfite PCR pyrosequencing	Differential methylation	[87]
	67 industrial workers, 65 residents, and 45 rural controls, Thailand	PBL	LINE-1, Alu, p16, p53, HIC1, and IL-6	Bisulfite PCR pyrosequencing	Hypomethylation at p53, IL-6, and LINE-1	[88]
	78 gasoline filling attendants, 77 urban traffic officers, 57 control office workers, Italy	PBL	LINE-1, Alu,; p15, and MAGE1	Bisulfite PCR pyrosequencing	Hypomethylation at LINE-1, Alu, and MAGE1; hypermethylation at p15	[89]
	78 gasoline filling attendants, 58 control office worker, Italy	PBL	Global	High-resolution GC-MS	Hypomethylation	[90]
	158 petrochemical workers and 50 control office workers, Bulgaria	PBL	LINE-1, Alu, p15, and MAGE1	Bisulfite PCR pyrosequencing	Hypomethylation at LINE-1 and p15	[91]
	141 asthmatic children and 70 controls, USA	Treg cells from PBL	Foxp3	?	Hypermethylation	[75]
	940 children, USA	Buccal cells	NOS1, NOS2A, and NOS3	Bisulfite PCR pyrosequencing	Differential methylation at NOS2A and NOS3	[76]
	56 mother-child pairs, USA	PBL (cord blood)	ACSL3	Methylation-specific PCR	Hypermethylation	[79]
	164 mother-child pairs, USA	PBL (cord blood)	Global	ELISA	Hypomethylation	[78]
	53 mother-child pairs, USA	PBL (cord blood)	IFNγ and IL-4	Bisulfite PCR sequencing	Hypermethylation at IFNγ	[80]
POPs	70 Inuits, Greenland	PBL	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypomethylation at Alu	[92]
	86 adults, South Korea	PBL	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypomethylation at Alu	[93]
	358 mother-child pairs, USA	PBL (cord blood and at 9 years)	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypomethylation at Alu	[98]
Bisphenol A	43 women undergoing IVF, USA	PBL	Epigenome-wide	Arrays	Hypomethylation at the TSP50	[62]
	46 preadolescent girls, Egypt	Saliva	Epigenome-wide	Arrays	Hypomethylation at several loci	[94]
PFASs	685 adults, USA	PBL	LINE-1	Bisulfite PCR pyrosequencing	Hypermethylation	[95]
	262 fertile men, Greenland/Poland/Ukraine	Sperm	Global; LINE-1, Alu, and	Flow cytometry immunodetection of 5-mC; bisulfite PCR pyrosequencing	No consistent changes	[96]
	30 mother-child pairs, USA	PBL (cord blood)	Global	ELISA	Hypomethylation	[97]
EDs	192 mother-child pairs, Spain	Placenta	LINE-1 subfamilies (L1HS, L1PA5, L1PA2, and L1Ta); Alu subfamilies (AluSx, AluYb8, and AluYd6); HERV subfamilies (MLT1D, ERV1, and ERV9)	Bisulfite PCR pyrosequencing	AluYb8 hypomethylation in boys	[99]
Tobacco smoke	177 adults, Germany	PBL	Epigenome-wide	Arrays	Hypomethylation at F2RL3	[103]
	374 adults, Italy	PBL	Epigenome-wide	Arrays	Hypomethylation at F2RL3, AHRR, and other loci	[105]
	261 adults, Italy	PBL	AHRR 6p21 (1 locus); 2q37 (2 loci)	Bisulfite PCR pyrosequencing	Differential methylation	[111]
	3,588 adults, Germany	PBL	F2RL3	MALDI-TOF MS	Hypomethylation	[106]
	399 African American youths, USA	PBL	Epigenome-wide	Arrays	Hypomethylation at AHRR	[109]
	107 African American young men, USA	PBL	Epigenome-wide	Arrays	Hypomethylation at AHRR	[110]
	111 adult African American women, USA	PBL	Epigenome-wide	Arrays	Differential methylation at 910 loci; hypomethylation at AHRR and GPR15	[112]
	348 mother-child pairs, USA	Child buccal cells	LINE-1, AluYb8	Bisulfite PCR pyrosequencing	Hypomethylation at AluYb8	[113]
	272 mother-child pairs, USA	Child buccal cells	Epigenome-wide	Arrays	Differential methylation in 8 genes; Hypermethylation at AXL and PTPRO	[113]
	173 mother-child pairs, USA	Child buccal cells	AXL	Bisulfite PCR pyrosequencing	Hypermethylation	[114]
	527 mother-asthmatic child pairs, USA	Child PBL	Epigenome-wide	Arrays	Differential methylation at 19 loci	[115]
	36 mother-child pairs (18 nonsmokers and 18 smokers), USA	Placenta	Epigenome-wide	Arrays	Differential methylation at several loci	[117]
	1,062 mother-child pairs, Norway	PBL (cord blood)	Epigenome-wide	Arrays	Differential methylation in 10 genes including AHRR, CYP1A1, and GFI1	[118]
	418 mother-child pairs, USA	PBL (cord blood)	DMRs of IGF2 and H19	Bisulfite PCR pyrosequencing	IGF2 DMR differential methylation	[119]
	380 mother-child pairs, USA	PBL (cord blood)	LINE-1, Alu	Bisulfite PCR pyrosequencing	Hypermethylation at AluYb8	[120]
	206 mother-child pairs, USA	Placenta	Epigenome-wide	Arrays	Hypermethylation at RUNX3	[121]
	132 mother-child pairs, Canada	PBL (adolescents)	Epigenome-wide	Arrays	Hypermethylation at MYO1G; hypomethylation at CNTNAP2	[122]