Environmental chemicals and DNA methylation in adults: a systematic review of the epidemiologic evidence

Ruiz-Hernandez, Adrian; Kuo, Chin-Chi; Rentero-Garrido, Pilar; Tang, Wan-Yee; Redon, Josep; Ordovas, Jose M; Navas-Acien, Ana; Tellez-Plaza, Maria

doi:10.1186/s13148-015-0055-7

Clinical Epigenetics

Table 1 Studies of cadmium exposure biomarkers and DNA methylation outcomes (6 studies available)

From: Environmental chemicals and DNA methylation in adults: a systematic review of the epidemiologic evidence

First author, year	Design	Population	Size	Men (%) ^a	Age Range (yr) ^a	Exposure assessment	Exposure categories	DNA methylation Assessment	DNA methylation endpoint	Association	95% Confidence Interval or p-value	Adjustment Factors
Hanna, 2012 [29]	CS	U.S. (Study of Metals and Assisted Reproductive Technologies [SMART])	42	0	Mean 36 (28 to 44)	Urine by DRC- ICPMS	Above and below the median	Whole blood	1,505 CpG sites percent methylation			Normalization. QC reported. BEE NR. CH partially addressed. Data unadjusted. MCC NR.
						Median = 0.38 μg/L		Site specific Illumina GoldenGate and bisulfite pyrosequencing of significant regions^b		A trend towards hypermethylation if difference score > \|30\| (p < 0.05)No significant region^b.
						Median = 0.38 μg/L		Global by bisulfite pyrosequencing of LINE-1		Approximately 0.2 % increase in median DNAm	p = 0.39
Hossain, 2012 [54]	CS	Andean plateau, Northern Argentina	202	0	Median 34 (18-64)		Per log-unit increase	Whole blood	Average percent methylation	Difference		QC reported. CH not addressed. Only 4 participants were smokers. Regression models adjusted for age, coca chewing, and arsenic in urine. Cadmium concentrations corrected to the mean specific gravity of urine.
								Bisulfite pyrosequencing
						Blood by DRC-ICPMS (Median = 0.36 μg/L)		Site specific
								MLH1		0.19	−0.53, 0.91
								CDKN2A		0.24	−0.29, 0.77
								Global LINE-1		0.45	−0.23, 1.12
						Urine by DRC-ICPMS (Median = 0.23 μg/L)		Site specific
								MLH1		−0.073	−0.50, 0.36
								CDKN2A		−0.11	−0.42, 0.21
								Global LINE-1		−0.42	−0.82, –0.025
Zhang, 2013 [55]	CS	Southern China	81	39.5	53.9 (IQR 48.0–59.0)	Graphite Furnace-AAS	Per log-unit increase	Whole blood				QC reported. CH not addressed. Regression models adjusted for age, sex, BMI, smoking, alcohol drinking, albumin, B2M, eGFR, N-acetyl-b-d glucosaminidase (NAG).
						Graphite Furnace-AAS	Per log-unit increase	Site specific by bisulfite pyrosequencing in:	Average percent methylation	Difference
						Blood (Median = 2.62 μg/L)		RASAL1		0.49	0.21, 0.77
						Blood (Median = 2.62 μg/L)		KLOTHO		1.18	0.54, 1.83
						Urine by (Median = 5.20 μg/g creatinine)		RASAL1		0.88	0.57, 1.20
						Urine by (Median = 5.20 μg/g creatinine)		KLOTHO		1.55	0.75, 2.35
Tajuddin, 2013 [30]	CS	Spain (EPICURO study)	659	89	66	Toenail by ICPMS (Median = 0.01 μg/g)	Per 1 μg/g increase	Blood granulocytes	Average percent methylation	Difference		QC reported. CH addressed. Adjusted for age, sex, study region, and smoking status
Tajuddin, 2013 [30]	CS	Spain (EPICURO study)	659	89	66	Toenail by ICPMS (Median = 0.01 μg/g)	Per 1 μg/g increase	Global by bisulfite pyrosequencing in LINE-1	Average percent methylation	0.1	−0.3, 0.6
Sanders, 2014 [53]	Nested sub-CO	Durham county, US (CEHI study)	17	0	Maternal age: 28 (19–42)	Blood Median = 0.2 μg/L	Above and below the median	Blood leukocytes	Average percent methylation in 16 421 CpG islands	General pattern toward increased methylation with increased cadmium in 92 significant^c genes		Normalization. BEE NR. CH addressed. No adjustment conducted, but evaluation of participant characteristics by cadmium and DNAm levels, with no significant differences reported. FDR corrected q-value provided. SNP-related clustering of DNA methylation not evaluated.
								Site specific MBD2b/ MBD3L1 enrichment in Affymetrix Human Promoter 1.0R array
										Fold-change of DNAm in top 5 significant sites:
										TWSG1 = 1.79	0.0007
										USP30 = 1.70	0.0023
										FAM83H = 1.52	0.0052
										PPP2R5B = 1.56	0.0060
										PRKCG = 1.44	0.0068
Tellez-Plaza, 2014 [19]	CS	13 American Indian communities, US (SHS)	48	31.3	55 ± 7.3	Urine by ICPMS Median = 0.87 μg/g	Above and below the median in 1989-1991	Global by ELISA-like commercial kit	Logit-transformed percent methylation relative to cytosine genomic content	Odds ratio		QC reported. Models adjusted for age, sex,smoking status, BMI and, in prospective analyses only, log-transformed total count of white blood cells and percent of neutrophils.
	CS							Blood leukocytes in 1989–1991		1.75	0.96, 3.20
	CO							Whole blood in 1997–1999		1.03	0.50, 2.11

AAS: atomic absorption spectometry; BEE: batch effects evaluation; BMI: body mass index; CC: case-control; CH: Cell heterogeneity; CI: confidence interval; CO: cohort; CS: cross-sectional; DNAm, DNA methylation; FDR: false discovery rate; MCC: multiple comparison correction; NR: not reported; LOD: limit of detection; QC: quality control.
^aSociodemographic data available in the article, not necessarily in the subsample without missing values in DNA methylation or exposures.
^bSignificance was defined as a difference score > |13| (p < 0.05) and >10% absolute difference between the means for each group.
^cSignificance defined as a minimum absolute change of 30% comparing exposure groups and a p-value < 0.05.

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