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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 regionsb A trend towards hypermethylation if difference score > |30| (p < 0.05)No significant regionb.
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).
Site specific by bisulfite pyrosequencing in: Average percent methylation Difference  
Blood (Median = 2.62 μg/L)   RASAL1 0.49 0.21, 0.77
KLOTHO 1.18 0.54, 1.83
Urine by (Median = 5.20 μg/g creatinine) RASAL1 0.88 0.57, 1.20
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
Global by bisulfite pyrosequencing in LINE-1 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 significantc 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.
Blood leukocytes in 1989–1991 1.75 0.96, 3.20
CO Whole blood in 1997–1999 1.03 0.50, 2.11
  1. 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.
  2. aSociodemographic data available in the article, not necessarily in the subsample without missing values in DNA methylation or exposures.
  3. bSignificance was defined as a difference score > |13| (p < 0.05) and >10% absolute difference between the means for each group.
  4. cSignificance defined as a minimum absolute change of 30% comparing exposure groups and a p-value < 0.05.