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BACKGROUND: Cadmium (Cd) is a ubiquitous environmental toxicant that can accumulate in the placenta during pregnancy, where it may impair placental function and affect fetal development.

OBJECTIVES: We aimed to investigate Cd-associated variations in placental DNA methylation (DNAM) and associations with gene expression; we also aimed to identify novel pathways involved in Cd-associated reproductive toxicity.

METHODS: Using placental DNAM and Cd concentrations in the New Hampshire Birth Cohort Study (NHBCS, n=343) and the Rhode Island Child Health Study (RICHS, n=141), we performed an epigenome-wide association study (EWAS) between Cd and DNAM, adjusting for tissue heterogeneity using a reference-free method. Cohort-specific results were aggregated via inverse variance weighted fixed effects meta-analysis, and variably methylated CpGs were associated with gene expression. We then performed functional enrichment analysis and tests for associations between gene expression and birth size metrics.

RESULTS: We identified 17 Cd-associated differentially methylated CpG sites with meta-analysis p-values < 1 x 10(-5), two of which were within a 5% false discovery rate (FDR). DNAM levels at 9 of the 17 loci were associated with increased expression of 6 genes (5% FDR): TNFAIP2, EXOC3L4, GAS7, SREBF1, ACOT7, and RORA. Higher placental expression of TNFAIP2 and ACOT7 and lower expression of RORA were associated with lower birth weight z-scores (p-values < 0.05).

CONCLUSION: Cd-associated differential DNAM and corresponding DNAM-expression associations were observed at loci involved in inflammatory signaling and cell growth. The expression levels of genes involved in inflammatory signaling (TNFAIP2, ACOT7, and RORA) were also associated with birth weight, suggesting a role for inflammatory processes in Cd-associated reproductive toxicity.