文章基本信息

标题：Cadmium-Associated Differential Methylation throughout the Placental Genome: Epigenome-Wide Association Study of Two U.S. Birth Cohorts
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作者：Todd M. Everson ; Tracy Punshon ; Brian P. Jackson 等
期刊名称：Environmental Health Perspectives
印刷版ISSN：0091-6765
电子版ISSN：1552-9924
出版年度：2018
卷号：126
期号：1
页码：017010
DOI：10.1289/EHP2192
语种：English
出版社：OCR Subscription Services Inc
摘要：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 × 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. https://doi.org/10.1289/EHP2192