Prenatal Arsenic Exposure and the Epigenome: Identifying Sites of 5-methylcytosine Alterations that Predict Functional Changes in Gene Expression in Newborn Cord Blood and Subsequent Birth Outcomes

Abstract

Prenatal exposure to inorganic arsenic (iAs) is detrimental to the health of newborns and increases the risk of disease development later in life. Here we examined a subset of newborn cord blood leukocyte samples collected from subjects enrolled in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico, who were exposed to a range of drinking water arsenic concentrations (0.456-236 µg/l). Changes in iAs-associated DNA 5-methylcytosine methylation were assessed across 424,935 CpG sites representing 18,761 genes and compared with corresponding mRNA expression levels and birth outcomes. In the context of arsenic exposure, a total of 2919 genes were identified with iAs-associated differences in DNA methylation. Site-specific analyses identified DNA methylation changes that were most predictive of gene expression levels where CpG methylation within CpG islands positioned within the first exon, the 5' untranslated region and 200 bp upstream of the transcription start site yielded the most significant association with gene expression levels. A set of 16 genes was identified with correlated iAs-associated changes in DNA methylation and mRNA expression and all were highly enriched for binding sites of the early growth response (EGR) and CCCTC-binding factor (CTCF) transcription factors. Furthermore, DNA methylation levels of 7 of these genes were associated with differences in birth outcomes including gestational age and head circumference.These data highlight the complex interplay between DNA methylation, functional changes in gene expression and health outcomes and underscore the need for functional analyses coupled to epigenetic assessments.

SExual Epigenetic Dimorphism in The Human Placenta: Implications for Susceptibility During The Prenatal Period

“…While it may be intuitive that X-inactivation would likely present as a pattern of hypermethylation in females as compared with male placentas, prior research has shown that gene silencing on the X-chromosome is dependent on gene region and in some cases hypomethylation-associated silencing has been observed [49,52,53]. Taken together, these data support that the functional impact of methylation on X-chromosome inactivation exhibits positional dependencies, similar to those observed previously [54].…”

Tracing human stem cell lineage during development using DNA methylation

“…2016), GSE62924 (Rojas et al 2015). Adult peripheral blood GSE74738 (Hanna et al 2016), GSE54399 (Montoya-Williams et al 2017.…”

Inuteroarsenic exposure and epigenome-wide associations in placenta, umbilical artery, and human umbilical vein endothelial cells

“…[21][22][23][24][25][26] However, significant DNA methylation disruption of unique loci along with enrichment of key regulatory CpG regions has been documented across different study populations. [22][23][24][25][26][27][28] Besides studies that examined cord and whole blood epigenome, only 2 studies to date have evaluated the association between arsenic exposure and CpG methylation of target tissue by evaluating DNA methylation in urothelial carcinoma samples and CpG methylation of exfoliated urothelial cells, respectively. 29,30 These studies found differentially methylated loci associated with arsenic exposure in key regulatory genes potentially involved in the development of arsenic-induced urothelial carcinoma.…”