Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

Abstract

Background: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. Methods: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE −/− ) mouse model of atherosclerosis. Results: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women’s Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. Conclusions: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Epigenomic insights into common human disease pathology

“…Arsenic-associated DMCs at 20 and 13 CpGs were associated with CVD incidence and mortality, respectively. Functional models of arsenic-induced atherosclerosis also support the hypothesis that diabetes and redox signalling are involved in its pathogenesis [ 281 ]. Arsenic exposure also leads to phenotypic DNAm clock age acceleration [ 282 ].…”

“…Arsenic exposure at low exposure levels in water and food is related to multiple health outcomes, including cardiovascular disease (CVD) and hypertension [ 281 ]. It can also induce epigenetic modifications in experimental exposure models.…”

Unveiling the Impact of Arsenic Toxicity on Immune Cells in Atherosclerotic Plaques: Insights from Single-Cell Multi-Omics Profiling

“…Arsenic is a known epigenetic modulator resulting in DNA methylation, histone modifications, and microRNA changes (41). For instance, Domingo-Relloso et al reported a consortium of genomic positions differentially methylated by arsenic exposure in human blood from the Strong Heart Study cohort that associated with cardiovascular disease and a proportion of these genes were also significantly altered in mouse model of atherosclerosis as a result of arsenic exposure (42). We discovered that several genes in the differentially altered cistopics, such as Col1a1, Tgfbr1, and Nav2, etc., in our scATAC-Seq data corresponded to differentially methylated genes that correlated with arsenic exposure in this human dataset.…”

Heavy Metal Exposure and Cardiovascular Disease

“…For example, arsenic-associated blood biomarkers based on DNA methylation can also explain part of the association between arsenic and CVD. 36 These epigenomic results of metals can further explain the overlap between environmental factors and precision cardiology, thus informing clinical decisions.…”

“…Toxic heavy metals have epigenomic effects that include effects on DNA methylation and histone modification that can influence gene expression and downstream transcription. 36,140 Epigenetic modifications caused by heavy metals like lead and cadmium may be attributed to their ability to replace zinc, an essential element of various enzymes involved in epigenetic regulation. 141 It has also been reported that Cr (VI) can induce DNA damage and might activate or silence the expression of critical genes, 112 thus altering DNA methylation levels as well as global and gene-specific histone posttranslational modifications.…”