Exposure to arsenic at different life-stages and DNA methylation meta-analysis in buccal cells and leukocytes

Abstract

Background Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS. Methods DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs. Results In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate. Conclusions Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.

The impact of prenatal and early-life arsenic exposure on epigenetic age acceleration among adults in Northern Chile

“…The study population and DNAm measurements have previously been described [ 18 ]. The study area is located in Region II of Chile, which includes the city of Antofagasta.…”

“…Data were processed with standard quality control procedures [ 18 ] and normalized using funnorm [ 21 ]. One buccal cell sample was removed due to poor quality; one PBMC and one buccal cell sample were removed due to a sex mismatch.…”

An exposomic framework to uncover environmental drivers of aging

“…Apart from integrating exposure estimates to cohort studies, it will be also be beneficial to consider ways to integrate data across cohorts representing different time points in the life course. This could be achieved by conducting parallel analyses that draw samples from cohorts at the different life course stages, like those conducted under the HELIX project in Europe [ 66 ] and in a study that leveraged data from people exposed to Arsenic in Chile and Bangladesh [ 67 ].…”

Source Apportionment and Health Risk Assessment of Heavy Metals in PM2.5 in Handan: A Typical Heavily Polluted City in North China

“…Cr (IV) is harmful to the human body, causes damage to internal organs such as the liver and kidneys, and easily induces premature senescent hepatocytes [56,57]. As exposure can lead to encephalopathy development and higher neurological dysfunction and can cause irreversible damage to the nervous system [58,59]. In general, there was a high carcinogenic risk of heavy metal elements in PM 2.5 in Handan.…”