Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation

Abstract

Exposure to inorganic arsenic (As), a carcinogen and epigenetic toxicant, has been associated with lower circulating levels of insulin-like growth factor 1 (IGF1) and impaired growth in children of pre-school age. The aim of this study was to assess the potential impact of exposure to As on IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) as well as DNA methylation changes in 9-year-old children. To this end, we studied 9-year-old children from a longitudinal mother–child cohort in rural Bangladesh (n = 551). Prenatal and concurrent exposure to As was assessed via concentrations in maternal urine at gestational week 8 and in child urine at 9 years, measured by HPLC-HG-ICPMS. Plasma IGF1 and IGFBP3 concentrations were quantified with immunoassays. DNA methylation was measured in blood mononuclear cells at 9 years in a sub-sample (n = 113) using the Infinium HumanMethylation450K BeadChip. In multivariable-adjusted linear regression models, prenatal As (natural log-transformed), but not children’s concurrent urinary As, was positively associated with IGFBP3 concentrations (β = 76, 95% CI 19, 133). As concentrations were not associated with IGF1. DNA methylation analysis revealed CpGs associated with both prenatal As and IGFBP3. Mediation analysis suggested that methylation of 12 CpG sites for all children was mediator of effect for the association between prenatal As and IGFBP3. We also found differentially methylated regions, generally hypermethylated, that were associated with both prenatal As and IGFBP3. In all, our study revealed that prenatal exposure to As was positively associated with IGFBP3 concentrations in children at 9 years, independent of IGF1, and this association may, at least in part, be epigenetically mediated.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2239-3) contains supplementary material, which is available to authorized users.

Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure

“…In addition, cg15019001 (HLA-DPB2), cg22809683 (LAMC1), cg07466788 (SLC16A3), cg19504605 (ZFP41), cg22143856 (ZNF389), cg13251666, and cg13844779, identified as differentially methylated between As-exposed and control families in China (n = 102) (Guo et al 2018), were nominally significant in our analyses. Among 4,427 CpGs previously associated with in utero As exposure (Cardenas et al 2015;Gliga et al 2018;Green et al 2016;Kaushal et al 2017;Kile et al 2014;Rojas et al 2015) 179 were nominally significant in the current study. Demanelis et al also reported all nominally significant loci, allowing us to check for significance of our FDR-significant CpGs.…”

“…Among 4,427 CpGs previously associated with in utero As exposure ( Cardenas et al. 2015 ; Gliga et al. 2018 ; Green et al.…”

“…Inconsistent results among epidemiological studies of the association between As exposure and epigenetic dysregulation may be due to differences between populations studied (e.g., age, sex, genetic structure), levels of As exposure, differential residual confounding, and methods for quantifying DNA methylation (Argos 2015). Previous EWAS of As exposure have included birth cohorts in the United States (Green et al 2016;Koestler et al 2013), Bangladesh (Broberg et al 2014;Cardenas et al 2015;Gliga et al 2018;Kile et al 2012), Mexico (Rojas et al 2015), and Taiwan (Kaushal et al 2017), and studies of adults in the United States , Bangladesh (Argos et al 2015;Demanelis et al 2019), Argentina (Ameer et al 2017), and China (Guo et al 2018). In addition, the samples sizes of previous EWAS have ranged from <50-400, resulting in limited statistical, particularly when interrogating a large number of CpG sites (Argos 2015).…”

Early-Life Cadmium Exposure and Bone-Related Biomarkers: A Longitudinal Study in Children

“…We also adjusted all the models for urinary arsenic (sum of metabolites; log2-tranformed) at each exposure time point because arsenic has previously been adversely associated with IGF-1 and IGFBP3 in this cohort (Ahmed et al. 2013; Gliga et al. 2018) and because it may occur in the same dietary sources as cadmium, particularly in rice (Kippler et al.…”

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

“…Hence, it is hard to postulate if the LYRM2 methylation change is epigenetic toxicity, adaptation or just a neutral biomarker of arsenic. This is the case with another arsenic-related study [109], and with a large body of research on the effect of the environment on epigenetic variation.…”