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.
Highlights
Inorganic arsenic (As) is a well-established carcinogen (IARC 2012 100C) and a potent toxicant with effects on, e.g. the immune and endocrine systems (Ferrario et al 2016; Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Raqib et al 2017; Sun et al 2016)
We evaluated the overlap between the top 2000 CpGs to identify CpGs that could act as mediators and we found a total of 14 sites that were associated with both prenatal As and insulin-like growth factor-binding protein 3 (IGFBP3) in all children
We evaluated whether the associations between prenatal As and IGFBP3 in plasma were epigenetically mediated by first looking into the DNA methylation of sites within the IGFBP3 gene
Summary
Prenatal exposure to As has been adversely associated with changes in foetal size parameters (Kippler et al 2012; Rahman et al 2009; Yang et al 2003) and exposure during early childhood has been associated with impaired growth (Gardner et al 2013; Saha et al 2012). Prenatal exposure to As has been associated with lower concentrations of the plasma insulin-like growth factor 1 (IGF1), a marker of foetal and child growth, at birth (Ahmed et al 2013). At 4.5 years of age, the children’s concurrent exposure to As, but not the prenatal exposure, was inversely associated with plasma IGF1 (Ahmed et al 2013). The association between As and IGF1 during early life is unclear
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