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.

Keywords: Early life; Epigenetic; Growth; IGF1; IGFBP3; Mediation.

Fig. 1

Prenatal arsenic (As) is associated with plasma concentrations of IGFBP3 in 9-year-old children. Prenatal (a) but not concurrent (b) exposure to As is associated with IGFBP3 plasma concentrations in 9-year-olds. Prenatal exposure corresponds to natural log-transformed maternal As in urine in gestational week 8 [ln(As in urine GW 8)], and concurrent exposure to natural log-transformed As in urine at 9 years [ln(As in urine 9 years)]. Black line indicates the linear regression line (crude model) and red line indicates the Loess line

Fig. 2

Methylation of cg16447589 is associated with IGFBP3 concentrations in plasma and prenatal arsenic exposure. a Methylation of cg16447589 is negatively associated with IGFBP3 concentrations in plasma in boys and positively associated in girls. b Prenatal exposure to As, expressed as natural log-transformed maternal arsenic in urine in gestational week 8 [ln(As in urine GW 8)], is negatively associated with methylation of cg16447589 in boys and positively associated in girls. Lines indicate the regression line, and the shadows represent the 95% confidence interval

Fig. 3

Top network of the genes defined by the differentially methylated CpG sites associated with the prenatal exposure to arsenic in boys (IGFBP3 was annotated for the CpG cg16447589). The main diseases and functions associated with this network are related to cancer, organismal injuries and abnormalities, melanoma and cell cycle progression. Asterisk indicates genes for which more than one CpG had been annotated