Unit of Metals and Health, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
Arch Toxicol. 2018 Aug;92(8):2487-2500. doi: 10.1007/s00204-018-2239-3. Epub 2018 Jun 8.
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.
接触无机砷（As），一种致癌物质和表观遗传毒物，与学龄前儿童循环胰岛素样生长因子 1（IGF1）水平降低和生长受损有关。本研究旨在评估 9 岁儿童接触砷对 IGF1 和胰岛素样生长因子结合蛋白 3（IGFBP3）以及 DNA 甲基化变化的潜在影响。为此，我们研究了孟加拉国农村一个纵向母婴队列中的 9 岁儿童（n=551）。通过 HPLC-HG-ICPMS 测量孕妇妊娠第 8 周和儿童 9 岁时尿液中的浓度，评估产前和同期暴露于 As 的情况。使用免疫测定法定量测定血浆 IGF1 和 IGFBP3 浓度。在一个亚样本（n=113）中，在 9 岁时使用 Infinium HumanMethylation450K BeadChip 测量血液单核细胞中的 DNA 甲基化。在多变量调整线性回归模型中，产前 As（自然对数转换），而不是儿童同期的尿液 As，与 IGFBP3 浓度呈正相关（β=76，95%CI 19，133）。As 浓度与 IGF1 无关。DNA 甲基化分析显示与产前 As 和 IGFBP3 相关的 CpG。中介分析表明，对于产前 As 与 IGFBP3 之间的关联，所有儿童的 12 个 CpG 位点的甲基化是效应的中介。我们还发现了与产前 As 和 IGFBP3 均相关的差异甲基化区域，通常呈高甲基化。总之，我们的研究表明，9 岁儿童的产前暴露于 As 与 IGFBP3 浓度呈正相关，与 IGF1 无关，这种关联至少部分可能是表观遗传介导的。
