Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Toxicol Appl Pharmacol. 2012 Nov 1;264(3):439-50. doi: 10.1016/j.taap.2012.08.022. Epub 2012 Aug 31.
Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring.
无机砷（iAs）是一种完全的胎盘致突变剂，在小鼠中是这样。先前的研究表明，子宫内暴露于 iAs 会促进成年小鼠后代的癌症，这可能是通过表观遗传机制起作用。人和啮齿动物将 iAs 酶促转化为其甲基化代谢物。此反应需要 S-腺苷甲硫氨酸（SAM）作为甲基供体。SAM 也需要用于 DNA 甲基化。补充叶酸，即 SAM 合成的主要膳食甲基供体，已被证明可以改变 iAs 代谢和 iAs 暴露的不良影响。然而，妊娠叶酸补充对 iAs 代谢和胎儿 DNA 甲基化的影响从未被彻底研究过。在本研究中，从妊娠第 5 天到第 18 天，给 CD1 妊娠小鼠喂食对照（即正常叶酸或 2.2mg/kg）或高叶酸饮食（11mg/kg），并从妊娠第 8 天到第 18 天饮用含 0 或 85ppm 的 As（亚砷酸盐）的水。iAs 的暴露显著降低了 GD18 胎儿的体重，并增加了胎肝中的 SAM 和 S-腺苷同型半胱氨酸（SAH）浓度。高叶酸摄入降低了母鼠肝脏中总砷的负担，但不能防止 iAs 暴露对胎儿体重或肝 SAM 和 SAH 浓度的影响。事实上，叶酸与 iAs 的联合暴露导致体重进一步显著减轻。值得注意的是，iAs 单独暴露对胎肝 DNA 甲基化影响不大。相反，叶酸与 iAs 的联合暴露改变了 2931 个基因的 CpG 岛甲基化，包括已知印迹的基因。这些基因中的大多数与神经发育、癌症、细胞周期和信号网络有关。调节胎儿发育的经典 Wnt 信号通路是受影响最严重的生物学通路之一。总之，我们的研究结果表明，宫内联合暴露于 iAs 和高叶酸摄入可能会对胎儿的 DNA 甲基化谱和体重产生不利影响，损害胎儿发育并可能增加后代早发性疾病的风险。
