BACKGROUND Increasing evidence suggests that prenatal exposure to arsenic, even at common environmental levels, adversely affects child health. These adverse effects include impaired fetal growth, which can carry serious health implications lifelong. However, the mechanisms by which arsenic affects fetal health and development remain unclear. METHODS We addressed this question using a group of 46 pregnant women selected from the New Hampshire Birth Cohort Study (NHBCS), a US cohort exposed to low-to-moderate arsenic levels in drinking water through the use of unregulated private wells. Prenatal arsenic exposure was assessed using maternal urine samples taken at mid-gestation. Samples of the fetal portion of the placenta were taken from the base of the umbilical cord insertion at the time of delivery, stored in RNAlater and frozen. We used RNA sequencing to analyze changes in global gene expression in the fetal placenta associated with in utero arsenic exposure, adjusting for maternal age. Gene set enrichment analysis and enrichment mapping were then used to identify biological processes represented by the differentially expressed genes. Since our previous analyses have identified considerable sex differences in placental gene expression associated with arsenic exposure, we analyzed male and female samples separately. RESULTS At FDR < 0.05, no genes were differentially expressed in female placenta, while 606 genes were differentially expressed in males. Genes showing the most significant associations with arsenic exposure in females were LEMD1 and UPK3B (fold changes 2.51 and 2.48), and in males, FIBIN and RANBP3L (fold changes 0.14 and 0.15). In gene set enrichment analyses, at FDR < 0.05, a total of 211 gene sets were enriched with differentially expressed genes in female placenta, and 154 in male placenta. In female but not male placenta, 103 of these gene sets were also associated with reduced birth weight. CONCLUSIONS Our results reveal multiple biological functions in the fetal placenta that are potentially affected by increased arsenic exposure, a subset of which is sex-dependent. Further, our data suggest that in female infants, the mechanisms underlying the arsenic-induced reduction of birth weight may involve activation of stress response pathways.

中文翻译：

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新罕布什尔州出生队列研究中与产前砷暴露相关的胎儿胎盘变化的全转录组分析。

背景越来越多的证据表明，产前接触砷，即使在普通环境水平下，也会对儿童健康产生不利影响。这些不利影响包括胎儿生长受损，这可能对终生带来严重的健康影响。然而，砷影响胎儿健康和发育的机制仍不清楚。方法 我们使用从新罕布什尔出生队列研究 (NHBCS) 中选出的 46 名孕妇解决这个问题，该研究是一个通过使用不受监管的私人水井而暴露于饮用水中低至中等砷水平的美国队列。使用在妊娠中期采集的母体尿液样本评估产前砷暴露。在分娩时从脐带插入物的底部取出胎盘胎儿部分的样本，储存在 RNAlater 中并冷冻。我们使用 RNA 测序来分析与子宫内砷暴露相关的胎儿胎盘中整体基因表达的变化，并根据母亲年龄进行调整。然后使用基因集富集分析和富集作图来识别差异表达基因所代表的生物过程。由于我们之前的分析已经确定了与砷暴露相关的胎盘基因表达的相当大的性别差异，我们分别分析了男性和女性样本。结果 在 FDR < 0.05 时，女性胎盘中没有基因差异表达，而男性胎盘中有 606 个基因差异表达。显示与女性砷暴露最显着关联的基因是 LEMD1 和 UPK3B（倍数变化 2.51 和 2.48），以及男性中的 FIBIN 和 RANBP3L（倍数变化 0.14 和 0.15）。在基因集富集分析中，在 FDR < 0.05 时，共有 211 个基因集富集了女性胎盘中的差异表达基因，154 个基因集富集在男性胎盘中。在女性而非男性胎盘中，这些基因组中有 103 个也与出生体重降低有关。结论 我们的结果揭示了胎儿胎盘中的多种生物学功能，这些功能可能受到砷暴露增加的影响，其中一个子集与性别有关。此外，我们的数据表明，在女婴中，砷诱导的出生体重降低的潜在机制可能涉及应激反应途径的激活。其中 103 个基因组也与出生体重降低有关。结论 我们的结果揭示了胎儿胎盘中的多种生物学功能，这些功能可能受到砷暴露增加的影响，其中一个子集与性别有关。此外，我们的数据表明，在女婴中，砷诱导的出生体重降低的潜在机制可能涉及应激反应途径的激活。其中 103 个基因组也与出生体重降低有关。结论 我们的结果揭示了胎儿胎盘中的多种生物学功能，这些功能可能受到砷暴露增加的影响，其中一个子集与性别有关。此外，我们的数据表明，在女婴中，砷诱导的出生体重降低的潜在机制可能涉及应激反应途径的激活。