Prenatal inorganic arsenic (iAs) exposure influences the expression of critical genes and proteins associated with adverse outcomes in newborns, in part through epigenetic mediators. The doses at which these genomic and epigenomic changes occur have yet to be evaluated in the context of dose–response modeling. The goal of the present study was to estimate iAs doses that correspond to changes in transcriptomic, proteomic, epigenomic, and integrated multi-omic signatures in human cord blood through benchmark dose (BMD) modeling. Genome-wide DNA methylation, microRNA expression, mRNA expression, and protein expression levels in cord blood were modeled against total urinary arsenic (U-tAs) levels from pregnant women exposed to varying levels of iAs. Dose–response relationships were modeled in BMDExpress, and BMDs representing 10% response levels were estimated. Overall, DNA methylation changes were estimated to occur at lower exposure concentrations in comparison to other molecular endpoints. Multi-omic module eigengenes were derived through weighted gene co-expression network analysis, representing co-modulated signatures across transcriptomic, proteomic, and epigenomic profiles. One module eigengene was associated with decreased gestational age occurring alongside increased iAs exposure. Genes/proteins within this module eigengene showed enrichment for organismal development, including potassium voltage-gated channel subfamily Q member 1 (KCNQ1), an imprinted gene showing differential methylation and expression in response to iAs. Modeling of this prioritized multi-omic module eigengene resulted in a BMD(BMDL) of 58(45) μg/L U-tAs, which was estimated to correspond to drinking water arsenic concentrations of 51(40) μg/L. Results are in line with epidemiological evidence supporting effects of prenatal iAs occurring at levels <100 μg As/L urine. Together, findings present a variety of BMD measures to estimate doses at which prenatal iAs exposure influences neonatal outcome-relevant transcriptomic, proteomic, and epigenomic profiles.

中文翻译：

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诱导妊娠队列中新生儿转录组、蛋白质组和表观基因组变化的无机砷浓度的基准剂量模型估计

产前无机砷 (iAs) 暴露会影响与新生儿不良后果相关的关键基因和蛋白质的表达，部分是通过表观遗传介质。这些基因组和表观基因组变化发生的剂量尚未在剂量反应模型的背景下进行评估。本研究的目标是通过基准剂量 (BMD) 建模来估计与人类脐带血中转录组学、蛋白质组学、表观基因组学和综合多组学特征变化相对应的 iAs 剂量。脐带血中的全基因组 DNA 甲基化、microRNA 表达、mRNA 表达和蛋白质表达水平根据暴露于不同水平 iAs 的孕妇的尿总砷 (U-tAs) 水平进行建模。剂量反应关系在 BMDExpress 中建模，估计了代表 10% 响应水平的 BMD。总体而言，与其他分子终点相比，估计 DNA 甲基化变化发生在较低的暴露浓度下。多组学模块特征基因是通过加权基因共表达网络分析得出的，代表了转录组学、蛋白质组学和表观基因组学的共同调制特征。一个模块 eigengene 与随着 iAs 暴露增加而发生的胎龄减少有关。该模块 eigengene 中的基因/蛋白质显示出对有机体发育的富集，包括钾电压门控通道亚家族 Q 成员 1（多组学模块特征基因是通过加权基因共表达网络分析得出的，代表了转录组学、蛋白质组学和表观基因组学的共同调制特征。一个模块 eigengene 与随着 iAs 暴露增加而发生的胎龄减少有关。该模块 eigengene 中的基因/蛋白质显示出对有机体发育的富集，包括钾电压门控通道亚家族 Q 成员 1（多组学模块特征基因是通过加权基因共表达网络分析得出的，代表了转录组学、蛋白质组学和表观基因组学的共同调制特征。一个模块 eigengene 与随着 iAs 暴露增加而发生的胎龄减少有关。该模块 eigengene 中的基因/蛋白质显示出对有机体发育的富集，包括钾电压门控通道亚家族 Q 成员 1（KCNQ1），一种印记基因，显示出响应 iAs 的差异甲基化和表达。这种优先多组学模块 eigengene 的建模导致 BMD(BMDL) 为 58(45) μg/L U-tAs，估计对应于 51(40) μg/L 的饮用水砷浓度。结果与支持产前 iAs 在 <100 μg As/L 尿液水平下产生影响的流行病学证据一致。总之，研究结果提出了多种 BMD 措施来估计产前 iAs 暴露影响新生儿结局相关转录组学、蛋白质组学和表观基因组学概况的剂量。