Prenatal Metal Mixtures, Fetal Growth, and the Role of MicroRNAs

项目概要/摘要 胎儿生长减少与广泛的不良健康结果有关。越来越多的证据 表明有毒金属暴露对胎儿生长有不利影响， 测量和低出生体重。虽然大多数人同时暴露于多种 金属，这可能会起到相加或协同作用，以减少胎儿的生长，大多数研究都集中在 个别金属的毒性。虽然金属诱导的胎儿生长减少的机制 虽然还不完全清楚，但有证据表明，表观遗传失调，包括改变的microRNA （miRNA）表达，有助于这些作用。除了表观遗传调节基因表达外， 母体循环miRNA在母体-胎盘-胎儿串扰中起重要作用。然而， 母体循环miRNA在介导金属混合物对胎儿生长的影响中的作用尚不清楚。的目标 拟议的项目是研究产前金属混合物暴露对胎儿生长的影响， 确定是否改变母体循环miRNA介导这些关系。在K99的指导下 在该奖项的第一阶段，Howe博士将利用现有的数据和来自500对母婴的生物标本， 来自环境和社会压力的孕产妇和发育风险（MADRES）研究，一项低- 以洛杉矶为基础的西班牙裔孕妇队列，调查潜在的附加和 产前暴露于15种金属与子宫内生长和出生体重之间的协同关系。到 为了实现这一目标，她将在MADRES妊娠队列中扩大金属暴露评估，并在 分析复杂环境混合物的方法，包括加权分位数和回归， 贝叶斯核机器回归。在R 00阶段，Howe博士将确定产妇是否 使用结构方程模型，循环miRNA介导金属混合物-胎儿生长关系， 通过分析母体-胎盘-胎儿内的mRNA表达水平来检查潜在的下游效应 轴，使用RNA-Seq，在母亲-新生儿对的子集（N = 50）中。拟议研究的结果可能是 用于提高公共卫生干预措施的有效性，以防止金属引起的 胎儿生长此外，它们将增加对潜在的潜在机制（改变母体的 循环中的miRNAs），并可能导致早期和相对非侵入性的金属生物标志物的鉴定 混合物暴露和胎儿生长减少。豪博士组建了一个指导团队， 南加州大学、波士顿大学和埃默里大学，具有金属毒性方面的专业知识， 环境混合物建模、表观遗传流行病学和围产期学。该团队将持续提供 反馈和现场培训机会，以补充课程、讲习班和研讨会， 支持豪博士的过渡，成为一个独立的研究计划，重点是 生命早期金属混合物暴露对表观基因组和胎儿生长的影响。

PROJECT SUMMARY/ABSTRACT Reduced fetal growth has been implicated in a broad range of adverse health outcomes. Growing evidence suggests that toxic metal exposures adversely affect fetal growth, indicated by reduced fetal ultrasound measurements and lower birth weight. Although most individuals are exposed simultaneously to multiple metals, which may act additively or synergistically to reduce fetal growth, the majority of studies have focused on the toxicity of individual metals. While the mechanisms underlying metal-induced reductions in fetal growth are incompletely understood, there is evidence that epigenetic dysregulation, including altered microRNA (miRNA) expression, contributes to these effects. In addition to epigenetically regulating gene expression, maternal circulating miRNAs play important roles in maternal-placental-fetal crosstalk. However, the potential role of maternal circulating miRNAs in mediating metal mixture effects on fetal growth is unknown. The goal of the proposed project is to examine the impact of prenatal metal mixture exposures on fetal growth and to determine whether altered maternal circulating miRNAs mediate these relationships. During the mentored K99 phase of this award, Dr. Howe will leverage existing data and biospecimens from 500 mother-newborn pairs in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study, a low- income predominately Hispanic pregnancy cohort based in Los Angeles, to investigate potential additive and synergistic relationships between prenatal exposure to 15 metals and in utero growth and birth weight. To accomplish this, she will expand metals exposure assessment in the MADRES pregnancy cohort and train in methods for analyzing complex environmental mixtures, including weighted quantile sum regression and Bayesian kernel machine regression. During the R00 phase, Dr. Howe will determine whether maternal circulating miRNAs mediate metal mixture-fetal growth relationships, using structural equation models, and will examine potential downstream effects by profiling mRNA expression levels within the maternal-placental-fetal axis, using RNA-Seq, in a subset (N = 50) of mother-newborn pairs. Results from the proposed studies may be used to improve the efficacy of public health interventions aimed at preventing metal-induced reductions in fetal growth. Furthermore, they will increase knowledge of a potential underlying mechanism (altered maternal circulating miRNAs) and may lead to the identification of early and relatively non-invasive biomarkers of metal mixture exposures and reduced fetal growth. Dr. Howe has assembled a mentoring team, spanning the University of Southern California, Boston University, and Emory University, with expertise in metals toxicity, environmental mixtures modeling, epigenetic epidemiology, and perinatology. This team will provide ongoing feedback and on-site training opportunities to complement coursework, workshops, and seminars, which will support Dr. Howe’s transition to become an independent investigator with a research program that focuses on the effects of early life metal mixture exposures on the epigenome and fetal growth.