Perturbations during the intrauterine period, including exposures to toxic levels of trace metals, may disrupt appropriate fetal growth and development and adversely impact health throughout the lifespan of the individual. The placenta is the principal organ interpreting cues from the intrauterine environment to inform fetal development, yet, changes in placental transcriptomic activity has not been systematically evaluated as a possible mediator of fetal growth abnormalities. Comprehensively assessing the interrelationship between metal mixture exposure, placental gene activity and fetal growth is becoming feasible with the increasing availability of high-dimensional exposure and genomic data, however, the potential to fully harness the biologic information retained in these large scale data-sets has yet to be realized. To address these existing gaps, we outlined research and training aims to conduct environmental mixture modeling in a population-based study in the context of high-throughput genomics data with verification in a biological system. The proposed study represents the first comprehensive integration of multi-metal exposure and placental genomics data in an epidemiologic setting. We will conduct this study using available resources in RICHS, an ongoing, previously funded cohort, enabling us to identify novel environmentally sensitive biomarkers in a cost-effective manner. The knowledge gained and tools developed through the proposed study may be applied in other settings and have the potential to inform more broadly on the influence of the in utero environment on health throughout the lifespan. To conduct the proposed study, I will train in advanced biostatistics, systems biology and molecular biology methods as I progress through the research aims with continual feedback from my advisory team throughout our regularly scheduled meetings. Through formal coursework and the mentored guidance provided by Drs. Jia Chen, Chris Gennings, Carmen Marsit, Ke Hao and Qian Lu, I will obtain the knowledge and training necessary to develop into an independent, interdisciplinary researcher with a focus on elucidating the molecular mechanism linking in utero environmental exposures to adverse birth outcomes.
The intrauterine phase is a period of heightened sensitivity to environmental insults, including toxic levels of trace metals, with the potential to disrupt fetal development as well as trigger health effects across the lifespan of the newborn. The proposed research seeks to comprehensively assess the impact of multi-metal exposure during pregnancy on fetal growth, examine the potential role of the placental transcriptome in the pathway linking in utero trace metal exposures to fetal growth and validate derived in silico findings in an in vitro model. More broadly, the knowledge and skill gained from this proposal can be applied to expand the literature on the impact of various in utero environmental exposures on a range of birth outcomes.