Graduate Thesis Or Dissertation

In Utero Exposure to Arsenic and Mercury : Epigenome-Wide Associations and Newborn Health Outcomes

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  • Mercury and arsenic are known developmental toxicants and environmental exposures are ubiquitous worldwide from natural and anthropogenic sources. Prenatal exposure to both contaminants are independently associated with adverse perinatal health outcomes and latent disease risk that could be in part mediated by epigenetic reprogramming events. Fetal programming events involving DNA methylation occur early during fetal development and are sensitive to environmental stimuli, potentially influencing disease risk throughout the life course. This research evaluated the epigenetic disruption of DNA methylation associated with exposure to mercury and arsenic in utero, and the potential impact on infant birth outcomes. The first study provides evidence that exposure to mercury during fetal development can contribute to epigenetic variability and immune cell proportion changes in infant cord-blood collected at birth. The data also suggests that exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome in cord-blood. The second study evaluated the epigenome wide association of arsenic exposure in utero for placenta, umbilical artery and umbilical vein endothelial cells (HUVEC). Our results show that prenatal arsenic exposure alters DNA methylation of umbilical artery and placenta but there is limited evidence for an association in HUVEC. We also identified DNA methylation disruption of key biological pathways related to adverse health outcomes previously associated with arsenic exposure in epidemiological studies. Lastly, the third study evaluated the direct association between prenatal arsenic exposure, birth gestational age and birth weight, as well as the indirect effect of arsenic exposure mediated through DNA methylation in cord-blood. We observed that the inverse relationship between arsenic exposure in utero and birth gestational age was completely mediated through DNA methylation of selected CpG loci. No association or mediation was observed between prenatal arsenic exposure and infant birth weight. These results provide evidence that exposure to arsenic and mercury in utero, two common environmental contaminants, can influence epigenetic programming of DNA methylation in different biological human tissues. Particularly, the effect of arsenic exposure on gestational age was mediated through CpG methylation of infant cord-blood, which is a critical parameter of infant health and associated with disease later in life. Future studies should evaluate if these epigenetic changes are persistent and associated with disease risk later in life. The design of public health interventions that target prevention of environmental exposures in utero that may increase disease risk later in life provide a unique opportunity for early disease prevention. Overall, these results will guide future research and inform regulatory guidelines to help reduce arsenic and mercury exposure, particularly during pregnancy.
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