Fetal Epigenetic Reprogramming: Evaluating the Role of Exposure to Maternal Dietary Metabolites and Bisphenols
McCabe, Carolyn
2020
Abstract
The Developmental Origins of Health and Disease (DOHaD) paradigm correlates a suboptimal intrauterine environment to increased risk of chronic disease. This association is well accepted, and recent work indicates that environmentally induced changes in cellular function and disease etiology are mediated by changes in the epigenetic profile. For the purpose of this dissertation, epigenetics is defined as the study of mitotically and/or meiotically heritable changes in gene expression that cannot be explained by changes in DNA sequence. While we are beginning to understand the outcomes associated with prenatal exposure to components like the maternal diet and bisphenol-A (BPA), few studies in humans assess the epigenetic impact of these exposures. In order to accurately discern the association between maternal exposure and epigenetic reprogramming, studies are needed that evaluate prenatal exposure to both bisphenols and maternal diet during early pregnancy. Additionally, more research is needed that establishes epigenetic signatures of exposure in peripheral tissues. We utilized the Michigan Mother-Infant Pairs (MMIP) cohort to assess (Aim 1) the association of prenatal exposure to bisphenols BPA, BPF, and BPS and infant cord blood leukocyte DNA methylation, (Aim 2) maternal one-carbon metabolites across pregnancy and in association with DNA methylation in infant cord blood leukocytes, (Aim 3a) DNA methylation at candidate genes across three tissue types and their association with bisphenol exposure, and (Aim 3b) the association between prenatal bisphenol exposure and placental DNA methylation. Cutting edge techniques of microarray technology to profile DNA methylation at >850,000 CpG sites in both infant cord blood and placenta, untargeted metabolomics, and pyrosequencing were combined to answer our research questions. Aim 1 results suggest that prenatal exposure to BPA, as measured in maternal urine between 8-14 weeks of gestation, was significantly associated with differential DNA methylation at 38 CpG sites and three differentially methylated regions. Gene-set analysis of BPA-associated CpG sites revealed enrichment for pathways associated with the nervous system, immune response, and neuroinflammation. Aim 2 results suggest that maternal third trimester and cord blood one-carbon metabolite S-adenosylhomocysteine (SAH) were significantly correlated with a shift in the global distribution of DNA methylation in infant cord blood leukocytes. This aim also provides evidence of patterns of one-carbon metabolites within time points and across pregnancy. Aim 3a results suggest that candidate gene DNA methylation and tissue-specific associations with prenatal bisphenol exposure do significantly differ at some but not all genes tested across cord blood, cord tissue, and placenta from the same individuals. For example, mixed effect regression revealed that placental tissue DNA methylation was significantly associated with bisphenol exposure at three out of four genes, as compared to one in cord blood and none in cord tissue. These data may inform selection of surrogate tissues for environmental epigenetic studies. Lastly, Aim 3b exploratory analysis of epigenome-wide placental DNA methylation suggests prenatal exposure to bisphenols may be associated with alternations in pathways related to inflammation, vascularization, and preeclampsia. This dissertation contributes to the burgeoning field of epigenomics and helps to establish a foundation in our understanding of maternal exposures and their influences on epigenetic programming. Advances in epigenome-wide association studies will ultimately enable researchers, clinicians, and policymakers to target risk factors (e.g. environmental and nutritional exposures that perturb the methylome and downstream birth outcomes) and to better understand a portion of the elements underlying the developmental origins of health and disease.Deep Blue DOI
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Epigenomics Prenatal exposures
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