Birth defects are a leading cause of infant mortality, and cardiac defects are among the most fatal. The majority of birth defects have no known cause whether environmental, genetic, or a combination of these factors. Toxic metals are likely contributors to birth defects in humans, yet the biological pathways that underlie these relationships remain largely unknown. The objective of this research was to assess the contributions of environmental metals to congenital heart defects using i) an ecologic study to evaluate the relationship between metals and birth defects in North Carolina and ii) an in vitro cardiomyocyte model to identify underlying metalaltered molecular pathways. This research evaluated the associations between arsenic, cadmium, manganese, and lead levels in private well water with the prevalence of specific birth defects using six years of data collected by the North Carolina Birth Defects Monitoring Program. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in census tracts with the highest average metal levels compared to the lowest average metal levels, adjusted for maternal age, race, and education status. We identified relationships between the highest category of arsenic exposure and the prevalence of conotruncal heart defects (PR: 1.3 95%CI: 0.9-1.8) as well as the highest category of manganese exposure and the prevalence of atrioventricular septal heart defects (PR: 1.8 95% CI: 1.1-3.1). The findings suggest an ecologic association between concentrations of metals in drinking water and the prevalence of specific birth defects. Next, we applied an in vitro approach to identify biological pathways that underlie metal-altered signaling in the heart. We exposed human-derived cardiomyocytes to low-level cadmium chloride (0.5 μM) and assessed changes in genome-wide microRNA (miRNA) and messenger RNA (mRNA) expression levels. We identified 8 miRNAs and 31 genes that were differentially expressed in cardiomyocytes exposed to cadmium compared to unexposed controls. A subset of 8 mRNAs were predicted targets of the cadmium-associated miRNAs. We identified miRNA-dependent signaling pathways that were enriched for gene expression, embryonic development, and organismal development. Taken together, the findings contribute to the understanding of potentially preventable environmentally-mediated birth defects.Doctor of Philosoph
