Metal Mixtures and Preterm Birth: Private Well Water Exposure and the Role of the Placenta

Preterm birth is a pressing global health issue with 15 million infants born prematurely worldwide. Exposure to metals and metal mixtures during pregnancy may increase the risk of preterm birth. Individuals can be exposed to high levels of metals in North Carolina (NC) via private well water, as private wells are not protected under the Safe Drinking Water Act. Metal exposure may activate inflammation-related biological pathways within the placenta, representing a potential underlying mechanism of metal-induced preterm birth. Using interdisciplinary approaches and mixtures methodologies, this dissertation examines the relationship between prenatal metal mixture exposure and preterm birth in NC. First, trends in private well water metal concentrations across NC over twenty years were examined. Over 117,000 well water tests were compiled and geocoded. High levels of inorganic arsenic, manganese, and lead were found in addition to common co-occurrence among many metals. Second, the relationship between well water concentrations of metals (inorganic arsenic, lead, manganese, cadmium, chromium, copper, and zinc), individually and in mixtures, and preterm birth was investigated by combining over 1.3 million birth certificate records with the dataset of private well water tests. Lead and cadmium were individually associated with an increased risk of preterm birth and a mixture of lead, cadmium, and chromium increased the risk of preterm birth as well. Lastly, to explore the mechanistic role of placental inflammation in metal-induced toxicity, genome-wide gene expression in the placenta was evaluated in relation to umbilical cord metal concentrations (including arsenic, lead, manganese, cadmium, copper, and zinc) in a human cohort study of extremely preterm infants. While individual metals were not associated with large transcriptomic responses, a mixture of lead and cadmium induced the strongest transcriptomic response, increasing the expression of genes related to Eukaryotic Initiation Factor 2 (EIF2)- and Nuclear Factor kappa B (NF-kB)-signaling. Taken together, findings from this dissertation highlight (1) the prevalence of co-exposure to multiple metals, especially via private well water; (2) that metal exposure during pregnancy, particularly to lead and cadmium, should be an urgent public health concern; and (3) that mixtures methodologies can highlight results not found by evaluating single exposures alone.Doctor of Philosoph