Per- and polyfluoroalkyl substances (PFASs) are synthetic chemicals widely used in consumer products for their stain- and water-resistant properties. These substances are known for their persistence in the environment and in the human body, leading to widespread contamination and increasing concerns about their potential health effects. PFAS have been linked to reproductive, developmental, liver, kidney, and immune effects. In 2018, high levels of PFAS (1600 ng/L) were discovered in the municipal wells of a small community in southwestern Michigan, linked to an abandoned paper mill and landfill. In 2020-2021, we conducted a detailed exposure assessment in this community. We examined the mixture of PFAS from this paper mill source in drinking water and its persistence in human serum. Serum was collected from 100 participants and analyzed for 35 PFASs using LC-MS/MS. Approximately half of the study participants had private wells with lower PFAS concentrations (<220 ng/L) compared to municipal water, thus assigned to low (private well) and high (municipal well) drinking water exposure groups. Participants in the high drinking water exposure group had significantly elevated serum concentrations of PFOA, PFOS, and PFHxS, demonstrating drinking water as a major source of PFAS exposure and highlighting the long-term risks posed by abandoned landfills. Epidemiological and experimental animal studies have observed immunomodulatory effects for several PFAS, including PFOA, PFOS, and PFHxS. The most sensitive endpoint reported is suppressed antibody response following vaccination in children. Results in adults are mixed, which may be related to increased variability in antibody titer from prior vaccinations and infections. To investigate this and to address community concerns, we quantified associations of COVID-19 antibody levels with serum PFAS. SARS-CoV-2 IgG spike (IgG spike) antibodies were measured for a subset (n=74) of adults fully vaccinated for COVID-19 within 1 to 6 months before blood collection. IgG Spike antibody concentrations were significantly negatively associated with ∑PFAS and PFHxS in serum and suggestively negatively associated with the other frequently detected PFAS. These results indicate that this functional test can work in adults by measuring antibody titer within the appropriate period following vaccination to a novel disease. Importantly, our findings indicate a potential increase in disease susceptibility among adults in PFAS-impacted communities. As this functional test requires vaccination to a novel disease for investigation in adults, other functional measures, such as alteration in immune cells, may have broader applicability for investigations in exposed populations. Therefore, we investigated associations between serum PFAS and immune cell profiles in a subset of adults (n=22) matched on age and gender between groups with low (<15 ug/L) and high (>55ug/L) serum PFAS concentrations. Whole blood was collected to determine white blood cell counts. Peripheral blood mononuclear cells were isolated and stained for flow cytometry under unstimulated and stimulated conditions to quantify cytotoxic and helper T cell subsets and markers of T cell activation. Supernatants from stimulated cells were analyzed for interleukin-2 using ELISA. We observed that elevated serum PFAS concentrations were associated with alterations in the percentages of neutrophils, lymphocytes, naïve cytotoxic T cells, and T cell activation, suggesting PFAS exposure may disrupt T cell homeostasis and contribute to immune dysregulation. Overall, this dissertation provides critical insights into the long-term persistence of PFAS exposure in a contaminated community and the potential immunotoxic effects.
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