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Publication Role of NRF2 and GSH in Response to PFOS Exposure in the Pancreas(2024-09) Pereira Marin, Marjorie GuidaPerfluorooctanesulfonic acid (PFOS) is a widespread legacy contaminant frequently detected in environmental and human samples. Notably, PFOS can cross the placenta and has been found in both cord blood and breastmilk, highlighting the importance of understanding its impacts during early development. This dissertation investigates the role of Nrf2, a transcription factor that regulates antioxidant genes, in mediating PFOS toxicity, particularly during critical windows of susceptibility such as pre-conception and embryonic development. Maternal PFOS exposure resulted in dose-dependent transfer to offspring, affecting both wildtype embryos with functional Nrf2a and Nrf2a mutants with a loss-of-function mutation. In wildtype offspring, PFOS exposure decreased nutrient uptake, while in Nrf2a mutants, it surprisingly increased. Additionally, the insulin-producing cells in larvae exposed maternally to PFOS were identified as a target, with wildtype embryos showing aberrant β-cell morphology, whereas Nrf2a mutants appeared protected. Further studies in zebrafish exposed to PFOS during embryonic development revealed a truncated exocrine pancreas phenotype, more severe in Nrf2a mutants. Tissue-specific effects were observed: PFOS exposure decreased S-glutathionylation in the pancreas of wildtype larvae, but this decrease was absent in Nrf2a mutants. No significant changes were noted in liver tissue. Moreover, PFOS exposure decreased β-cell insulin fluorescence in wildtype larvae, a reduction not seen in Nrf2a mutants. In vitro experiments with pancreatic βTC-6 cells demonstrated that PFOS affected the expression of genes involved in lipid metabolism, hormone regulation, and endoplasmic reticulum stress. The glutathione redox potential shifted in response to PFOS, coinciding with decreased glucose-stimulated insulin secretion. PFOS also increased the amount of proinsulin disulfide-linked complexes, suggesting that PFOS disrupts insulin biosynthesis—a potential novel mechanism of PFOS toxicity. This dissertation advances our understanding of how the Nrf2 pathway mediates the adverse effects of PFOS during critical developmental windows and identifies the pancreas as a primary target organ. Furthermore, it demonstrates how PFOS induces lasting alterations in pancreatic β-cell redox homeostasis and function. Given the ubiquity of this pollutant, exploring the mechanisms underlying PFOS toxicity is crucial. Future research can build on these findings to deepen our understanding of PFOS toxicity and to identify populations vulnerable to the potential lifelong consequences of early-life exposure to PFOS.