Saturday, March 15, 2025
3/15/2025
Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants that have been investigated as developmental toxicants, with little information on long-term neurotoxicity and clinical outcomes. Our preliminary data suggest that PFAS may produce neurotransmission changes relevant to psychiatric disorders involving abnormal reward processing, specifically anhedonia. We will test the hypothesis that: early life PFAS exposure will produce alterations in reward processing mediated through specific neurotransmission targets. Importantly, the hypothesis will be tested in animal models and humans, utilizing innovative translational approaches. We will test our hypothesis through 3 aims. Aim 1 will establish a brain - specific translational PFAS dosing regimen in mice, based upon published and preliminary data from human brain samples and sentinel animal studies. Here, we will develop a translational dosing strategy, specific to brain levels that is expected to considerably increase the human health relevance of these and future studies. This aim sets the stage for studies on the potential role of PFAS exposures in psychiatric disorders. Aim 2 will determine if PFAS exposure produces alterations in behavioral phenotypes relevant to reward processing in mice. In light of our preliminary data and the gap in the literature, there is a critical need to evaluate developmental neurotoxicity in higher order species. We will assess the emergence of neurological phenotypes through neurobehavioral analyses, neurotransmitter measurements, neuropathology studies, and determination of the biochemical underpinnings of a reward processing phenotype. Aim 3 will determine whether serum PFAS (individual compounds or as a mixture) are linked to human reward processing deficits. To achieve bi- directional translation, we will conduct human studies informed by our animal data. Conversely, data from this aim will inform ongoing animal studies. To identify links to psychiatric disorders, we will conduct a cross- sectional study of adults aged 18 to 30 years. In this study we will: identify correlations between serum PFAS, self-reported anhedonia severity, and clinician-rated anhedonia severity; test for clinical specificity by examining correlations with broader symptoms of depression, mania, and psychosis; and identify correlations between serum PFAS and neurophysiological measures of reward sensitivity, which may represent intermediate phenotypes with disease relevance. Our findings may suggest that individuals with high PFAS levels be carefully monitored for the emergence of psychiatric symptoms. We expect this project to have a significant impact on the understating of environment influences of neuropsychiatric diseases. For the first time, we will establish whether specific PFAS exposures may influence the etiology of reward processing disorders. We will do so in both animal models and human studies – where resultant data from each line of research informs each other to achieve bidirectional translation with respect to experimental design and interpretation.
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