Parkinson's disease (PD) is a debilitating movement disorder (affecting ~5 million world‐wide) resulting from selective death of dopamine (DA) neurons. To date, numerous rarely encountered exposures have been investigated as risk factors, but none have been clearly linked to PD. Further, the translation of therapeutics that are promising in animal studies to successful clinical trials has been very poor. These gaps in the field suggest serious weaknesses in the utilization of animal models in PD research. Most PD studies test hypotheses in single model systems. However, there are clear advantages with respect to increasing the strength of the findings and advancing the field through understanding species differences. This R21 aims to be highly responsive to PAR‐ 17‐039 (Comparative Biology of Neurodegeneration) by testing PD‐relevant neurodegeneration across three phylogenetically diverse animal model systems. In the spirit of an R21, the proposal utilizes high risk/high reward approaches, where novel risk factors will be tested to advance the understanding of the biology of PD. Per‐ and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants that have been investigated as developmental toxicants, with little information on long‐term neurotoxicity. Our preliminary mechanistic and neuropathology data in nematode and amphibian models suggest that exposure to PFAS, especially perfluorooctane sulfonate (PFOS) induces selective PD‐relevant, DAergic neurotoxicity. This project will address an important gap on how PFAS exposure leads to long‐term neurological disease risk. We will test the hypothesis: that species‐specific responses to PFOS‐induced dopaminergic neurodegeneration will advance understanding of the biology of PD. Importantly, the hypothesis will be tested across 3 animal model systems, where concordance will strengthen findings, and discordance will identify biological aspects of species‐specific sensitivity to environmentally‐induced neurodegeneration. We will test our hypothesis through two aims: Aim 1. To identify species specific‐PFOS doses that induce DAergic neurodegeneration. PFOS doses will be harmonized across systems to achieve brain levels that bear environmental relevance. Harmonization of internal dose levels to set external applied dosages for each model system will allow us to interrogate mechanistic hypothesis under comparable insults; Aim 2. Identify neurobiological underpinnings across species that contribute to differential sensitivity to PFOS‐induced dopaminergic neurodegeneration. Here, we will identify species‐specific differences in neurodegeneration that may underlie critical aspects of selective dopaminergic neurotoxicity induced by PFOS exposure. We will conduct comparative biology studies that are both phenotypic and mechanistic. Resultant data will be critical in determining: 1) Which species is best suited to PFOS neurodegeneration studies; 2) Identifying which pathogenic pathways directly c...