R21AG068787 is entitled, “PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models”. The primary focus is on Parkinson’s disease (PD) endpoints as part of NIA’s Comparative Biology of Neurodegeneration (to PAR-17-039) program. 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 data in nematode and amphibian models suggest that exposure to PFAS, especially perfluorooctane sulfonate (PFOS) induces neurotoxicity. The main project addresses an important gap on how PFAS exposure leads to long-term neurological disease risk through testing the following hypothesis: that species-specific responses to PFOS-induced dopaminergic neurodegeneration will advance understanding of the biology of PD. This hypothesis is being 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. The funded project has 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 neurotoxicity induced by PFOS exposure. Throughout our examination of the PFAS literature, along with our own preliminary data newly collected from R21AG068787, it has become apparent that Alzheimer’s disease (AD)-relevant expansion is strongly supported. PFAS (specifically PFOS) exposure produces modulation of several critical AD proteins in multiple model systems. Thus, in an effort to be highly responsive to NOT-AG-20-034 (entitled, “Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease”), we will leverage R21AG068787 to test the following hypothesis that is aimed at exploring overlap between AD and PD: PFOS exposure will produce an AD-relevant phenotype and that species-specific responses will advance understanding of the biology of AD. This supplement leverages the original scope, adding AD-relevant endpoints, where amyloid beta aggregation, tau aggregation/hyperphosphorylation and other key AD biochemical events will be assessed. Furthermore, AD-relevant neurobehavioral analyses are added in this supplement. Given PFAS exposures are widespread (detectable in >99% of human blood), it is critical to determine if such exposures represent a neurologica...