Elucidation of mitochondrial mechanisms critical to mediating PFAS neurotoxicity

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Project Summary: This NIH K99/R00 proposal seeks support for the development of an independent research program aimed at addressing the questions pertaining to perfluorooctane sulfonic acid (PFOS) as a potential risk factor dopaminergic cell loss. Polyfluoroalkyl substances (PFAS) have important usage in firefighting equipment, nonstick cookware, carpets, etc. due to their unique capabilities to repel oil and water. These chemicals pose an immediate environmental health threat due to their protracted half-life and ability to resist environmental degradation, owing to its strong carbon-fluorine bond. The extensive presence and huge gaps in knowledge pertaining to neurotoxic effects and underlying mechanisms alongside a larger percentage of sporadic cases in major neurodegenerative disorders compel the dire need to investigate such compounds. Our preliminary studies on PFOS in C. elegans have shown DA neurotoxicity, reduction in mitochondrial content, and increased reactive oxygen species (Sammi et al., 2019). These effects are characteristic manifestations in Parkinson’s disease (PD), with cause largely unknown in 90% of sporadic PD cases. In light of the preliminary data in Caenorhabditis elegans, showing DA cell loss in response to PFOS, I will develop expertise in Induced pluripotent stem cells. A multi-pronged approach comprising of in vivo and in vitro models will be conducted to further identify neurotoxic and neurodevelopmental defects with a larger focus to elucidate how mitochondria and GSH extend their role in neuropathology. Conventionally, toxicity evaluation relies heavily on end-point based studies, while mechanistic aspects remain largely understudied. Deleterious effects of the chemicals appear over the span of time in the form of pathologies, which is a collective result of mechanistic alterations or aberrations. Therefore, identification of the series of biochemical events culminating in neurotoxicity is vital to define the Adverse outcome pathway (AOP). The identified mechanisms warrant the ability to design interventions, mechanistic assessment of similar compounds and synthesis of safer compounds. My approach consists of in vitro and in vivo systems to elucidate the neurotoxic effects of PFOS. Information pertaining to AOPs will serve as mechanistic endpoints/markers for comparative evaluation amongst a similar class of compounds (PFAS), facilitating derivation of the structure-activity relationship. In summary, I will draw an in vivo, in vitro signature of PFOS mediated Dopamine toxicity. Additionally, a detailed career development program entailing coursework, learning new techniques/model systems, representation and attendance at scientific meetings and feedback from the advisory committee has been constructed to help the candidate. My plan includes mentored training in critical new techniques/model systems, combined with my existing expertise that will enable the development of a scientific focus distinct from the mentor’s lab and promoting an independent research career.