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.