Project Grant R01ES035429

COMPARATIVE NEUROTOXICITY OF PFAS - PROJECT SUMMARY EXPOSURE TO PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) IS HIGHLY PREVALENT IN THE US POPULATION AND HAS BEEN ASSOCIATED WITH NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISEASES PARTICULARLY VIA CHANGES IN DOPAMINERGIC (DA) NEURONS. CONVENTIONAL PFAS CHEMICALS ARE BEING RAPIDLY REPLACED BY NOVEL CHEMICALS WITH UNKNOWN LONG- TERM NEUROTOXICITY NECESSITATING THE COMPARISON OF NEUROTOXICITY OF VARIOUS PFAS. THE GOAL OF THE PROPOSED RESEARCH IS TO EVALUATE AND COMPARE THE IMPACT OF A DEVELOPMENTAL EXPOSURE TO SELECTED PFAS CHEMICALS INCLUDING THE LEGACY PFAS, PFOA, AND ITS PFAS REPLACEMENTS, PFBA AND GENX, AT LOW DOSES ON THE PLASTICITY OF NEURONAL COMPARTMENTS; AND SUBSEQUENTLY CHARACTERIZE THEIR VULNERABILITY TO ESTABLISHED NEUROTOXINS PROMOTING DA NEURON DEGENERATION. THERE ARE LIMITED STUDIES COMPARING DEVELOPMENTAL NEUROTOXICITY OF PFAS AND THE LASTING IMPACTS ON THE CENTRAL NERVOUS SYSTEM, ESPECIALLY REPLACEMENT PFAS DUE TO THE SCARCITY OF LONGITUDINAL EPIDEMIOLOGICAL STUDIES. OUR STUDIES USING THE ZEBRAFISH MODEL SUGGEST ALTHOUGH LETHALITY DECREASES IN PFAS WITH SHORTER CARBON CHAIN LENGTH AND ADDITION OF SIDE CHAINS COMMON IN REPLACEMENT PFAS, PERTURBATIONS ON DEVELOPMENT, BEHAVIOR, AND DOPAMINE (DA) CONCENTRATIONS OCCUR AT LOWER DOSE EXPOSURES IN PFAS REPLACEMENTS (E.G., PFBA AND GENX). THESE FINDINGS WERE FURTHER CORROBORATED USING DOPAMINERGIC-LIKE CELLS DIFFERENTIATED FROM SH-SY5Y AND FLOOR PLATE PROGENITOR CELLS DERIVED FOR HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS). COLLECTIVELY, PFOA SEEMS TO HAVE A DISTINCTIVE NEUROTOXIC MECHANISM COMPARED TO PFBA AND GENX, WHILE ALL THREE PFAS CAN RESULT IN PERSISTENT ALTERATIONS AT VARIOUS SUB-CELLULAR COMPARTMENTS AND PERTURB CALCIUM (CA) HOMEOSTASIS. WE WILL THUS TEST OUR CENTRAL HYPOTHESIS THAT LOW DOSE PFAS EXPOSURE DISRUPTS COMMUNICATION BETWEEN DIFFERENT CELLULAR COMPARTMENTS VIA ALTERED INTRACELLULAR CA CONCENTRATIONS, LEADING TO SYSTEMATIC DISRUPTIONS IN MULTIPLE CELLULAR COMPARTMENTS, INTERRUPTING THE FORMATION OF THE NEURONAL NETWORK, AND INCREASING RISK OF NEURON DAMAGE AND DEGENERATION. WE WILL USE A COMBINATION OF THE ZEBRAFISH ANIMAL MODEL AND DA NEURONS DERIVED FROM HIPSC TO EVALUATE IMMEDIATE IMPACT OF DEVELOPMENTAL PFAS EXPOSURE (SA1) AND LATENT LONG-TERM NEUROTOXICITY (SA2) EMPHASIZING THE DOPAMINERGIC PATHWAY. THROUGHOUT SA1 AND SA2, WE WILL DETERMINE CHANGES IN NEURONAL VULNERABILITY TO ESTABLISHED NEUROTOXINS FOR ALTERED VIABILITY AND ACCUMULATION OF DEGENERATIVE MARKERS, SUCH AS SYNUCLEIN AGGREGATES. SUB-CELLULAR AND NETWORK CA ACTIVITY WILL BE RECORDED AND CORRELATED TO REVEAL DRIVING PATHOGENIC MECHANISMS FOR ABNORMAL NEURONAL ACTIVITY AND NEURODEGENERATION INDUCED BY DEVELOPMENTAL PFAS EXPOSURE, WHILE EXPLORING NORMALIZATION OPTIONS (SA3). COLLECTIVELY, WE WILL DETERMINE UNIQUE AND SHARED NEUROTOXICITY ASSOCIATED WITH SELECTED PFAS; REVEAL SUB-CELLULAR COMPARTMENTS MOST COMPROMISED AND CONFERRING TO THE NEURODEGENERATIVE-LIKE PHENOTYPE; AND EXPLORE THE FEASIBILITY OF RESTORING NEURONAL PLASTICITY VIA TARGETED INTERVENTIONS.