Defining the neurotoxic and neurodevelopmental health risks of per- and polyfluoroalkyl substances - PROJECT SUMMARY Per- and polyfluoroalkyl substances (PFAS) are a diverse class of used chemicals that have become ubiquitous in the environment, contaminating our food and water supplies. A recent survey showed 97% of Americans have detectable PFAS levels in their blood, resulting from unintentional exposures and bioaccumulation of PFAS. Exposure to PFAS has been linked to neurotoxicity and negative neurodevelopmental effects, among other major health risks to humans. Studies examining the connections of PFAS with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorders (ADHD), and other behavioral and cognitive disturbances in children showed conflicting results. The specific effects of PFAS exposure on neurons and health risks associated with such exposure are poorly defined. Our preliminary analyses suggest the cellular uptake of PFAS might be mediated by a fatty acid transporter, CD36, and PFAS may have different interactions with transporter proteins based on their chemical structure. Further, we showed in a zebrafish model that bioaccumulation of perfluorooctane sulfonic acid, a legacy PFAS, impacts learning capabilities. The long-term objective of this study is to characterize the mechanisms through which PFAS affect brain development and function. We hypothesize PFAS uptake and bioaccumulation is facilitated by transporter proteins and exposure to PFAS during embryogenesis has lasting impacts and contributes to the etiology of neurodevelopmental disorders. The specific aims of this study are to: (1) define the chemical interactions that mediate neuronal uptake and accumulation of PFAS; (2) elucidate the neurotoxic effects of PFAS and their mixtures in vitro and in vivo; and (3) assess impacts of PFAS on neurodevelopment, and on the development of complex behaviors in vivo using gene expression analysis and phenotypic assays. Zebrafish will be used as a model species to define the effect of PFAS on neurodevelopment and associated behaviors. Our workflow, combining molecular dynamics simulations, direct binding assays, and cellular and organismal assays, will define the mechanism of cellular uptake and identify the effects of PFAS exposure on mitochondrial dysfunction, apoptosis, and neural activity. We will implement a two-tiered exposure study. First, since cellular bioavailability of PFAS is limited by binding to serum proteins, we will use high concentrations to achieve levels relevant for tissue bioaccumulation and to establish relative cytotoxicity of different PFAS in vitro and in vivo using phenotypic endpoint assays. Second, we will utilize environmentally relevant exposure conditions and investigate the effect of PFAS on gene expression targeting pathways related to neurotoxicity and development. The results of this study will provide valuable information on PFAS uptake mechanisms, cellular processes, and cell types impacted by PFAS exposure. Overall, our findings will shed light on the risks associated with specific PFAS and enable effective interventions for treatment and monitoring of these chemicals.
