Developmental Origins of Neurotoxicity of the PFAS GenX

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PROJECT SUMMARY / ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are synthetic fluorine-containing compounds that are present in many applications due to their non-stick and stain-resistant properties. Longer carbon chain compounds [C8; e.g., perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS)], were phased out based on health risks. Shorter carbon chain (<C8) PFAS were produced to minimize environmental persistence and bioaccumulation. PFAS are an emerging class of environmental chemical contaminants and the replacement PFAS are not regulated by federal agencies. The developing central nervous system is particularly sensitive to toxicant exposure and a growing body of evidence suggests developmental neurotoxicity (DNT) may result from PFAS exposures including increased risk for attention deficit/hyperactivity disorder and reduced motor and executive functioning. Similar to other PFAS toxicity studies, the limited DNT laboratory studies have mainly focused on PFOS or PFOA. Some of these DNT studies suggest impacts to the dopaminergic (DA) system. It is now estimated there are >4000 PFAS with most having limited to no toxicity information available. Futhermore, some studies including our preliminary data indicate similar toxicity outcomes with some even being more potent than the C8 compounds. Moreover, most PFAS are present in the environment in a mixture, which can result in various mixture interactions. As such, a significant gap remains in our basic understanding of DNT of PFAS and PFAS mixtures, mechanisms and functional impacts to the developing CNS, and the risk of persistent neurotoxicity in the developmental origins of health and disease paradigm (DOHaD). PFAS of particular concern are GenX (C6, replacement for PFOA) and PFBS (perfluorobutanesulfonic acid, C4, replacement for PFOS). These PFAS alternatives are detected in environmental samples and in treated drinking water. Questions remain on DNT and persistent neurotoxicity of a short-term developmental exposure (e.g., the DOHaD paradigm). This question is significant considering GenX is reported to be more potent than PFOA and is likely that co-exposure to GenX and PFOA will occur. Our CENTRAL HYPOTHESIS is that exposure to GenX at early developmental stages will result in DNT targeting the DA system and persistent neurotoxicity in adults with the combined effects of GenX and PFOA resulting in an additive toxicity response. We will first define DNT of GenX using the zebrafish by assessing gross and fine morphological changes, behavior, and targets associated with the DA system. Results will be compared to PFOA, PFBS, and GenX/PFOA mixtures and alterations in the serotonergic system (aim 1). Second, we will assess persistent neurotoxicity of the developmental PFAS exposure in the DOHaD paradigm (aim 2). The zebrafish, a well- established model to study DNT and neurobehavior, will be used as an integrative vertebrate animal model to assess short and long-term neurological outcomes. Several endpoints will be assessed to define mechanisms of neurotoxicity from single and binary PFAS exposures to inform and guide future regulatory decisions.