Brain Response after Exposure to Fluorotelomer Carboxylic Acid: Evidence of Region-Specific Neuroinflammation and Behavioral Remodeling in Avian and Rodent Models

Abstract Poly- and perfluoroalkyl substances (PFAS) are persistent organic pollutants that pose health and environmental concerns. Although a few legacy PFAS are regulated, the toxicity of less scrutinized substances, precursors, and breakdown products is not well investigated. Fluorotelomer alcohols (FTOHs) are volatile precursors to perfluorinated carboxylic acids, including 7:3 fluorotelomer carboxylic acid (7:3FTCA), which is increasingly found in wildlife tissues. This study investigates the neurotoxicity of 7:3FTCA at an environmentally relevant concentration, using a comparative approach in gull embryos and adult mice. In gulls, 7:3FTCA exposure via egg injection induced significant neuroinflammation specifically in the pallium. In mice, a three-week exposure via food intake caused behavioral remodeling, marked by reduced photophobia and increased social interaction. Behavioral alteration in mice was associated with a 20% increase in prefrontal cortex (PFC) calcium activity and microglial activation. Our study reveals region-specific sensitivity (pallium/PFC) without overt neuronal loss, suggesting that 7:3FTCA drives functional brain remodeling, possibly through microglia-mediated pathways rather than acute cell death. These findings provide the first evidence of a neurotoxic response to fluorotelomer carboxylic acids in wildlife and laboratory models, highlighting a critical need to reassess the neurological risks of PFASs beyond legacy compounds.