DEVELOPMENTAL NEUROTOXIC EFFECTS OF SELECT PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) IN A MOUSE MODEL

Abstract

Connections between the nervous and immune systems, particularly those formed during development, can be perturbed by exogenous agents such as per- and polyfluoroalkyl substances (PFAS). PFAS have been used extensively in industrial and consumer products to resist heat, oil, and water. Their production and use have led to widespread environmental contamination, with a notable occurrence in the Cape Fear River in North Carolina of the United States (U.S.). Many PFAS studied to date have been implicated in adverse health effects in humans, including increased risks of some cancers, weakened immune response, liver damage, and developmental effects. Despite recent regulatory efforts for some PFAS, gaps remain in knowledge about less well studied PFAS, especially those found in the Cape Fear River and with respect to neuroimmune effects. In this study, a series of experiments to investigate developmental neuroimmune effects of PFO5-DoA (0, 0.005, 0.05, or 0.5 mg/kg) or GenX (0, 1, 5, 10 mg/kg) in B6C3F1 mice exposed from gestational day one through 17 were conducted. A homing behavior test was conducted on postnatal day (PND) 10 in GenX pups and tissue samples were collected at PND 21 and PND 56. Brain sections collected from the prefrontal/frontal cortex were stained with ionized calcium binding adaptor molecule 1 (IBA1) to visualize microglial numbers and percent area covered brain and interleukin 1 beta (IL-1) to estimate pro-inflammatory cytokine staining intensity. Average brain weights and relative brain and body weights were not statistically different for either PFO5-DoA or GenX groups. In the homing behavior test, pups exposed to 5 or 10 mg/kg had less success in finding home bedding squares than counterparts exposed to 0 or 1 mg/kg. In PND21 brains, the average number of microglia and percent area covered by microglia in mice exposed to 0.05 mg/kg of PFO5DoA were significantly decreased compared to control mice. Additionally, the average percent area covered by IL-1 staining for mice exposed to 0.05 mg/kg of PFO5DoA were significantly decreased in both PND21 and PND56 brains. Overall, while this study did not find statistically significant developmental neuroimmune effects of GenX or PFO5DoA, the potential for these PFAS to affect neuroimmune development cannot be ruled out as effects may be long-term, affected by sex hormones, and/or occur outside of the 56-day experimental lifespan of this study. Further research is needed to analyze differences between microglial abundance and phenotype early in life (from PND0-30) compared to late in life (PND60-112).