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However, epidemiological studies have been inconclusive on the risks of PFAS exposure on neurodevelopment. Developmental neurotoxicity has also been observed in other species, including chicken 12 and zebrafish larvae 13, 14. In mice and rats exposed pre- and/or neonatally to PFOS or PFOA, increased motor activity, decreased habituation and deficits in spatial learning and memory abilities have been observed 6– 11. Research has demonstrated that the (developing) nervous system is one of the most sensitive targets for PFOS and PFOA. Recent studies indicate that these efforts may be responsible for a reduction in human blood levels in some areas, but the long half-lives of PFOS and PFOA result in slow elimination from environment and humans 4, 5. By 2002, production of PFOS was phased out and production phase out of PFOA followed in 2006 3. The strong carbon-fluorine bond renders PFOS and PFOA highly persistent and studies have shown their presence in the environment, wildlife and even human blood (for reviews see 1, 2). Their combined hydrophobic, hydrophilic, oleophobic and lipophobic properties make them ideal industrial surfactants for the manufacturing of consumer products, including paint, stain repellents, fire-fighting foams, and non-stick cookware coatings. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are well-known perfluoroalkyl substances (PFAS) consisting of an eight-carbon chain in which hydrogen atoms have been substituted with fluorine. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk. LOECs for PFAS on GABA A receptor and neuronal activity reported here are within or below the range found in blood levels of occupationally exposed humans. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. The higher sensitivity of the α 1β 2γ 2L GABA A receptor for PFAS as compared to neuronal networks suggests that PFAS have additional mechanisms of action, or that compensatory mechanisms are at play. However, exposure of networks of human induced pluripotent stem cell (hiPSC)-derived neurons decreased neuronal activity.
Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM). PFOS (Lowest Observed Effect Concentration (LOEC) 0.1 µM) and PFOA (LOEC 1 µM) inhibited the GABA-evoked current and acted as non-competitive human GABA A receptor antagonists. Considering the importance of the GABA A receptor in neuronal function, we investigated acute effects of PFAS on this receptor and on spontaneous neuronal network activity. Concerns about the neurotoxic potential of polyfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) increase, although their neurotoxic mechanisms of action remain debated.