Abstract
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. Considering the importance of the GABAA receptor in neuronal function, we investigated acute effects of PFAS on this receptor and on spontaneous neuronal network activity. 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 GABAA receptor antagonists. Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM). However, exposure of networks of human induced pluripotent stem cell (hiPSC)-derived neurons decreased neuronal activity. The higher sensitivity of the α1β2γ2L GABAA receptor for PFAS as compared to neuronal networks suggests that PFAS have additional mechanisms of action, or that compensatory mechanisms are at play. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. LOECs for PFAS on GABAA receptor and neuronal activity reported here are within or below the range found in blood levels of occupationally exposed humans. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk.
Highlights
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
To determine possible partial agonistic or antagonistic effects, perfluorooctane sulfonate (PFOS) and PFOA were co-applied with a low concentration of GABA (~EC20) and the lowest observed effect concentrations (LOEC; defined as the lowest test concentration that is significantly different from the control) of PFOS and PFOA were calculated
In the present study we show for the first time that PFOS and PFOA exhibit concentration-dependent antagonistic effects on the human α1β2γ2L GABAA receptor at sub-micromolar concentrations (Fig. 1, Table 1)
Summary
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. We investigated whether the effects of PFOS and PFOA on the α1β2γ2L GABAA receptor are reflected in the level of spontaneous neuronal network activity using micro-electrode array (MEA) recordings in rat primary cortical neuronal networks, the current gold standard for MEA assays. These experiments were followed by measurements in human iPSC-derived neuronal models to investigate whether they were affected by PFAS exposure as the rodent model
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