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Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human ?₁?₂?_2L GABA_A receptor and spontaneous neuronal network function in vitro.

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 GABA_A 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 GABA_A 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 ?₁?₂?_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. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. 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. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk.

SUBMITTER: Tukker AM

PROVIDER: S-EPMC7093421 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α1β2γ2L GABAA receptor and spontaneous neuronal network function in vitro.

Tukker Anke M AM Bouwman Lianne M S LMS van Kleef Regina G D M RGDM Hendriks Hester S HS Legler Juliette J Westerink Remco H S RHS

Scientific reports 20200324 1

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 ...[more]

PMID: 32210279

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Project description:Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health concern. Although the literature suggests that PFOS may induce neurotoxicity, neurotoxic mechanisms, and neuropathology are poorly understood. Thus, the primary goal of this study was to determine if PFOS is selectively neurotoxic and potentially relevant to specific neurological diseases. Nematodes (Caenorhabditis elegans) were exposed to PFOS or related per- and polyfluoroalkyl substances (PFAS) for 72 h and tested for evidence of neuropathology through examination of cholinergic, dopaminergic, gamma-amino butyric acid (GABA)ergic, and serotoninergic neuronal morphologies. Dopaminergic and cholinergic functional analyses were assessed through 1-nonanol and Aldicarb assay. Mechanistic studies assessed total reactive oxygen species, superoxide ions, and mitochondrial content. Finally, therapeutic approaches were utilized to further examine pathogenic mechanisms. Dopaminergic neuropathology occurred at lower exposure levels (25 ppm, approximately 50 µM) than required to produce neuropathology in GABAergic, serotonergic, and cholinergic neurons (100 ppm, approximately 200 µM). Further, PFOS exposure led to dopamine-dependent functional deficits, without altering acetylcholine-dependent paralysis. Mitochondrial content was affected by PFOS at far lower exposure level than required to induce pathology (≥1 ppm, approximately 2 µM). Perfluorooctane sulfonate exposure also enhanced oxidative stress. Further, mutation in mitochondrial superoxide dismutase rendered animals more vulnerable. Neuroprotective approaches such as antioxidants, PFAS-protein dissociation, and targeted (mitochondrial) radical and electron scavenging were neuroprotective, suggesting specific mechanisms of action. In general, other tested PFAS were less neurotoxic. The primary impact is to prompt research into potential adverse outcomes related to PFAS-induced dopaminergic neurotoxicity in humans.

Dataset Information

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human ?₁?₂?_2L GABA_A receptor and spontaneous neuronal network function in vitro.

Publications

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α<sub>1</sub>β<sub>2</sub>γ<sub>2L</sub> GABA<sub>A</sub> receptor and spontaneous neuronal network function in vitro.

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Dataset Information

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human ?1?2?2L GABAA receptor and spontaneous neuronal network function in vitro.

Publications

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human α<sub>1</sub>β<sub>2</sub>γ<sub>2L</sub> GABA<sub>A</sub> receptor and spontaneous neuronal network function in vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human ?₁?₂?_2L GABA_A receptor and spontaneous neuronal network function in vitro.