γ-glutamyl-cysteine is a critical intermediate in glutathione-led amelioration of PFOS-neurotoxicity

Per/polyfluoroalkyl substances (PFAS) are used in a variety of industrial and consumer applications due to their distinctive properties. Nonetheless, these substances are ubiquitous and pose significant risks to the environment, wildlife, and human health. Perfluorooctane sulfonate (PFOS), which was previously one of the most commonly utilized PFAS, has prolonged half-life in both humans and the environment. Despite the cessation of its production, PFOS remains one of the prevalent contaminants amongst PFAS. Recent research demonstrates that PFOS is relatively resistant to elimination from the human body and accumulates to a greater extent in older adults. PFOS has been shown to affect the nervous system and its functions, although the intricate mechanisms underlying its toxicity remain largely obscure. Earlier studies utilizing Caenorhabditis elegans indicated that dopaminergic neurons are particularly vulnerable to PFOS neurotoxicity, with glutathione (GSH) playing a role in mitigating neurodegeneration. Curiously, none of the antioxidant treatments evaluated, including N-acetyl-cysteine, produced favorable outcomes, despite N-acetyl-cysteine being a precursor to GSH. This study investigates the GSH synthesis pathway to elucidate critical mechanisms. We assessed the effects of GSH precursors and intermediates on PFOS neurotoxicity. The GSH precursors, cysteine, glutamate, and the combination of cysteine and glutamate did not demonstrate beneficial effects. However, the crucial GSH synthesis intermediate, {gamma}-glutamyl-cysteine, provided neuroprotection comparable to that of GSH. Notably, no changes were observed at the transcriptomic or proteomic levels of GSH synthesis enzymes in C. elegans and SH-SY5Y cells, respectively. This study effectively uncovers a novel mechanism that addresses existing knowledge gaps pertaining to PFOS neurotoxicity. HighlightsO_LIPFOS elicits dopaminergic neurodegeneration in C. elegans C_LIO_LIPrevious research shows that only GSH ameliorated PFOS-induced neurodegeneration, amongst several antioxidants tested. C_LIO_LIUpon testing the precursors and intermediates in the GSH pathway, GGC was realized as a key intermediate C_LIO_LIThe studies highlight the critical component of GSH pathway in alleviating PFOS neurotoxicity C_LI