Kynurenine pathway mediated multi-generational neurotoxicity induced by fluoride exposure in Caenorhabditis elegans

Environmental fluoride exposure has been epidemiologically linked to cognitive deficits in children, yet the mechanisms underlying its potential multi-generational neurotoxicity remain poorly understood. Here, we demonstrate that sodium fluoride (NaF) induces multi-generational neurobehavioral impairments in Caenorhabditis elegans through dysregulation of the kynurenine pathway (KP). Continuous exposure at environmentally relevant concentrations (20-50 mg/L) resulted in cumulative deficits in locomotion, feeding, and learning memory across F0 to F3 generations, followed by gradual recovery by F5. Multi-omics analyses revealed persistent upregulation of kynurenine 3-monooxygenase (kmo-1) and progressive accumulation of its neurotoxic metabolite, 3-hydroxykynurenine (3-HK), while the neuroprotective metabolite kynurenic acid (KYNA) decreased. Genetic perturbation of kmo-1 via RNAi or mutation robustly attenuated the multi-generational toxicity, preserving neuronal structural integrity and abrogating oxidative stress and mitochondrial dysfunction. Exogenous 3-HK supplementation recapitulated neurotoxicity in kmo-1-deficient strains, confirming its role as the primary effector. Furthermore, glutathione (GSH) administration reversed NaF-induced deficits by counteracting 3-HK mediated oxidative damage. Our findings establish the KP specifically KMO-1 dependent 3-HK fluxas a critical mechanistic node in fluoride-induced multi-generational neurotoxicity revealing metabolic reprogramming as a novel mode of action, and suggesting that antioxidant intervention might be a potential strategy for further investigation in model systems.