Neurotoxic effects of citronellol induced by the conversion of kynurenine to 3-hydroxykynurenine

Citronellol is widely utilized in consumer products, including cosmetics, fragrances, and household items. However, despite being considered a relatively safe chemical, the health effects and toxicity mechanisms associated with exposure to high concentrations of citronellol, based on product content, remain inadequately understood. Here, we aimed to analyze the neurological effects of citronellol in zebrafish larvae using behavioral and histological analyses and elucidate the mechanisms underlying its neurotoxicity in vivo. Exposure to citronellol (2, 4 and 8 mg/L) in zebrafish larvae induced a range of neurotoxic effects, including locomotor impairments, anxiety-like behaviors, oxidative stress, an inflammatory response, and apoptosis in the brain. Additionally, citronellol exposure compromised the blood-brain barrier (BBB) integrity, permitting the infiltration of inflammatory cell into the brain. Neurotoxic effects were further sustained by increased kynurenine (KYN) metabolism to the neurotoxic metabolite 3-hydroxykynurenine (3-HK), accompanied by altered neurosteroid levels, including reduced progesterone and allopregnanolone, and elevated cortisol. Similar metabolic dysregulation was observed in mouse models following oral administration (345, 690 and 3450 mg/kg) and in human brain organoids exposed to citronellol (1, 10 and 100 μM), suggesting conserved mechanisms across species. Notably, experiments using zebrafish, mice and brain-chip systems confirmed that citronellol crosses the BBB and accumulates in the brain. Overall, we identified a novel neurotoxic pathway involving the KYN to 3-HK metabolic pathway, oxidative stress, and neuroinflammation, underscoring the potential risks of prolonged citronellol exposure.