Abstract
<title>Abstract</title> <p>Citronellol is a monoterpenoid, one of the most frequently used chemical groups in fragranced consumer products. Although monoterpenoid neurotoxicity has been reported, the underlying mechanism in mammals remains poorly understood. We investigated the neurobehavioral and mechanistic effects of repeated citronellol exposure in male ICR mice treated by oral gavage (34.5 or 172.5 mg/kg/day) for 21 days. Behavioral assessments were combined with neurochemical, protein, and gene expression analyses in the brain, particularly the hippocampus, amygdala, and cortex. Repeated citronellol exposure induced anxiety-like behaviors and altered recognition memory without locomotor deficits. Citronellol elevated glucocorticoids across brain regions and activated the kynurenine (KYN) pathway, resulting in accumulation of KYN and 3-hydroxykynurenine, while kynurenic acid remained unchanged. It also enhanced glutamate accumulation, reduced glutamate transporter expression, and altered neuroinflammatory responses. Citronellol induced region-specific α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor remodeling, with reduced GluA2 expression in the hippocampus and cortex and increased expression in the amygdala, accompanied by elevated caspase-3 expression in the hippocampus and cortex but reduced apoptotic signaling in the amygdala. These findings support a glucocorticoid–KYN–AMPA receptor excitotoxic mechanism underlying citronellol-induced neurotoxicity. Furthermore, these effects have not yet been considered for toxicity safety threshold, suggesting that the potential neurotoxicity of monoterpenoid fragrance compounds including citronellol warrants further investigation.</p>