Cyromazine induces neurotoxicity associated with damage to dopamine, serotonin, glutamate, and GABA neuronal systems through reactive oxygen species (ROS) generation in Caenorhabditis elegans

Cyromazine (CYR) is a widely used insect growth regulator. Its metabolite, melamine, is classified as a Group 2B carcinogen and has been associated with urinary tract lesions and tumors. While previous toxicological studies have largely focused on high-concentration exposures, the mechanisms of toxicity at environmentally relevant concentrations remain poorly understood. In this study, using Caenorhabditis elegans as a model, we demonstrated that CYR induces dose-dependent neurotoxicity, developmental impairment, reproductive toxicity, and oxidative stress. Transcriptomic analysis revealed disruptions in glutamate, dopamine, GABA, and glutathione metabolic pathways. CYR exposure caused damage to dopaminergic and glutamatergic neurons, decreased levels of several neurotransmitters, and downregulated key genes including dop-3 , tph-1 , and eat-4 , resulting in behavioral deficits such as impaired pharyngeal pumping, body bending, and head thrashing. Parental exposure to CYR significantly elevated reactive oxygen species (ROS) and lipofuscin accumulation, activated the glutathione-mediated antioxidant pathway, and disturbed enzymatic balance, indicating a central role for oxidative stress in CYR-induced neurotoxicity. By systematically elucidating the mechanism of ROS-mediated oxidative stress in neurobehavioral toxicity, this study provides a mechanistic foundation for understanding the broader toxicological profile of CYR, thereby offering critical insights for assessing its comprehensive health risks at environmental levels.