Direct exposure to vinclozolin induces sex-dependent mitochondrial dysfunction in mouse liver

Vinclozolin is a dicarboximide anti-androgenic fungicide that has endocrine-disrupting impact on mammals. Endocrine disruptors are reported to impair mitochondrial function and reduce adenosine triphosphate (ATP) production. Moreover, increasing evidence has linked exposure to endocrine disruptors with metabolic diseases. However, the toxicity of direct exposure to vinclozolin on mitochondrial function remains insufficiently explored. In this study, mitochondria were isolated from mouse liver-one of the primary organs involved in the uptake and processing of toxicants-and directly exposed to vinclozolin. Several markers, including citrate synthase, mitochondrial complex IV (CIV) activity, ATP production, reactive oxygen species/reactive nitrogen species (ROS/RNS) levels, cytochrome c release, glutathione (GSH) levels, and superoxide dismutase (SOD) activity were measured. The results indicated that vinclozolin decreased citrate synthase activity in both sexes and significantly reduced CIV activity only in males. ATP levels showed a decreasing tendency, while ROS/RNS levels showed an increasing tendency particularly in males, without statistical significance. Notably, SOD activity exhibited a sex-dependent increase specifically in females, whereas vinclozolin exposure did not significantly alter GSH levels in either sex. Despite this, basal GSH levels remained significantly higher in females than in males. In both sexes, an increase in cytochrome c release was observed. Collectively, direct mitochondrial exposure to vinclozolin induced dysfunction by impairing energy production, a process mediated by sex-specific antioxidant responses.