Comenic acid as a modulator of the gut-testis axis in pyridaben-induced toxicity.

Pyridaben is an acaricide that inhibits mitochondrial complex I, which disrupts mitochondrial viability and causes oxidative stress. Pyridaben administration was associated with significant damage to mitochondrial DNA (mtDNA) in mice. The oxidative stress related to pyridaben exposure also co-occurred with alterations in the morphology of the testes and intestines, leading to the activation of the Nrf2-dependent protective pathway in testicular tissue, reduction of the seminiferous tubule lumen accompanied by interstitial tissue swelling, and adaptive changes in the intestinal epithelial tissue. Comenic acid (CA) exhibits active antioxidant properties; in the group receiving CA, the mtDNA copy number increased. Functionally, pyridaben considerably reduced the alpha diversity of the intestinal microbiome, while CA administration appeared to normalize this indicator, also mitigating shifts in beta diversity. Taxonomic analysis revealed that pyridaben elevated the abundance of the families Bacteroidaceae and Muribaculaceae, which aligned with a functional upregulation of endotoxic dTDP-β-L-rhamnose and L-lysine biosynthesis pathways. Conversely, CA treatment attenuated these shifts, reducing opportunistic taxa while concurrently upregulating protective pathways, including folate transformations and CDP-diacylglycerol biosynthesis. These findings suggest that CA, potentially due to its antioxidant properties and modulation of the intestinal microbial and functional profiles, may exert a compensatory effect against pyridaben-induced toxicity via the gut-testis axis.