Yttrium Nitrate Exacerbates Oxidative Stress in the Mouse Epididymis by Inhibiting GPX5 Expression

Environmental concerns regarding yttrium are growing due to its increasing presence in the environment, yet there remains a scarcity of toxicological data to evaluate its potential toxicity and mechanisms of action on the epididymis. In this study, utilizing both mouse models and primary epididymal epithelial cells, we assessed epididymal tissue structure following yttrium nitrate exposure via hematoxylin-eosin staining. The expression of tight junction proteins occludin and JAM-A, and the antioxidant enzyme GPX5, was measured using RT-qPCR and Western blot. Alterations in oxidative stress levels were evaluated by measuring MDA and GSH concentrations through biochemical assays. Following intervention with the antioxidant NAC, subsequent changes in MDA, GSH, and GPX5 levels were detected. Finally, RNA interference was employed to knock down GPX5 expression, and the resulting accumulation of MDA was quantified. The results demonstrated that yttrium nitrate exposure induced structural abnormalities in the mouse epididymis and downregulated the mRNA and protein expression of tight junction proteins occludin and JAM-A. Additionally, it led to increased MDA accumulation, decreased GSH levels, and reduced mRNA and protein expression of GPX5 in the epididymis. NAC intervention effectively reversed the yttrium nitrate-induced increase in MDA, decrease in GSH, and reduction in GPX5 expression at both mRNA and protein levels. Furthermore, knockdown of GPX5 expression exacerbated yttrium nitrate-induced oxidative stress in the epididymis. Collectively, these results identify GPX5 as a critical target of yttrium nitrate and confirm that oxidative stress is the central mechanism underlying its epididymal toxicity.