Increased NAD+ levels protect female mouse reproductive system against zearalenone-impaired glycolysis, lipid metabolism, antioxidant capacity and inflammation

The reproductive system is a primary target organ for zearalenone (ZEN, a widespread fusarium mycotoxin) to exert its toxic effects, including decreased antioxidant capacity and aggravated inflammatory response. These ZEN-induced reproductive abnormalities are partially caused by the declining levels of nicotinamide adenine dinucleotide (NAD+), which results in an imbalance in lipid/glucose metabolism. Accordingly, the present study aimed to investigate whether supplements of nicotinamide mononucleotide (NMN, a NAD+ precursor) in female mice could protect against ZEN-induced reproductive toxicity. In this study, thirty female mice were randomly divided into three groups that were intragastrically administered with i) 0.5% DMSO (the Ctrl group), ii) 3 mg/(kg bw.d) ZEN (the ZEN group), or iii) ZEN + 500 mg/(kg bw.d) NMN (the ZEN/NMN group) for two weeks. The results revealed that, compared with the Ctrl group, animals exposed to ZEN exhibited reproductive toxicity, such as decreased antioxidant capacity and aggravated inflammatory response in reproductive tissues. These effects were strongly correlated with lower activities in key glycolytic enzymes (e.g., ALDOA and PGK), but increased expressions in key lipid-synthesis genes (e.g., LPIN1 and ATGL). These changes contribute to lipid accumulation, specifically for diacylglycerols (DAGs). Furthermore, these ZEN-induced changes were linked with disturbed NAD+ synthesis/degradation, and subsequently decreased NAD+ levels. Notably, NMN supplements in mice protected against these ZEN-induced reproductive abnormalities by boosting NAD+ levels. Herein, the present findings demonstrate that potential strategies to enhance NAD+ levels can protect against ZEN-induced reproductive toxicity.