Protective mechanisms of zinc and/or selenium supplementation against BPA-induced male and offspring reproductive toxicity: Insights from multiomics analysis

Bisphenol A (BPA), a common environmental endocrine disruptor, has been shown to adversely affect male reproductive function. However, the mechanisms of reproductive impairment in both BPA-exposed males (F0) and their unexposed offspring (F1) remain unclear. Furthermore, there are currently no reports on that paternal Zinc (Zn) and/or Selenium (Se) supplementation ameliorate BPA-induced and transgenerational reproductive damage in F0 and F1, respectively. This study aimed to address these scientific issues by integrating transcriptomics and metabolomics. Our results revealed that BPA induced reproductive damage of F0 by altering the transport and homeostasis of Zn and Se, disrupting the synthesis and transformation balances of testosterone (T) and estradiol (E2), and increasing the oxidative stress and apoptosis levels. Furthermore, most of the changes of F0 was transmitted to F1 generation, causing reproductive damage to the male offspring. In contrast, supplementing with Zn and/or Se for F0 could alleviate these impacts of BPA on F0 and F1. Notably, the combination of Zn and Se was generally more effective compared to individual supplementation. The transcriptomics and metabolomics analyses revealed the overall mechanisms of Zn and/or Se alleviating BPA-induced testicular damage in F0 and F1 male mice. The reason why Zn and Se combined is superior to Zn or Se alone is related to their unique or additive regulatory roles on the oxidative phosphorylation pathway and antioxidant functions, which exhibits the characteristic of intergenerational transmission in male mice.