Synergistic effect of PS-MPs and Cd on male reproductive toxicity: Ferroptosis via Keap1-Nrf2 pathway

It has been wildly reported that microplastics (MPs) can adsorb heavy metals and act as carriers for their transport into organisms. However, the combined toxicity of MPs and heavy metals remains poorly studied. In this study, we established single or co-exposure (i.e. complex/combined exposure) mice models to investigate the combined toxicity of MPs and cadmium (Cd) on male reproduction. The complexation of MPs and Cd enhanced the bioavailability of Cd, while the combination of MPs and Cd exerted synergistic effect. Ultimately, the co-exposure was reported to enhance the reproduction toxicity by single exposure, which reflected in testicular structure, spermatogenesis and sex hormone synthesis. More in-depth mechanistic investigation suggested that MPs and Cd synergistically inhibited the Keap1-Nrf2 pathway and its downstream genes, induced lipid peroxidation and ferroptosis, ultimately caused damage to reproductive structures and functions. Our results highlighted the synergistic effect of MPs and Cd on the reproductive toxicity in male mammals for the first time, which also provided valuable insights into the combined toxicity mechanisms of MPs and other pollutants. The widely distributed microplastics (MPs) found in marine and soil environments are likely to coexist and interact with cadmium (Cd), which has a low excretion rate and high toxicity. However, the biological toxicity resulting from the co-exposure remains unclear. This study investigated the effects of co-exposure on male reproduction and explored the potential mechanisms. Our findings contributed to give an early warning of male reproductive toxicity by co-exposure to MPs and Cd, and provide a new insight into the synergistic toxicity mechanisms of MPs and other environmental pollutants.