Co-exposure to environmentally relevant concentrations of cadmium and polystyrene nanoplastics induced oxidative stress, ferroptosis and excessive mitophagy in mice kidney

Nanoplastics (NPs) are defined as a group of emerging pollutants. However, the adverse effect of NPs and/or heavy metals on mammals is still largely unclear. Therefore, we performed a 35-day chronic toxicity experiment with mice to observe the impacts of exposure to Cadmium (Cd) and/or polystyrene nanoplastics (PSNPs). This study revealed that combined exposure to Cd and PSNPs added to the mice's growth toxicity and kidney damage. Moreover, Cd and PSNPs co-exposure obviously increased the MDA level and expressions of 4-HNE and 8-OHDG while decreasing the activity of antioxidase in kidneys via inhibiting the Nrf2 pathway and its downstream genes and proteins expression. More importantly, the results suggested for the first time that Cd and PSNPs co-exposure synergistically increased iron concentration in kidneys, and induced ferroptosis through regulating expression levels of SLC7A11, GPX4, PTGS2, HMGB1, FTH1 and FTL. Simultaneously, Cd and PSNPs co-exposure further increased the expression levels of Pink, Parkin, ATG5, Beclin1, and LC3 while significantly reducing the P62 expression level. In brief, this study found that combined exposure to Cd and PSNPs synergistically caused oxidative stress, ferroptosis and excessive mitophagy ultimately aggravating kidney damage in mice, which provided new insight into the combined toxic effect between heavy metals and PSNPs on mammals. Cadmium (Cd) and polystyrene nanoplastics (PSNPs) co-exposure increased the levels of MDA, 4-HNE and 8-OHDG as well as decreased the activities of antioxidant enzymes via inhibiting the Nrf2 pathway. More importantly, Cd and PSNPs co-exposure synergistically induced ferroptosis and excessive mitophagy in mice kidneys. [Display omitted] •The combined toxic effect of Cd and PSNPs was assessed in male mice.•Cd and PSNPs co-exposure induced growth toxicity and renal toxicity in mice.•Cd and PSNPs co-exposure induced oxidative damage via inhibiting Nrf2 pathway.•Ferroptosis and mitophagy synergistically induce kidney injury in Cd + PSNPs exposure.