Polystyrene nanoplastics disrupted cholesterol/testosterone homeostasis via Smurf1-dependent FTO degradation

Polystyrene nanoplastics (PS-NPs) exposure can induce testosterone decline, but the underlying mechanism remains elusive. In the present study, prepubertal PS-NPs exposure caused testicular injury and reduced testosterone levels. RNA sequence analysis indicated that cholesterol homeostasis and PPARα signaling pathways may be involved in the disruption of testosterone biosynthesis. Compared with the control group, exposure to PS-NPs resulted in no significant change in serum cholesterol levels but a marked reduction in testicular and TM3 cell cholesterol levels. Western blot analysis revealed prepubertal PS-NPs exposure activated the PPARα pathway, with a consequent significant downregulation in the expression of cholesterol uptake receptors SCARB1 and LDLR. Using immunoprecipitation, we found that PS-NPs disrupted cholesterol uptake by facilitating the ubiquitin-dependent degradation of FTO. Ultimately, we observed that PS-NPs exposure markedly upregulated Smurf1 protein expression. Knocking down Smurf1 repressed PS-NPs caused the ubiquitin-dependent degradation of FTO protein, thereby alleviating cholesterol and testosterone decline. Overall, our study elucidated a novel mechanism by which prepubertal PS-NPs exposure disrupted cholesterol/testosterone homeostasis via Smurf1-dependent FTO degradation.