Polystyrene nanoplastics inhibit StAR expression by activating HIF-1α via ERK1/2 MAPK and AKT pathways in TM3 Leydig cells and testicular tissues of mice

Microplastics (MPs) and nanoplastics (NPs) are widely found in water, food and air, and have been found in human blood, lung and feces. Several studies in vivo have shown that MPs and NPs decrease testosterone level. However, the molecular mechanism of MPs and NPs leading to testosterone reduction remains unclear. In the present study, mice were treated with 50 μg/kg·day polystyrene (PS)-NPs by tail vein injection once daily for two consecutive days, the mRNA and protein levels of steroidogenic acute regulatory protein (StAR) decreased significantly in testis. TM3 Leydig cells were treated with non-toxic doses of PS-NPs, hypoxia-inducible factor-1α (HIF-1α) mRNA translation was induced by PS-NPs through mTOR/4E-BP1 pathway, which was activated by the ERK1/2 MAPK and AKT pathways. Simultaneously, increased HIF-1α protein inhibited StAR transcription. Additionally, reactive oxygen species production induced by PS-NPs played a central role in the activation of ERK1/2 MAPK/mTOR and AKT/mTOR signaling pathways. These results suggest that PS-NPs down-regulate StAR expression by increasing HIF-1α, which is induced by activation of mTOR/4E-BP1 through the ERK1/2 MAPK and AKT signaling pathways. Our findings provide new insight into the potential molecular mechanism by which PS-NPs impair testosterone synthesis and male reproductive function.