Exposure to polyethylene microplastics induces a male testosterone synthesis disorder via oxidative stress-mediated ferroptosis.

Abstract

Polyethylene microplastics (PE-MPs) have been shown to induce male reproductive toxicity in male mice but the mechanism underlying this toxicity is poorly understood. To address this knowledge gap, in vivo and in vitro experiments were performed to determine the mechanism governing PE-MP-induced male reproductive toxicity. Male mice were exposed to PE-MPs at doses of 14, 28, and 56 mg/kg of body weight for 28 consecutive days for the in vivo experiments. The results demonstrated that PE-MP exposure impaired testicular testosterone (T) synthesis, as evidenced by reduced sperm motility, decreased serum T levels, and an elevated sperm abnormality rate. In addition, PE-MP exposure downregulated the levels of key T-synthesizing protein expression in the testes, including StAR, P450scc, 3β-HSD, and CYP17A1. Concurrently, PE-MPs activated oxidative stress responses, as shown by altered levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), Nrf2, NQO1, and HO-1, and triggered ferroptosis, as indicated by modified expression of ferroptosis-related markers (PTGS2, SLC7A11, GPX4, and FTH1), in male mice. TM3 cells (a Leydig cell line) were treated with PE-MPs at concentrations of 100, 200, and 400 μg/mL for 24 h in the in vitro experiments. PE-MP treatment impaired T synthesis in Leydig cells, which was consistent with the in vivo observations. Further analyses revealed that PE-MP exposure not only activated oxidative stress and ferroptosis pathways but also reduced the expression of T synthase proteins in TM3 cells. Notably, these PE-MP-induced adverse effects were mitigated when the cells were co-treated with a ferroptosis or oxidative stress inhibitor. In conclusion, PE-MPs caused a male T synthesis disorder via activating oxidative stress-mediated ferroptosis, which provides novel insights into the biological effects of PE-MPs on male reproductive function and offers a potential mechanistic basis for understanding PE-MP-associated male reproductive toxicity.

Key Findings

• Exposure to polyethylene microplastics (PE-MPs) impairs testicular testosterone synthesis in male mice, reducing sperm motility and serum testosterone levels while increasing sperm abnormalities.
• PE-MP exposure activates oxidative stress responses and triggers ferroptosis, as evidenced by altered levels of oxidative stress markers (SOD, GSH, MDA, Nrf2, NQO1, HO-1) and ferroptosis-related proteins (PTGS2, SLC7A11, GPX4, FTH1).
• In vitro treatment of Leydig cells with PE-MPs replicates the in vivo testosterone synthesis impairment and oxidative stress-mediated ferroptosis, effects that are mitigated by ferroptosis or oxidative stress inhibitors.

Clinical Significance

Citation

Yang You, Zhai Lingling, Wang Siyuet al.. Exposure to polyethylene microplastics induces a male testosterone synthesis disorder via oxidative stress-mediated ferroptosis. Chemico-biological interactions. 2026-Jul-25.