Epididymal macrophage senescence contributes to sperm motility decrease upon environmental stress

Environmental stressors-induced male infertility has become a major public health issue. Sperm motility is the key to conception. However, the immunological mechanism for environmental stress-induced sperm motility reduction remains unknown. Our experiments find that three classical environmental stressors, including lead, cadmium, and mercury, are the key heavy metals reducing sperm motility. We reveal that environmental stress induces epididymal macrophage senescence, whereas the clearance of above cells significantly alleviates environmental stress-reduced sperm motility. In vivo and in vitro experiments further demonstrate that environmental stress induces macrophage senescence via down-regulating Foxo3 expression. Mechanistically, environmental stress increases the epididymal Foxo3 N6-methyladenosine level and inhibits the FTO. Overexpression of Fto in vitro and S-adenosylhomocysteine supplementation in vivo alleviates environmental stress-induced macrophage senescence. Together, these results suggest that epididymal macrophage senescence contributes to sperm motility decrease upon environmental stress. Clearing senescent epididymal macrophages will provide a previously unknown strategy for preventing male infertility.