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Epididymitis can be caused by infectious and noninfectious etiological factors.While microbial infections are responsible for infectious epididymitis,the etiological factors contributing to noninfectious epididymitis remain to be defined.The present study demonstrated that damaged male germ cells (DMGCs) induce epididymitis in mice.Intraperitoneal injection of the alkylating agent busulfan damaged murine male germ cells.Epididymitis was observed in mice 4 weeks after the injection of busulfan and was characterized by massive macrophage infiltration.Epididymitis was coincident with an accumulation of DMGCs in the epididymis.In contrast,busulfan injection into mice lacking male germ cells did not induce epididymitis.DMGCs induced innate immune responses in epididymal epithelial cells (EECs),thereby upregulating the pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α),interleukin-6 (IL-6),and interleukin-1β (IL-1β),as well as the chemokines such as monocyte chemotactic protein-1 (MCP-1),monocyte chemotactic protein-5 (MCP-5),and chemokine ligand-10 (CXCL10).These results suggest that male germ cell damage may induce noninfectious epididymitis through the induction of innate immune responses in EECs.These findings provide novel insights into the mechanisms underlying noninfectious epididymitis,which might aid in the diagnosis and treatment of the disease.