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Manganese (Mn), a vital trace element for biological functions, has raised health concerns due to potential toxicity. Excessive Mn impairs male reproduction by reducing testosterone, inducing oxidative stress, and disrupting spermatogenesis. However, its mechanisms targeting Leydig and Sertoli cells remain unclear. This study investigates Mn’s reproductive toxicity by utilizing Leydig cell line TM3 and Sertoli cell line TM4, MTT assays revealed median lethal concentrations of 230 μM (TM3) and 170 μM (TM4), with AO/EB/DAPI staining confirming condensed nuclei and enhanced fluorescence. Apoptosis inhibitor Z-VAD-FMK (20 μM) suppressed cell death in both cell lines, whereas ferroptosis inhibitor Ferrostatin-1 (10 μM) specifically attenuated TM4 cell death. Necrosis inhibitor Necrostatin-1 (10 μM) showed no protective effect. Mn triggered ROS elevation in TM4 cells, accompanied by upregulated  Caspase 3, Casp8ap2, GPX4, Gtf3c1, Mtfr1, HMOX1, and SLC7A2 , while downregulating  SLC7A15 . These findings reveal Mn activates apoptosis in TM3 cells and concurrent apoptosis/ferroptosis in TM4 cells through ROS-dependent dysregulation of apoptosis- and ferroptosis-related genes. These findings establish distinct toxic mechanisms in TM4 cells and highlight the  SLC7A15/HMOX1  axis as a therapeutic target to mitigate Mn-induced spermatogenic damage.

Manganese exposure: a study on apoptosis and Ferroptosis in mouse Leydig and Sertoli cells