| Summary: | Seminolipid (also known as sulfogalactosylglycerolipid-SGG), present selectively in male germ cells, plays important roles in spermatogenesis and sperm–egg interaction. The proper degradation of SGG in apoptotic germ cells is also as important. Sertoli cells first phagocytose apoptotic germ cells, then Sertoli lysosomal arylsulfatase A (ARSA) desulfates SGG, the first step of SGG degradation. We have reported that aging male <i>Arsa<sup>−/−</sup></i> mice become subfertile with SGG accumulation in Sertoli cell lysosomes, typical of a lysosomal storage disorder (LSD). Since reactive oxygen species (ROS) levels are increased in other glycolipid-accumulated LSDs, we quantified ROS in <i>Arsa<sup>−/−</sup></i> Sertoli cells. Our analyses indicated increases in superoxide and H<sub>2</sub>O<sub>2</sub> in <i>Arsa<sup>−/−</sup></i> Sertoli cells with elevated apoptosis rates, relative to WT counterparts. Excess H<sub>2</sub>O<sub>2</sub> from <i>Arsa<sup>−/−</sup></i> Sertoli cells could travel into testicular germ cells (TGCs) to induce ROS production. Our results indeed indicated higher superoxide levels in <i>Arsa<sup>−/−</sup></i> TGCs, compared with WT TGCs. Increased ROS levels in <i>Arsa<sup>−/−</sup></i> Sertoli cells and TGCs likely caused the decrease in spermatogenesis and increased the abnormal sperm population in aging <i>Arsa<sup>−/−</sup></i> mice, including the 50% decrease in sperm SGG with egg binding ability. In summary, our study indicated that increased ROS production was the mechanism through which subfertility manifested following SGG accumulation in Sertoli cells.
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