Arsenic trioxide impairs spermatogenesis via reducing gene expression levels in testosterone synthesis pathway

Arsenic trioxide (As₂O₃) has recently received a great deal of attention because of its capacity to cause complete remission of acute promyelocytic leukemia (APL). To evaluate possible toxicity on the male reproductive system during arsenic therapy, male mice were used as a model. Outbred mice (ICR/CD1 and S-W, 6 weeks old) were subcutaneously administered As₂O₃ continuously for 5 days, with a 2-day interval, for a period of 3 weeks. As₂O₃ doses were 0, 0.15, 0.3, 1.5, and 3.0 mg/kg of body weight, respectively. No mice died in any dosage group. Our data showed no significant changes in food consumption or in the weight of the body, liver, testis, or epididymis after As₂O₃ treatment. Using histological observation to identify the stages of seminiferous tubules, we showed that As₂O₃ treatment resulted in the inhibition of spermatogenesis. The frequency of mature seminiferous tubules (stages VII and VIII) was markedly decreased after As₂O₃ treatment. A significant decrease in sperm motility and viability also was found with computer-assisted sperm analysis (CASA) and a SYBR14/PI staining assay. Using an enzyme-linked immunosorbent assay (ELISA), we found a significant decrease in levels of plasma luteinizing hormone (LH) at a dose of 3.0 mg/kg body weight. No significant difference was found in plasma follicle-stimulating hormone (FSH) in all dosages. A significant decrease was found in plasma testosterone in all dosages, but no difference in intratesticular testosterone, with the exception of As₂O₃ at a dose of 3.0 mg/kg body weight. Moreover, there was a significant decrease in the levels of mRNA involved in testicular testosterone synthesis, cytochrome P450 side chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), and cytochrome P450 17-α hydroxylase/C17-20 lyase (Cyp17). The use of immunohistological observation showed no obvious difference in the testosterone level of Leydig cells of mice treated with As₂O₃ at doses of 0.3 and 1.5 mg/kg body weight. We concluded that As₂O₃ treatment caused damage to sperm mobility and viability. As₂O ₃ treatment disturbed spermatogenesis via reducing gene expression of the key enzymes in testosterone synthesis.