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), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and cytochrome P450 17-alpha 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. As2O3 treatment disturbed spermatogenesis via reducing gene expression of the key enzymes in testosterone synthesis.
Chiou
Tzeon-Jye
TJ
Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan. tjchiou@vghtpe.gov.tw
Chu
Sin-Tak
ST
Tzeng
Woan-Fang
WF
Huang
Yu-Chen
YC
Liao
Chi-Jr
CJ
D000818:Animals; D021461:Animals, Outbred Strains; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000633:toxicity*; D007279:Injections, Subcutaneous; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010087:Oxides / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D012671:Seminiferous Tubules / Q000187:drug effects / Q000378:metabolism; D013081:Sperm Motility / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects* / Q000502:physiology; D013094:Spermatozoa / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D013737:Testis / Q000737:chemistry / Q000378:metabolism; D013739:Testosterone / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D001152:Arsenicals; D006131:Growth Inhibitors; D010087:Oxides; D012333:RNA, Messenger; D013739:Testosterone; D007986:Luteinizing Hormone; D003577:Cytochrome P-450 Enzyme System; D000077237:Arsenic Trioxide