Sperm Production and Reproductive Performance in Male Mice Treated with the Immunosuppressive Drug Used for Inflammatory Bowel Disease 6-Mercapto Purine

Abstract

Objectives: The Purine analogue 6-mercapto Purine (6MP) is an immunosuppressive agent indicated for the therapy of Inflammatory Bowel Diseases (IBD) ulcerative colitis & Crohn’s disease. Issues regarding the potential adverse effects of this agent on the male reproductive system are very authentic and practical since most patients are young. Despite extensive use, no firm, well established data is available regarding the effect of 6MP on male reproduction. The objectives of this study were to investigate the long-term effects of 6MP on sperm production and morphology. To study reproductive outcome & embryonic development following chronic exposure of male mice to 6MP. Design: An animal study on male mice treated with 6MP. The effects of treatment effects on sperm production, and morphology. Reproduction and embryonic development were assessed by mating exposed males with fertile females. Materials and Methods: Highly inbreed Balb/c adult (10–12w) mice were daily injected intraperitoneally with 6MP (2,5,8, mg/kg) for 51 days (controls injected with saline). Following 45 days of treatment, young females (8 w) were mated with males in a 3/1 ratio. Fertilized females were kept for 13 pregnancy days. Then, pregnancies and resorptions were counted. Embryos were weighted and inspected for gross anomalies. Following 51 days testis and epididimis were removed and evaluated coordinately for sperm production and sperm morphology. Results: Decreased sperm production following 6MP was demonstrated in testicular tubules. However, sperm morphology was not affected compared with controls (70% normal sperm). Pregnancy rates showed direct dose effect 42%, 35%, 20% for 2,5 and 8 mg/kg 6MP respectively compared with 52% in controls. Resorption rates significantly increased from 21% (S.D.11.4%) in controls to 49%–50% (S.D. 13.9%, 14.8%, 13.5% for 2, 5 and 8 mg/kg respectively P<0.0002) in all treatment groups with no significant differences within the three treatment groups. In all treated groups major congenital malformations were not increased (2%). Conclusions: Sperm production was decreased and pregnancy rates fell in a dose effect relations following treatment of male mice with 6MP. Late embryonic resorption was high indicating sperm damage that induced high rate of lethal embryonic damage. These results correlate with recently presented clinical observation. This study provides an alarm and points to the adverse effects of treatment in couples where the male is suffering from IBD and is treated with 6MP.