Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice.
OBJECTIVE
Azathioprine and 6-mercaptopurine interact in purine metabolism and DNA synthesis, thus their potential mutagenic effects have been of concern in the management of inflammatory bowel disease (IBD), especially in patients of childbearing age. Although several clinical studies have indicated their safety in both reproduction and pregnancy, in a recent large epidemiological study concerns were raised about their adverse effects in pregnant patients with IBD, and experimental or basic data on this subject are limited. The aim of this study was to investigate sperm production, sperm quality, and reproductive outcome following prolonged 6-MP administration to male mice.


METHODS
Highly inbred Balb/c adult male mice were used. 6-MP at doses of 2, 5, and 8 mg/kg (n = 9 for each group) was given daily for 51 days and the treatment group was compared with controls. After 45 days of treatment, the mice were mated with females. Following 13 days of pregnancy, the products of conception were evaluated and live fetuses were examined for gross malformations. Sperm production and morphology were examined after 51 days of 6-MP administration.


RESULTS
Treatment with 6-MP at all doses did not affect sperm morphology and sperm production in the testicular tubules, as compared with controls (70% normal sperm). However, pregnancy rates were inversely related to escalating doses of 6-MP: 55%, 41%, 28%, and 16% for control, 2, 5, and 8 mg/kg groups, respectively. Resorption rates (abortions) were 21% in the control group as compared with 45-50% in all the treatment groups, but the incidence of major congenital malformations was not increased.


CONCLUSIONS
Long-term 6-MP treatment in male mice did not impair sperm production and sperm morphology. However, a significantly high rate of embryonic resorption indicated occult sperm damage. Thus, normal sperm analysis does not necessarily imply that sperm damage at genetic level did not occur. It is difficult to extrapolate from these results to the clinical use of 6-MP/azathioprine in IBD patients; however, further basic genetic testing for DNA damage and clinical follow-up are warranted.
Ligumsky
Moshe
M
Gastroenterology Unit, Division of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Badaan
Shadi
S
Lewis
Hadassa
H
Meirow
Dror
D
D000818:Animals; D020964:Embryo Loss / Q000139:chemically induced; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007248:Infertility, Male / Q000139:chemically induced; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects*; D051379:Mice; D011247:Pregnancy; D011256:Pregnancy Outcome; D012098:Reproduction / Q000187:drug effects*; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000002:abnormalities / Q000187:drug effects
D007166:Immunosuppressive Agents; D015122:Mercaptopurine