Biology of Reproduction, Vol 22, 367-375, Copyright © 1980 by Society for the Study of Reproduction

Bi-Generational Effects of 6-Mercaptopurine on Reproduction in Mice

¹ Department of Physiology and Biophysics, Animal Reproduction Laboratory, Colorado State University, Fort Collins, Colorado 80523

Effects of the mutagenic, immunosuppressive drug 6-mercaptopurine (6-MP) on reproductive function were examined in two generations of mice. CD1/CR mice (G₀ generation) received either physiological saline (Group A) or 0.5 (Group B), 1.5 (Group C) or 3.0 (Group D) mg/kg 6-MP daily during pregnancy. Three mg/kg/day administered to G₀ mice reduced mean litter sizes (P<0.01), whereas the other doses had no effect. The surviving offspring (G₁ generation) were paired for breeding with untreated mice an 70 days of age. Although body weights and general appearance were normal, the interval from the day of pairing of G₁ females in Group D (4.9 ± 0.6 days) with untreated males to the day of breeding was longer (P<0.01) than for G₁ females in Group A (2.7 ± 0.3 days). A smaller percentage of the G₁ females was pregnant in Groups C (78.8%, P<0.05) and D (22.2%, P<0.01) than in Group A (100%). Ovaries from G₁ females in Group D weighed 2.2 ± 0.8 mg, whereas those from G₁ females in Group A weighed 8.6 ± 0.5 mg (P<0.01). Many ovaries in Groups C and D had fewer follicles, oocytes and corpora lutea than did control ovaries. The mean number of G₂ fetuses/pregnant G₁ female was lower (P<0.01) in Groups C (10.6 ± 0.4) and D (6.5 ± 1.3) than in Group A (13.0 ± 0.4). A large percentage of G₂ fetuses in Groups C (25.3 ± 2.7%) and D (41.7 ± 9.1%) were dead; 12.8 ± 2.6% were dead in Group A (P<0.01). Most fetuses died early in gestation. Weights of the live G₂ fetuses and placentas were non different among groups. After G₁ males were paired with untreated females, 60% and 55.6% of the females were pregnant in Groups C and D, respectively, whereas 100% were pregnant in Group A (P>0.05). Testes from G₁ males in Groups C (155.7 ± 18.8 mg) and D (104.2 ± 11.6 mg) weighed less (P<0.01) than testes from G₁ males in Group A (258.0 ± 5.5 mg). Many seminiferous tubules in testes of G₁ males were devoid of germ cells. The interval from pairing to breeding, litter sizes, percentage of G₂ fetuses dead and G₂ fetal and placental weights were not affected when G₁ males were mated. Our results show that 6-MP not only had direct embryotoxic effects when administered to pregnant mice, but also severely impaired reproductive function of the surviving offspring a full generation after the drug was administered.