Bi-Generational Effects of 6-Mercaptopurine on Reproduction in Mice1

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Abstract
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 (P1 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 (P1 females in Group A (2.7 ± 0.3 days). A smaller percentage of the G1 females was pregnant in Groups C (78.8%, P1 females in Group D weighed 2.2 ± 0.8 mg, whereas those from G1 females in Group A weighed 8.6 ± 0.5 mg (P2 fetuses/pregnant G1 female was lower (P2 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 (P0.05). Testes from G1 males in Groups C (155.7 ± 18.8 mg) and D (104.2 ± 11.6 mg) weighed less (P1 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.