Reproductive toxicity evaluation of acetaminophen in Swiss CD-1 mice using a continuous breeding protocol

Abstract

Acetaminophen (APAP) was evaluated for reproductive toxicity in Swiss CD-1 mice using a continuous breeding protocol. APAP was administered in the diet at 0, 0.25, 0.5, and 1.0% (w/w), which represented average daily intakes of 0, 357, 715, and 1430 mg APAP/kg/day, respectively. Exposure of parental (P) breeding pairs to 1% APAP in the diet for 14 weeks during cohabitation significantly decreased the number of litters per pair, and reduced, although not significantly, the number of live pups per litter. Importantly, 6 of 19 high-dose P pairs failed to produce a fifth litter, and this fully accounted for the diminished number of litters in this group. In addition, the fifth litter that was produced by the 13 high-dose P pairs averaged only about 9 live pups per litter, which correspondingly reduced the overall group average for this parameter. In comparison, the control and two lower-dose P pairs produced 11 or 12 live pups per litter on average. Although the birth weights for F 1 pups in the final litter were unaffected by prenatal APAP exposure, postnatal growth was adversely affected as evidenced by retarded weight gain as measured at 28 and 74 ± 10 days of age for all three dietary levels. At 1% APAP this weight gain effect was more pronounced at Day 28 than at Day 74 ± 10, suggesting that nursing pups may have been exposed to higher concentrations or may be more sensitive to APAP and/or an active metabolite than were the young adults. A mating trial of F 1 pairs at 74 ± 10 days of age indicated that mating, fertility, and reproductive performance were normal, except that the birth weight of F 2 pups was significantly depressed at 1% APAP. This latter effect may have been attributable to maternal toxicity in that body weight and relative pituitary weight were significantly decreased, and relative brain and liver weight significantly increased, in high-dose F 1 females. In addition, body weight was significantly reduced in the high-dose F 1 males at necropsy. No treatmentrelated effects on reproductive organ weights and no gross or histological changes in the reproductive tissues of the high-dose F 1 male and female mice were observed. Continuous exposure of F 1 males at 1% APAP, however, significantly increased the percentage of abnormal epididymal sperm, while sperm density and percentage of motile sperm were unaffected. Collectively, these data indicated that continuous exposure to 1% APAP via the diet (1.43 g/kg/day) led to cumulative effects on reproduction in the P pairs, to retarded growth and abnormal sperm in the F 1 mice, and to reduced birth weight of F 2 pups.