Reproductive effects of theophylline in mice and rats

Theophylline was administered by gavage in 13-week studies to B6C3F1 mice (0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150 mg/kg/day) with significant reductions in male mouse terminal body and testicular weights. Male rats also displayed reduced testicular weight, as well as nonsignificant but dose-related decreases in body weight. There was a significant but non-dose-related decrease in female mouse body weight. In parallel studies of B6C3F1 mice and F344 rats, theophylline administered in the diet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminal body weights in male and female mice, but not rats. In rats, cauda epididymis weight was reduced at the high dose compared to the control group, and there was an increase in abnormal sperm. These studies were followed by continuous breeding reproductive assays in CD-1 mice in which theophylline was administered in feed (0.0, 0.075, 0.15, and 0.30%; calculated doses of 0, 125, 265, and 530 mg/kg/day, respectively) to breeding pairs for 14 weeks. There was a dose-dependent decrease in the number of live pups produced per litter, a significant decrease in the number of litters produced per pair (0.30%) and in the adjusted live pup weight (0.30%), a decrease in the percentage of pups born alive (0.15 and 0.30%), and an increase in the number of days needed to produce each litter (0.30%). After 19 weeks of continuous treatment at 0.30%, a crossover mating trial indicated that females and males were adversely affected by theophylline, as judged by the decreased percentage of pups born alive, the decreased live pup weight, and the decreased number of live pups per litter relative to matings within the control group, but the effects in females were more extensive. Based on other studies, there is a suggestion that the observed changes in fertility may be partially attributed to embryotoxicity.