Chronic di-n-butyl phthalate exposure in rats reduces fertility and alters ovarian function during pregnancy in female long Evans hooded rats

Testis function in fetal and peripubertal male rats is disrupted by subchronic exposure to phthalate esters (PEs). In contrast to the male rat, it is generally held that reproduction in female rats is much less sensitive to phthalate-induced disruption. However, the current study demonstrates that oral administration of dibutyl phthalate (DBP) to female Long Evans (LE) hooded rats from weaning, through puberty, mating, and gestation disrupts pregnancy maintenance at dose levels similar to those that affect testis function in male rats. Administration of 500 and 1000 mg DBP/kg/day, but not 250 mg DBP/kg/day, to female LE rats induced midpregnancy abortions. The percentage of females delivering live pups was reduced by more than 50% at 500 mg/kg/day and by 90% at 1000 mg/kg/day in the absence of overt toxicity, whereas the ages at vaginal opening and first estrus, estrous cyclicity, and mating indices (N mated/N paired or N pregnant/N mated) were not significantly affected. On gestational day 13, prior to the stage when litters were being aborted, ex vivo ovarian hormone production was significantly decreased by in vivo DBP treatment at 500 and 1000 mg/kg/day. These results should be considered when evaluating mechanisms of reproductive toxicity for the PE because it is likely that these reproductive alterations in the female rat arise via a mode of action similar to that operative in male rats.