The degree to which one form of endocrine toxicity predominates over the other (i.e., AR antagonism versus inhibition of aromatase) to disrupt reproductive function in the fetal male versus the pregnant dam depends to some degree on the duration of exposure. When PZ is administered at 250 mg/kg-BW per day or less for a brief period antiandrogenic effects are expressed along with delays in delivery that are not severe enough to reduce maternal or pup viability. However, had we expanded the dosing period to include the perinatal period it is likely that the effects on delivery would be more severe and occurred at lower dosage levels, which would preclude the survival of malformed pups.
Because antiandrogenic effects of short-term dosing can be observed without mortality, the antiandro-genicity of PZ is likely more relevant to an acute risk assessment, compared with PZ effects on aromatase, which may be better examined in a longer-term, multigenerational study.
In addition to the current study, there are other reports of decreased gestational weight gain, delays in pup delivery, and loss of litters in dams in which PZ was administered during gestation. PZ may both inhibit and induce multiple P450 enzymes and extended delivery times produced through PZ exposure may have resulted from reduced secretion of estrogens controlling the normal progression of pregnancy. Dose-related delays in parturition may be related to aromatase inhibition.