SummaryPhenobartital (PB) (40 mg/kg/day) was administered to pregnant rats at 12 to 20, 14 to 20, and 17 to 20 days of gestation and female offspring were tested for the onset of puberty, estrous cycle pattern, and fertility. Another group of rats received PB (20 mg/kg/day) during the neonatal period (1 to 8 days). PB administration during both the pre- and postnatal periods resulted in a significant delay in the onset of puberty (control: 34.6 ± 1.2 days, PB: 37.5 ±1.2 days), disorders of estrous cycle (control: normal cycles 91%, PB: normal cycles 40%), and infertility (control: 100% fertile PB: 50% fertile). Associated with these effects, we observed high levels of estrogen in plasma (control: 58.5 ± 12.2 pg/ml, PB: 155.2 ± 25.1 pg/ml) and increased estrogen receptors in the uterus (control: 0.136 ± 0.026 pmole/mg protein, PB: 0.242 ± 0.031 pmole/mg protein. This study shows that PB administration only during the period of neuroendocrine differentiation (17 to 20 days of pregnancy and 1 to 8 postnatal days) is capable of producing all of the adverse effects of PB, indicating that its action is upon neuroendocrine development.SpeculationSince phenobarbital (PB) administration during 17 to 20 days of pregnancy is capable of producing reproductive disorders in the offspring, the results suggest that PB interferes with neuroendocrine differentiation. The mechanism of action of PB, however, has not been delineated. Neuroendocrine differentiation is mediated by gonadotropin, present during the neonatal period. PB may act at this site by interfering with gonadotrophin release or action. Support for this hypothesis is derived from the observation that PB can inhibit gonadotrophin secretion in the adult rat.