Phenobarbital-induced alterations in the sexual differentiation of the female rat: reversal by hydroxyurea and cycloheximide

The possible mechanism of action of phenobarbital in prenatal female rats has been studied using different inhibitors of protein/DNA/RNA synthesis. Administration of phenobarbital (40 mg/kg/day) subcutaneously from day 17 to day 20 of pregnancy resulted in a delay of the onset of puberty, disorders of estrous cycle, infertility, and high estrogen levels in the female offspring. Cycloheximide (60 microg/kg/day)--a protein synthesis inhibitor and hydroxyurea (160 mg/kg/day)--a DNA synthesis inhibitor when combined with phenobarbital, significantly reduced the incidence of reproductive dysfunctions listed above. Alpha-amanitin (15 microg/kg/day), an inhibitor of m-RNA synthesis, produced reproductive disorders in the female offspring when administered alone to pregnant rats and also failed to reverse the PB-induced reproductive alterations. Cycloheximide and hydroxyurea produced no effect upon reproductive function when administered alone. Cycloheximide administration resulted in low body weight at birth and delayed eye opening. These results suggest that prenatal administration of phenobarbital produces its effect via new protein synthesis and that cycloheximide and hydroxyurea protect the offspring from phenobarbital-induced toxic effects by inhibiting its biochemical action.