Hepatic histidase was used as an enzyme marker for the study of neonatal programming in intact rats. Diethylstilbestrol (DES) or 17 beta-estradiol (E2) treatment for days, 2, 4, and 6 post partum resulted in decreased histidase activities in the adult female, but no effect was seen in prepubertal male and female rats or in adult males. In contrast, similar neonatal doses of testosterone propionate (TP) had no effect on histidase. Dose-response experiments demonstrate a 3-fold greater neonatal sensitivity to DES than to E2. The action of neonatal estrogen treatment is demonstrated to be permanent and irreversible. Neonatal treatment with E2, DES, or TP resulted in decreased uterine wet weights in adult females (E2 less than DES less than TP less than controls). Circulating sera estrogen levels were lower in adult E2- and DES-treated females than in TP-treated and control females. Our results suggest that these alterations may be due to direct toxic effects on the postnatal development of the female reproductive tract and endocrine system and/or to organizational effects on nerve endings in the hypothalamus that result in programming for altered sexual differentiation of hepatic metabolism.