Delayed effects of neonatal exposure to 17alpha-ethynylestradiol on the estrous cycle and uterine carcinogenesis in Wistar Hannover GALAS rats

• Neonatal exposure to EE induces early onset of anovulation dose dependently.
• Estrous cyclicity is a useful indicator of delayed adverse effects.
• Early onset of anovulation can increase the risk for uterine carcinogenesis.
• Neonatal exposure to EE can directly affect differentiation of mammary glands.

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24 h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N′-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis.