Delayed adverse effects of neonatal exposure to diethylstilbestrol and their dose dependency in female rats

Abstract

Neonatal exposure to estrogenic chemicals causes irreversible complex damage to the hypothalamus-pituitary-gonadal axis and reproductive system in females. Some lesions are noted after maturation as delayed adverse effects. We investigated the characteristics and dose dependence of delayed effects using female rats neonatally exposed to diethylstilbestrol (DES). Female Donryu rats were subcutaneously injected with a single dose of DES of 0 (control), 0.15, 1.5, 15, 150, or 1,500 μg/kg bw after birth. All except the lowest dose had estrogenic activity in a uterotrophic assay. All rats at 1500 μg/kg and some at 150 μg/kg showed abnormal morphologies in the genital tract, indicating they were androgenized before maturation. Although no morphological abnormalities were noted at 15 μg/kg or lower, onset of persistent estrus was significantly accelerated in the 1.5, 15, and 150 μg/kg groups with dose dependency, and the latest onset was from seventeen to twenty-one weeks of age at 1.5 μg/kg. The neonatal exposure to DES increased uterine adenocarcinoma development only at 150 μg/kg, although uterine anomalies were detected at 1,500 μg/kg. These results indicate that neonatal exposure to DES, which exerts estrogenic activity in vivo, induces delayed adverse effects in female rats in a dose-dependent manner. Early onset of persistent estrus appears to be the most sensitive parameter. © 2011 by The Author(s).