90-Day Feeding and One-Generation Reproduction Study in Crl:CD BR Rats with 17β-Estradiol

• Published in: Toxicological sciences 1998-08, Vol.44 (2), p.116-142
• Main Authors: Biegel, Lisa B., Flaws, Jodi A., Hirshfield, Anne N., O'Connor, John C., Elliott, Glenn S., Ladics, Gregory S., Silbergeld, Ellen K., Van Pelt, Carolyn S., Hurtt, Mark E., Cook, Jon C., Frame, Steven R.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Estradiol - toxicity; Female; Fetus - drug effects; Male; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - pathology; Medical sciences; Organ Size - drug effects; Ovary - drug effects; Ovary - pathology; Pregnancy; Rats; Reproduction - drug effects; Testis - drug effects; Testis - pathology; Toxicology; Vagina - drug effects; Vagina - pathology; Various organic compounds
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1006/toxs.1998.2468

Over the past several years, there has been increasing concern that chemicals and pesticides found in the environment may mimic endogenous estrogens, potentially producing adverse effects in wildlife and human populations. Because estrogenicity is one of the primary concerns, a 90-day/one-generation reproduction study with 17β-estradiol was designed to set dose levels for future multigenerational reproduction and combined chronic toxicity/oncogenicity studies. The purpose of these studies is to evaluate the significance of a range of responses as well as to provide benchmark data for a risk assessment for chemicals with estrogen-like activities. This 90-day/one-generation reproduction study was conducted in male and female Crl:CD BR rats using dietary concentrations of 0, 0.05, 2.5, 10, and 50 ppm 17β-estradiol. Endpoints were chosen in order to evaluate both subchronic and reproductive toxicity. In addition, several mechanistic/biochemical endpoints were evaluated for their usefulness in follow-up studies. In the P1generation, dietary administration of 2.5, 10, and 50 ppm 17β-estradiol produced dose-dependent decreases in body weight, body weight gain, food consumption, and food efficiency. At 10 and 50 ppm 17β-estradiol, minimal to mild nonregenerative anemia, lymphopenia, decreased serum cholesterol (50 ppm only), and altered splenic lymphocyte subtypes were also observed in the P1generation. Additionally, at these concentrations, there were changes in the weights of several organs. Evidence of ovarian malfunction, characterized by reduced numbers of corpora lutea and large antral follicles, was observed at 2.5 ppm 17β-estradiol and above. Other pathologic changes in males and females fed 10 and 50 ppm 17β-estradiol included centrilobular hepatocellular hypertrophy; diffuse hyperplasia of the pituitary gland; feminization of the male mammary glands; mammary gland hyperplasia in females; increased number of cystic follicles in the ovary; hypertrophy of the endometrium and endometrial glands in the uterus; degeneration of seminiferous epithelium; and atrophy of the testes and the accessory sex glands. In the reproduction portion of this study, rats fed 10 or 50 ppm 17β-estradiol did not produce litters. While there was no evidence that the 50 ppm treated rats mated, 33.3% of the rats fed 10 ppm mated but did not produce litters. No effects on mating and fertility indices were observed in rats fed 0.05 and 2.5 ppm 17β-estradiol. Pup weights at birth were s