Toxicologic/carcinogenic Effects of Endocrine Disrupting Chemicals on the Female Genital Organs of Rodents

Abstract

Toxicologic/carcinogenic effects of some representative endocrine disrupting chemicals (EDCs) having estrogenic activity, such as alkylphenols, on the female genital organs of rodents, especially rats, are reviewed and discussed, focusing on our recent research. Neonatal treatment of high-dose p-tert octylphenol (t-OP, 100 mg/kg s.c. injection every other day from postnatal day 1 (PND 1) to PND 15) induced various long-term persistent irreversible effects on the female reproductive system of Donryu rats, such as lower gonadotropin levels at prepuberty, inhibition of uterine gland genesis, persistent estrus and polycystic ovaries. The result indicates that neonatal high-dose treatment of estrogenic EDCs can affect gonadotropin secretion during the developmental period of sexual maturation with direct masculinization of the hypothalamic function. Exposure limited to the first 5 days after birth (PNDs 1-5) to 100 mg/ kg t-OP, however, caused delayed influence which was characterized by accerelated appearance of atrophic ovary, manifested by early-occurring and long-term continuing persistent estrus after puberty, whereas no abnormalities could be found with regard to growth and differentiation of the reproductive organs and the hypothalamo-pituitary-gonadal control system up to maturation, the influence being caused by delayed modulation of the hypothalamo-pituitary-gonadal control system. The most notable effect on the female reproductive system when normal cycling rats were exposed to high-doses t-OP for 28 days, was disappearance of the estrous cycle, but no clear changes were detected in other parameters such as uterine weight and morphology. These results indicate that the most serious issue with EDCs is the potential effects of prenatal and/or neonatal exposure on rodents. Well or moderately differentiated adenocarcinomas increased in Donryu rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, when high-dose t-OP was given subcutaneously during adulthood. Neonatal exposure for PNDs 1-5 to high-dose t-OP also showed promoting effects on uterine adenocarcinoma development. However, in rats given t-OP for PNDs 1-15, uterine tumor malignancy was clearly increased, although there was no significant alteration in the total incidence of adenocarcinomas. The results are very interesting in consideration of the histogenesis of uterine adenocarcinomas. However, maternal exposure to low doses of EDCs such as nonylphenol and bisphenol A at actual human exposure levels by the oral route showed no effects on growth and development of the female reproductive system or uterine carcinogenesis. These results indicate that dietary exposure to low doses of EDCs might not induce any adverse effects on the female genital system in mammals including humans. (J Toxicol Pathol 2004; 17: 69-83)

Involvements of Estrogen Receptor, Proliferating Cell Nuclear Antigen and p53 in Endometrial Adenocarcinoma Development in Donryu Rats

“…The mechanisms of rat uterine cancer development are not fully determined; however, estrogens are accepted to play a crucial role in the development in rodents 4 , 5 , 6 , 7 , 8 , 9 , 10 as well as endometriod adenocarcinomas in humans 11 , 12 . Maekawa and co-workers 13 found a high-occurrence of spontaneous uterine endometrial adenocarcinomas in aged Donryu rats, which are similar to human cases as follows: 1) multistep development of uterine lesions from atypical hyperplasias to adenocarcinomas 2) ovarian hormonal imbalance especially elevation of the serum 17β-estradiol (E2) level relative to progesterone, which manifests as atrophic ovaries with cystic follicles and lack of a corpus luteum and 3) morphologic similarities to endometrioid adenocarcinomas of humans 11 , 12 .…”