Effects of endocrine disrupting chemicals on uterine carcinogenesis in rats and their mechanisms

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In 2000, we investigated effects of p-tert octyiphenol (OP), an endocrine disrupting chemical (EDC) with estrogenic activities, on uterine carinogenesis when exposed during adulthood or newborn. Administration of high dose OP subcutaneously for 12 months in adult Donryu rats with intrauterine pretreatment to carcinogen significantly increased well-differentiated endometrial adenocarcinomas. On the contrary, neonatal treatment (from 1 to 15 day-old) to high dose OP did not increase incidence of uterine cancers, however it significantly increased their malignancy such as increased moderately/poorly differentiated adenocaricnomas and invasion/metastasis. These results clearly indicate a possibility that high dose treatment to EDCs with estrogenic activity exerts enhancement of uterine carcinogenesis in rats exposed during both adulthood and newborn periods.In 2001, we investigated a sequential alteration of the rat uterus exposed neonataily to high dose OP from birth up to puberty. As for … More serious and irreversible effects, the neonatal exposure to OP disrupted the hypothalamus-pituitary-gonadal control system named androgenization and clearly depressed serum gonadotropin levels at prepuberty. The disruption led anovulation and the atrophic ovaries with polycystic follicles and lack of corpus luteum, resulting in elevation of relative serum estrogen levels. The status induced persistent estrus and endometrial hyperplasias at 8 week-old. As direct action of OP to the uteri, the neonatal treatment altered uterine gland-genesis and estrogen receptor (ER) expression of the uterus at prepuberty, indicating abnormal uterine growth and development by high dose OP.On the immunohistochemical examination using adult Donryu rats, ER expression in the uterine epithelium was increased with development of proliferative lesions of the uterus except moderately/poorly differentiated endometrial adenocarcinomas. The results demonstrate that hormone dependent property might be related to tumor formation, but the property might be changed to hormone independent type with advanced malignancy, similar to human cases.These results indicate high dose exposure to EDCs enhances uterine carcinogenesis in rats when treated during adulthood or newborn period. Interestingly, the properties of uterine tumors observed were different between adult and newborn treatment, indicating a possibility that mechanisms of uterine turmoigenesis might be different dependent on exposure period. In adult-exposure study, prolonged treatment to OP might increase cell proliferating activity of the uterine epithelium as estrogenic action. In neonatal exposure, the increased relative serum estrogen levels caused by disruption of the hypothalamus-pituitary-gonadal control system and the abnormal uterine growth and development might be related with the increased malignancy of uterine tumors. The doses in the present studies are markedly high compared with environmental levels, suggesting that a possibility of uterine tumor development induced by exposure to EDCs at environmental levels is extremely low. Less