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

2000年，我们研究了对叔辛基酚（OP），一种具有雌激素活性的内分泌干扰物（EDC），在成年期或新生儿期暴露时对子宫隆凸发生的影响。高剂量OP皮下给药12个月，在宫内预处理致癌剂的成年东柳大鼠显着增加分化良好的子宫内膜腺癌。相反，新生儿（1 - 15日龄）给予高剂量OP并未增加子宫癌的发病率，但显著增加了其恶性程度，如中/低分化腺癌和浸润/转移增加。这些结果清楚地表明了一种可能性，即高剂量治疗雌激素活性的内分泌干扰物发挥增强子宫癌发生在大鼠暴露在成年期和新生儿periods.In 2001年，我们调查了大鼠子宫暴露于高剂量OP从出生到青春期的连续变化。至于 ...更多信息 严重和不可逆的影响，新生儿暴露于OP破坏下丘脑-垂体-性腺控制系统，称为雄激素化，并明显降低青春期前血清促性腺激素水平。卵巢破裂导致无排卵、卵巢萎缩、多囊卵泡和黄体缺乏，导致血清雌激素水平升高。该状态诱导持续发情和子宫内膜增生，在8周龄。作为OP对子宫的直接作用，新生儿治疗改变了子宫腺的发生和雌激素受体（ER）的表达，在青春期前的子宫，表明异常的子宫生长和发育的高剂量OP。在免疫组化检查使用成年东柳大鼠，ER在子宫上皮细胞的表达增加，子宫增生性病变的发展，除了中/低分化的子宫内膜腺癌。结果表明，内分泌干扰物的激素依赖性可能与肿瘤的形成有关，但当肿瘤进展到一定程度时，这种激素依赖性可能转变为激素非依赖性，与人类的情况相似，提示成年期或新生期高剂量内分泌干扰物暴露可增强大鼠子宫癌的发生。有趣的是，观察到的子宫肿瘤的特性在成人和新生儿治疗之间是不同的，这表明子宫肿瘤发生的机制可能取决于暴露时间而不同。在成人暴露研究中，OP长期给药可增加子宫上皮细胞增殖活性，表现为雌激素样作用。新生儿暴露后，下丘脑-垂体-性腺控制系统紊乱，子宫生长发育异常，引起血清雌激素水平升高，可能与子宫肿瘤恶性程度增高有关。与环境水平相比，本研究中的剂量明显较高，表明在环境水平下暴露于内分泌干扰物诱导子宫肿瘤发展的可能性极低。少

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