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化学物质（EDC），在成年或新生儿暴露时对子宫癌变的影响。成年东流大鼠经子宫内预处理后皮下注射高剂量OP 12个月，可显著增加高分化子宫内膜腺癌的发生。相反，新生儿（1 ~ 15日龄）接受高剂量OP治疗并未增加子宫癌的发病率，但明显增加了其恶性程度，如中/低分化腺癌和侵袭/转移增加。这些结果清楚地表明，在成年期和新生期暴露于具有雌激素活性的EDCs的大鼠中，高剂量治疗可能会增强子宫癌的发生。2001年，我们研究了从出生到青春期暴露于高剂量OP的大鼠子宫的顺序变化。更严重和不可逆的影响是，新生儿暴露于OP破坏了下丘脑-垂体-性腺控制系统雄激素化，并明显降低了青春期前血清促性腺激素水平。这种破坏导致无排卵和卵巢萎缩，伴有多囊卵泡和黄体缺乏，导致血清相对雌激素水平升高。8周龄时，状态诱发持续发情和子宫内膜增生。由于OP对子宫的直接作用，新生儿治疗改变了青春期前子宫腺体发生和子宫雌激素受体（ER）的表达，提示高剂量OP导致子宫生长发育异常。在成年东流大鼠的免疫组化检查中，除了中/低分化子宫内膜腺癌外，子宫上皮ER表达随着子宫增生性病变的发展而增加。结果表明，激素依赖性可能与肿瘤的形成有关，但随着恶性肿瘤的进展，这种性质可能转变为激素独立型，类似于人类病例。这些结果表明，在成年期或新生儿时期，大剂量暴露于EDCs可促进大鼠子宫癌的发生。有趣的是，观察到的子宫肿瘤的性质在成人和新生儿治疗期间是不同的，这表明子宫动荡的机制可能取决于暴露时间。在成人暴露研究中，长期使用OP可能会增加子宫上皮细胞的增殖活性，如雌激素作用。新生儿暴露后，下丘脑-垂体-性腺控制系统被破坏，导致血清相对雌激素水平升高，子宫生长发育异常，可能与子宫肿瘤恶性程度增加有关。与环境水平相比，目前研究中的剂量明显高，这表明环境水平的EDCs暴露诱发子宫肿瘤的可能性极低。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