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

2000年，我们研究了对叔辛基苯酚(OP)，一种具有雌激素活性的内分泌干扰物(EDC)，在成年或新生儿暴露时对子宫癌变的影响。成年Donryu大鼠皮下注射大剂量OP 12个月后，宫内注射致癌物可显著增加高分化子宫内膜腺癌的发生。相反，新生儿治疗(从出生后1~15天)到大剂量OP并没有增加子宫癌的发病率，但它显著增加了子宫癌的恶性程度，如增加了中/低分化腺癌和侵袭/转移。这些结果清楚地表明，对具有雌激素活性的EDCs进行高剂量处理，可能会促进成年期和新生期暴露的大鼠子宫癌的发生。2001年，我们研究了从出生到青春期大鼠子宫对高剂量OP暴露的顺序变化。至于…更严重和不可逆转的影响是，新生儿暴露于OP扰乱了下丘脑-垂体-性腺控制系统，称为雄激素生成，并明显抑制了青春期前的血清促性腺激素水平。阻断导致无排卵和卵巢萎缩，伴有多囊卵泡和黄体缺乏，导致相对血清雌激素水平升高。这种状态导致8周龄持续发情和子宫内膜增生。作为OP对子宫的直接作用，新生治疗改变了青春期前子宫腺体的发生和子宫的雌激素受体(ER)的表达，表明大剂量OP导致子宫生长发育异常。在成年Donryu大鼠的免疫组织化学检查中，除中/低分化子宫内膜腺癌外，子宫上皮ER的表达随着子宫增生性病变的发展而增加。这些结果表明，激素依赖性可能与肿瘤的形成有关，但与人类的情况相似，这种激素依赖型可能会转变为激素非依赖型，与人类的情况相似。这些结果表明，在成年或新生期接受治疗时，高剂量的EDCs暴露会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的治疗中是不同的，这表明子宫混乱的发生机制可能因暴露时间的不同而不同。在成人暴露研究中，OP的长期治疗可能作为雌激素作用增加子宫上皮细胞的增殖活性。在新生儿暴露中，下丘脑-垂体-性腺控制系统紊乱和子宫生长发育异常引起的血清雌激素水平升高可能与子宫肿瘤的恶性程度增加有关。与环境水平相比，本研究中的剂量明显较高，这表明暴露于环境水平的EDCs导致子宫肿瘤发生的可能性极低。较少

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