Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol.
Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol.
复制标题
与产前接触己烯雌酚相关的对雌性小鼠生殖道的长期影响。
作者：
J. Mclachlan;R. Newbold;B. Bullock
摘要妊娠妇女使用己烯雌酚（DES）治疗与其雌性后代生殖道异常之间的关系是众所周知的。关于动物子宫内暴露的报告很少。本研究用妊娠远交系小鼠皮下给药。妊娠第9 - 16天DES日剂量范围为0.01 - 100 µg/kg。这一时期与小鼠生殖道的主要器官发生相对应。在相同的时间间隔内，用100 μg/kg剂量的二甲基己烯雌酚（DMS）（DES的弱雌激素性结构类似物）或17β-雌二醇（一种强效甾体雌激素）处理其他妊娠小鼠组。当妊娠期暴露于DES的小鼠的雌性后代在12至18个月大时被处死时，在其整个生殖道中发现病变。阴道的特征为过度角化和雌性尿道下裂，在100 µg/kg剂量下，20只小鼠中有5只患有阴道表皮样肿瘤;在来自DES（10 µg/kg）处理母体的35只小鼠中，观察到阴道腺癌。暴露于DES的后代的子宫颈增大，尽管其管腔的大小与对照组没有差异。宫颈间质刺激明显，良性（平滑肌瘤、乳头状瘤）和恶性（间质细胞肉瘤、平滑肌肉瘤）肿瘤的发生率较低。有证据表明，刺激上皮细胞，子宫间质和囊性子宫内膜增生是常见的;良性（平滑肌瘤）和恶性（腺癌，间质细胞肉瘤）肿瘤的发生率较低。产前DES处理的雌性动物的卵巢比相应对照组的卵巢更常为囊性;在最高剂量下，观察到3个卵巢肿瘤，输卵管发炎和先天性畸形。生殖道肿瘤没有看到在85个对照组女性或12或10个女性产前暴露于雌二醇或DMS，分别。事实上，在妊娠期间暴露于DES（100 µg/kg）的12- 13月龄雌性小鼠中，常见的发现包括：阴道结石和过度角化;宫颈增大;子宫鳞状上皮化生和囊性子宫内膜增生;以及输卵管畸形，这些发现在对照组、雌二醇治疗组或DMS治疗组小鼠中不存在或发生率极低。DES、雌二醇和DMS之间的作用差异可能与化合物对胎儿靶组织的相对生物利用度差异有关。结果表明，不同的胚胎雏形以及组织成分在妊娠期暴露于DES对女性生殖道的长期影响中发挥作用。此外，这样的产前研究与DES在小鼠中可能有助于了解雌激素的作用，在生殖道的功能发育，并可能最终提供一个有用的实验模型。
Abstract The association between treatment of pregnant women with diethylstilbestrol (DES) and reproductive tract abnormalities in their female offspring is well known. Reports of comparable in utero exposure in animals are few. In this paper, pregnant outbred mice were treated s.c. with daily doses of DES ranging from 0.01 to 100 µg/kg on Days 9 to 16 of gestation. This period corresponds with major organogenesis of the reproductive tract in the mouse. Additional groups of pregnant mice were treated during the same time interval with 100-µg/kg doses of either dimethylstilbestrol (DMS), a weakly estrogenic estructural analog of DES, or 17β-estradiol, a potent steroidal estrogen. When female offspring of mice gestationally exposed to DES were sacrificed at 12 to 18 months of age, lesions were found throughout their reproductive tracts. The vagina was characterized by excess keratinization and female hypospadias, and, at the dose of 100 µg/kg, 5 of 20 mice had epidermoid tumors of the vagina; in one of the 35 mice derived from mothers treated with DES (10 µg/kg), vaginal adenocarcinoma was observed. The cervix in the DES-exposed offspring was enlarged, even though the size of its lumen was not different from that in the controls. Stromal stimulation of the cervix was apparent, and a low incidence of benign (leiomyoma, papilloma) as well as malignant (stromal cell sarcoma, leiomyosarcoma) tumors were seen. There was evidence of stimulation in the epithelium, and stroma of the uterus and cystic endometrial hyperplasia was common; a low incidence of benign (leiomyomas) and malignant (adenocarcinoma, stromal cell sarcoma) tumors was observed. The ovaries of prenatally DES-treated females were cystic more often than were those of the corresponding controls; at the highest dose, three ovarian tumors were noted, and the fallopian tubes were inflamed and congenitally malformed. Genital tract tumors were not seen in 85 control females or in the 12 or 10 females exposed prenatally to estradiol or DMS, respectively. In fact, in 12- to 13-month-old females derived from mice exposed during pregnancy to DES (100 µg/kg), common findings, which were absent or in very low incidence in control, estradiol-treated, or DMS-treated mice, included: vaginal concretions and excess keratinization; cervical enlargement; uterine squamous metaplasia and cystic endometrial hyperplasia; and oviductal malformations. The differences in effects among DES, estradiol, and DMS may be linked to differences in relative bioavailability of the compounds to the fetal target tissue. The results presented suggest a role for different embryonic rudiments as well as for tissue components in the observed long-term effects of gestational exposure to DES on the female reproductive tract. Moreover, such prenatal studies with DES in mice may be helpful in understanding the role of estrogens in the functional development of the genital tract and may ultimately provide a useful experimental model.