Newbold R R, McLachlan J A
Cancer Res. 1982 May;42(5):2003-11.
The association of intrauterine exposure to diethylstilbestrol (DES) and the subsequent development of reproductive tract abnormalities in young women has been well documented. Although the incidence of vaginal adenocarcinoma was low in the exposed population, vaginal adenosis, a nonmalignant abnormality, was quite common. In order to study the pathogenesis of adenocarcinoma and to determine the frequency of adenosis following prenatal exposure to DES, timed pregnant CD-1 mice were treated s.c. with DES (dose range, 5 to 100 micrograms/kg/day) on Days 9 though 16 of gestation. This period corresponds to major organogenesis of the reproductive tract in the mouse. Female offspring were sacrificed between 1 and 18 months of age. In addition to nonmalignant abnormalities, some of which have been described in women exposed prenatally to DES, two cases of vaginal adenocarcinoma (2%) were observed in 91 prenatally DES-treated animals. No comparable epithelial lesions were seen in 158 control female mice. One other case of adenocarcinoma of the vagina was reported previously by this laboratory using the prenatally exposed animal model. In another series of mice treated prenatally with DES, 100 micrograms/kg/day, 3 of 20 (15%) 1-month-old animals and one of 10 (10%) 18-month-old treated offspring had glandular epithelium abnormally located in the vaginal fornices (adenosis). Other cervicovaginal abnormalities observed after prenatal DES exposure included structural alterations, cervical enlargement, squamous metaplasia in the endocervical canal, excess keratinization of the ectocervix and vagina, transverse folds and basal cell hyperplasia in the upper vagina, and prominent Wolffian duct remnants. Thus, vaginal adenosis in the mouse does not appear to be a common abnormality following treatment with DES in utero. Neonatal exposure to DES on Days 1 to 5, on the other hand, resulted in six of eight (75%) animals with adenosis at 35 days of age. Since perinatal mouse studies have reported high incidences of vaginal adenosis, but, to our knowledge, no cases of vaginal adenocarcinoma, the results presented in this report suggest that the stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities.
子宫内暴露于己烯雌酚（DES）与年轻女性生殖道异常的后续发展之间的关联已有充分记录。尽管暴露人群中阴道腺癌的发病率较低，但阴道腺病（一种非恶性异常）却相当常见。为了研究腺癌的发病机制并确定产前暴露于DES后腺病的发生率，在妊娠第9至16天，对定时怀孕的CD-1小鼠进行皮下注射DES（剂量范围为5至100微克/千克/天）。这个时期对应于小鼠生殖道的主要器官形成期。雌性后代在1至18个月龄时被处死。除了非恶性异常（其中一些在产前暴露于DES的女性中已有描述）外，在91只产前接受DES治疗的动物中观察到2例阴道腺癌（2%）。在158只对照雌性小鼠中未见到类似的上皮病变。本实验室先前使用产前暴露动物模型报告过另一例阴道腺癌病例。在另一组产前用100微克/千克/天的DES治疗的小鼠中，20只1月龄动物中有3只（15%）以及10只18月龄治疗后代中有1只（10%）的腺上皮异常位于阴道穹窿（腺病）。产前暴露于DES后观察到的其他宫颈阴道异常包括结构改变、宫颈增大、宫颈管内鳞状化生、宫颈外口和阴道过度角化、阴道上部的横褶和基底细胞增生以及明显的中肾管残余。因此，在子宫内用DES治疗后，小鼠的阴道腺病似乎不是常见异常。另一方面，在出生后第1至5天暴露于DES的新生小鼠中，8只中有6只（75%）在35日龄时出现腺病。由于围产期小鼠研究报告了阴道腺病的高发生率，但据我们所知，没有阴道腺癌病例，本报告中的结果表明，DES暴露时的细胞分化阶段可能对这些异常的最终表现至关重要。
