Newbold Retha R, Jefferson Wendy N, Grissom Sherry F, Padilla-Banks Elizabeth, Snyder Ryan J, Lobenhofer Edward K
Developmental Endocrinology and Endocrine Disruptor Section, Laboratory of Molecular Toxicology, NIEHS, Research Triangle Park, North Carolina 27709, USA.
Mol Carcinog. 2007 Sep;46(9):783-96. doi: 10.1002/mc.20308.
Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 microg/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 microg/kg/d) on days 1-5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose-responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17beta estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental DES exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis.
此前，我们描述了一种小鼠模型，在该模型中，具有雌激素活性的著名生殖致癌物己烯雌酚（DES）在新生小鼠接受治疗后引发了子宫腺癌。肿瘤发生率呈剂量依赖性，在用1000微克/千克/天的DES对新生小鼠进行治疗后18个月时达到>90%。这些肿瘤遵循激素致癌作用的启动/促进模型，发育暴露作为启动因素，青春期暴露于卵巢激素作为促进因素。为了确定参与DES启动事件的分子途径，在第1至5天暴露于DES（1、10或1000微克/千克/天）的青春期前小鼠中检查子宫基因表达谱，并与对照组进行比较。在超过20000个转录本中，与对照组相比，至少在一个DES治疗组中有约3%的转录本差异表达；一些转录本表现出剂量反应性。基因本体注释评估显示，与细胞生长、分化和黏附相关的基因发生了改变。当将表达谱与已发表的关于5日龄DES处理小鼠或用17β-雌二醇处理的成年小鼠子宫的研究进行比较时，发现了相似之处，这表明发育性DES暴露后雌激素反应基因持续存在差异表达。此外，在人类子宫腺癌中鉴定出了几个改变的基因。选择四个改变的基因[乳铁传递蛋白（Ltf）、转化生长因子β诱导型（Tgfb1）、细胞周期蛋白D1（Ccnd1）和分泌型卷曲相关蛋白4（Sfrp4）]进行实时RT-PCR分析，其结果与微阵列数据的方向性相关性良好。这些数据表明，在治疗停止2周后观察到的基因表达谱改变在发育暴露时就已确立，并且可能与导致致癌作用的启动事件有关。
