Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life
- 29 March 2007
- journal article
- research article
- Published by Wiley in Molecular Carcinogenesis
- Vol. 46 (9), 783-796
- https://doi.org/10.1002/mc.20308
Abstract
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 µg/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 µg/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 17β 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.Keywords
This publication has 58 references indexed in Scilit:
- A new mathematical model for relative quantification in real-time RT-PCRNucleic Acids Research, 2001
- Cell proliferation effect of lactoferrin in human endometrial stroma cellsMolecular Human Reproduction, 2000
- Abnormal Cell Differentiation and p21 Expression of Endometrial Epithelial Cells Following Developmental Exposure to Diethylstilbestrol (DES)Toxicologic Pathology, 2000
- Effects of Neonatal Diethylstilbestrol (DES) Exposure on Morphology and Growth Patterns of Endometrial Epithelial Cells in CD-1 MiceToxicologic Pathology, 1999
- Immunohistochemical studies on the expression and estrogen dependency of EGF and its receptor and C-fos proto-oncogene in the uterus and vagina of normal and neonatally estrogen-treated miceThe Anatomical Record, 1996
- Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in uteroCancer, 1996
- Developmental effects of endocrine-disrupting chemicals in wildlife and humans.Environmental Health Perspectives, 1993
- Regulation of uterine epidermal growth factor (EGF) receptors by estrogen in the mature rat and during the estrous cycleJournal of Steroid Biochemistry, 1989
- Delayed Effects of Prenatal or Postnatal Exposure to Diethylstilbestrol in the Adult Female Guinea PigCells Tissues Organs, 1987
- Diethylstilbestrol Induces Neoplastic Transformation Without Measurable Gene Mutation at Two LociScience, 1981