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Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.

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 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.

SUBMITTER: Newbold RR

PROVIDER: S-EPMC2254327 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.

Newbold Retha R RR Jefferson Wendy N WN Grissom Sherry F SF Padilla-Banks Elizabeth E Snyder Ryan J RJ Lobenhofer Edward K EK

Molecular carcinogenesis 20070901 9

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 i ...[more]

PMID: 17394237

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Project description:Previously, we described a mouse model where the well-known reproductive carcinogen, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo. following 1000 µg/kg/day of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as the 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/day) on days 1-5 and compared to age-matched controls. Of more than 20,000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; several 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 day 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 significantly altered genes have been identified in human uterine adenocarcinomas. Four altered genes [Lactotransferrin (Ltf), Transforming growth factor beta inducible (Tgfβ1), 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 suggest altered gene expression profiles observed two weeks after treatment ceased, were imprinted at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis. Experiment Overall Design: There were 3 DES doses (1, 10 and 1000 ug/kg/day) administered to neonates on days 1-5. RNA was pooled for 10 mice, with each dose having its own matching control (corn oil). Dye-flipped hybridizations were performed for each paired comparison.

Dataset Information

Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.

Publications

Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.

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