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Series GSE5825

Query DataSets for GSE5825

Status

Public on Jun 14, 2007

Title

Developmental Exposure to DES Alters Uterine Gene Expression That Maybe Associated with Neoplasia Later in Life

Organism

Mus musculus

Experiment type

Expression profiling by array

Summary

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.
Keywords: dose reponse

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.

Contributor(s)

Newbold RR, Jefferson WN, Grissom SF, Padilla-Banks E, Snyder RJ, Lobenhofer EK

Citation(s)

17394237

Submission date

Sep 13, 2006

Last update date

Dec 06, 2012

Contact name

NIEHS Microarray Core

E-mail(s)

microarray@niehs.nih.gov, liuliw@niehs.nih.gov