Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life.
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.
Newbold
Retha R
RR
Developmental Endocrinology and Endocrine Disruptor Section, Laboratory of Molecular Toxicology, NIEHS, Research Triangle Park, North Carolina 27709, USA.
Jefferson
Wendy N
WN
Grissom
Sherry F
SF
Padilla-Banks
Elizabeth
E
Snyder
Ryan J
RJ
Lobenhofer
Edward K
EK
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D004054:Diethylstilbestrol / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013997:Time Factors; D014594:Uterine Neoplasms / Q000139:chemically induced / Q000235:genetics*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D004958:Estradiol; D004054:Diethylstilbestrol