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 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 frizzledrelated 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.

Impact of environmental endocrine disrupting chemicals on the development of obesity

“…However, genes involved in fat distribution were altered; Thbd and Nr2f1 were significantly down-regulated and Sfrp2 was significantly up-regulated in DES-treated uteri compared to controls. 56 These findings support the idea that environmental estrogens may play a role in regulating the expression of obesity-related genes in development. The identification of genes and molecular mechanisms that may be associated with EDCs and obesity is an exciting area of new research.…”

Lactotransferrin: A candidate tumor suppressor—Deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen‐activated protein kinase pathway

“…27 Recently, LTF has been found to have antitumor activity to regulate tumorigenesis. [28][29][30] Our previous studies and those of others have shown that the NPC susceptibility locus was mapped to a 13.6-cM region of chromosome 3p21.31-21.2, a site of frequent loss of heterozygosity in NPC. 2,[31][32][33][34][35][36] In our study, we characterized the expression profiles of 288 cDNA clones from chromosome 3p21 using a custom-made cDNA microarray of 22 human NPC and 10 nontumor nasopharyngeal epithelial tissues.…”

Adverse Effects on Female Human Reproductive Health from Exposure to Endocrine Disruptors: Focus on Endometrial Lesions

“…Four altered genes (lactotransferrin, transforming growth factor beta inducible, cyclin D1, and secreted frizzled-related protein 4), 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 weeks after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis [70]. Higher circulating 17β-estradiol levels and non-classical signaling may be related to the earlier incidence of uterine cancer in transgenic mice.…”