Identification of temporal patterns of gene expression in the uteri of immature, ovariectomized mice following exposure to ethynylestradiol

Abstract

Estrogen induction of uterine wet weight provides an excellent model to investigate relationships between changes in global gene expression and well-characterized physiological responses. In this study, time course microarray GeneChip data were analyzed using a novel approach to identify temporal changes in uterine gene expression following treatment of immature ovariectomized C57BL/6 mice with 0.1 mg/kg 17alpha-ethynylestradiol. Functional gene annotation information from public databases facilitated the association of changes in gene expression with physiological outcomes, which allowed detailed mechanistic inferences to be drawn regarding cell cycle control and proliferation, transcription and translation, structural tissue remodeling, and immunologic responses. These systematic approaches confirm previously established responses, identify novel estrogen-regulated transcriptional effects, and disclose the coordinated activation of multiple modes of action that support the uterotrophic response elicited by estrogen. In particular, it was possible to elucidate the physiological significance of the dramatic induction of arginase, a classic estrogenic response, by elucidating its mechanistic relevance and delineating the role of arginine and ornithine utilization in the estrogen-stimulated induction of uterine wet weight.

Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

“…A conservative statistical P1(t) cutoff of 0.9999 combined with a differential expression of Ϯ1.5 fold relative to TMVCs was used to identify lists of differentially active genes. Gene expression responses to EE alone displayed the expected complex transcriptional profile as reported previously (Fertuck et al, 2003;Kwekel et al, 2005) with a total of 3,746 features, representing 2,753 unique genes, identified as differentially 3. EE, TCDD, and EE ϩ TCDD effects on temporal uterine weights.…”

“…Functional annotation of gene expression responses was performed using data extracted from public databases and published literature. The functions of EE differentially expressed genes have been associated with transcription factors, mRNA and protein synthesis, cell cycle regulation, cellular proliferation, energetics and structural constituents (Fertuck et al, 2003;Moggs et al, 2004;Kwekel et al, 2005). Functional annotation of EE-mediated gene expression responses that were inhibited upon cotreatment with TCDD were associated with the regulation of cell proliferation and growth, water/ion E4 M4 E12 M12 T12 E24 M24 E72 M72 T24 T72 T4 EE EE+TCDD TCDD E4 E12 E24 E72 M4 M12 M24 M72 T4 T12 T24 T72 A B…”

“…Estrogen induction of uterine weight involves a coordinated proliferative response that is mediated through a well orchestrated series of changes in gene expression (Fertuck et al, 2003;Moggs et al, 2004;Kwekel et al, 2005). Cotreatment with TCDD disrupted several EE-induced A, scatter plots of the log 2 expression ratios of EE versus EE ϩ TCDD at the 12-h time point revealed that the majority of the responses were of the same magnitude relative to the TMVCs with a correlation of 0.95.…”

The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol

“…However, there is another compelling alternate explanation. Using gene screen technology, Fertuck et al [22] have recently shown that 17β-estradiol induces arginase I (AGI), an enzyme that utilizes arginine to produce ornithine, the first step in polyamine production. Since polyamines are well known to have critical roles in cell physiology, including enhancement of transcription factor binding and coactivator function, modulation of polyamines is a likely outcome of estrogen's action on cells.…”

Dioxin Induces an Estrogen-Like, Estrogen Receptor-Dependent Gene Expression Response in the Murine Uterus

“…To independently examine the estrogen-like gene expression responses of TCDD, six genes were chosen for verification by QRTPCR. Arginine-rich, mutated in early stage tumors (Armet), asparagine synthetase (Asns), activating transcription factor 4 (Atf4), expressed in nonmetastatic cells 1 (Nme1), proliferating cell nuclear antigen (Pcna), and solute carrier family 25 member 5 (Slc25a5) were specifically selected because they displayed similar responses to EE and TCDD and have been previously identified as estrogen inducible in the rodent uterus in independent studies (Watanabe Fertuck et al, 2003;Moggs et al, 2004b;Kwekel et al, 2005). QRTPCR analyses confirmed the microarray results indicating these genes were induced by both EE and TCDD (Fig.…”