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Analysis of 17?-estradiol (E2) role in the regulation of corpus luteum function in pregnant rats: Involvement of IGFBP5 in the E2-mediated actions.

ABSTRACT: In several species, considerably higher levels of estradiol-17 (E2) are synthesized in the CL. E2 has been suggested to participate in the regulation of luteal steroidogenesis and luteal cell morphology. In pregnant rats, several experiments have been carried out to examine the effects of inhibition of luteal E2 synthesis on CL structure and function.During days 12-15 of pregnancy in rats, luteal E2 was inhibited by way of daily oral administration of anastrozole (AI), a selective non-steroidal aromatase inhibitor, and experiments were also performed with E2 replacement i.e. AI+ E2 treatments. Luteal tissues from different treatment groups were subjected to microarray analysis and the differentially expressed genes in E2 treated group were further examined for expression of specific E2 responsive genes. Additional experiments were carried out employing recombinant growth hormone preparation and flutamide, an androgen receptor antagonist, to further address the specificity of E2 effects on the luteal tissue.Microarray analysis of CL collected on day 16 of pregnancy post AI and AI+E2 treatments showed significantly lowered cyp19a1 expression, E2 levels and differential expression of a number of genes, and several of them were reversed in E2 replacement studies. From the differentially expressed genes, a number of E2 responsive genes were identified. In CL of AI pregnant rats, non-significant increase in expression of igf1, significant increase in igbp5, igf1r and decrease in expression of Er? were observed. In liver of AI treated rats, igf1 expression did not increase, but GH treatment significantly increased expression that was further increased with AI treatment. In CL of GH and AI+GH treated rats, expression of igfbp5 was higher. Administration of flutamide during days 12-15 of pregnancy resulted in non-significant increase in igfbp5 expression, however, combination of flutamide+AI treatments caused increased protein expression. Expression of few of the molecules in PI3K/Akt kinase pathway in different treatments was determined.The results suggest a role for E2 in the regulation of luteal steroidogenesis, morphology and proliferation. igfbp5 was identified as one the E2 responsive genes with important role in the mediation of E2 actions such as E2-induced phosphorylation of PI3K/Akt kinase pathway.

SUBMITTER: Tripathy S

PROVIDER: S-EPMC4830059 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Analysis of 17β-estradiol (E2) role in the regulation of corpus luteum function in pregnant rats: Involvement of IGFBP5 in the E2-mediated actions.

Tripathy Sudeshna S Asaithambi Killivalavan K Jayaram P P Medhamurthy R R

Reproductive biology and endocrinology : RB&E 20160412

<h4>Background</h4>In several species, considerably higher levels of estradiol-17 (E2) are synthesized in the CL. E2 has been suggested to participate in the regulation of luteal steroidogenesis and luteal cell morphology. In pregnant rats, several experiments have been carried out to examine the effects of inhibition of luteal E2 synthesis on CL structure and function.<h4>Methods</h4>During days 12-15 of pregnancy in rats, luteal E2 was inhibited by way of daily oral administration of anastrozo ...[more]

PMID: 27072650

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Project description:Corpus luteum (CL) is a transient endocrine tissue formed from the remnants of the ovarian follicle after ovulation. In response to gonadotropin surge, the ovulating follicle undergoes dramatic changes in expression of genes and differentiation of follicular cells into luteal cells. In several species, of the several genes that are down- regulated post ovulation, Cyp19A1 that codes for aromatase, essential for biosynthesis of estradiol- 17M-NM-2 (E2), also get down- regulated but appears to get up- regulated at later time points in the estrous cycle to have critical role in E2 secretion. In primates and rodents, higher expression and higher E2 levels has been observed in CL. Surprisingly, in the recently carried out gene expression profiling of PGF2M-NM-1- induced luteolysis studies in the bovine species [GSE27961], it was observed that expression of one of the earliest genes that was down- regulated was Cyp19A1 in the CL. However, the specific role of E2 in the regulation of CL function remains poorly defined. Thus, in the present study, efforts were made to examine the temporal changes in the global gene expression profile in the CL of pregnant rats after treatment with aromatase inhibitor (AI), Anastrozole, and E2 supplementation. The results obtained will further expand our knowledge on E2 target/responsive genes and the basic mechanism(s) that regulates the CL function. Key words: CL, E2, AI, Gene expression The objective of this study was to identify the effect of E2 deprivation and supplementation on CL function and temporal changes in the transcriptome of pregnant rat CL during day 12 to 16 of pregnancy following E2 deprivation by Anastrozole (AI, Aromatase inhibitor) treatment in pregnant rats, AI (1mg/ kg bw orally) treatment beginning on day 12 daily for 4 days. In the E2 supplementation experiments, together with AI, the rats were treated with E2 (10M-BM-5g/ day s.c.). CL tissues were collected on day 12 (no treatment; n=3 animals/ time point), day 16 (vehicle treatment; n=3 animals/ time point), day 16 (AI treatment; n=3 animals/ time point) and day 16 (AI+ E2 treatment; n=3 animals/ time point) to examine gene expression changes associated with E2 deprivation and recovery in the system. Following retrieval of CL from the ovary, corpora lutea were flash frozen in liquid nitrogen and stored at -70oC for the purpose of RNA isolation. The isolated RNA was labelled and hybridized to Affymetrix GeneChipM-BM-. Rat Gene 1.0 ST arrays as per the manufacturerM-bM-^@M-^Ys instructions.

Project description:Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.

Dataset Information

Analysis of 17?-estradiol (E2) role in the regulation of corpus luteum function in pregnant rats: Involvement of IGFBP5 in the E2-mediated actions.

Publications

Analysis of 17β-estradiol (E2) role in the regulation of corpus luteum function in pregnant rats: Involvement of IGFBP5 in the E2-mediated actions.

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