Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of rat testis by transplacental exposure to estrogen receptor (ER) agonists - high and low doses of 17a-Ethynyl estradiol, genistein or bisphenol A

ABSTRACT: The purpose of this study was to determine 1) the transcriptional program elicited by exposure to three estrogen receptor (ER) agonists: 17 a-ethynyl estradiol (EE), genistein (Ges) and bisphenol A (BPA) during fetal development of the rat testis and epididymis; and 2) whether very low dosages of estrogens (evaluated over five orders of magnitude of dosage) produce unexpected changes in gene expression (i.e., a non-monotonic dose-response curve). In three independently conducted experiments, Sprague-Dawley rats were dosed (s.c.) with 0.001-10mg EE/kg/day, 0.001-100 mg Ges/kg/day or 0.002-400mg BPA/kg/day. While morphological changes in the developing reproductive system were not observed, the gene expression profile of target tissues were modified in a dose-responsive manner. Independent dose-response analyses of the three studies identified 56 genes that are significantly modified by EE, 28 genes by Ges and 15 genes by BPA (out of 8740). Even more genes were observed to be significantly changed when only the high dose is compared with all lower doses: 141, 46 and 67 genes, respectively. Global analyses aimed at detecting genes consistently modified by all of the chemicals identified 52 genes whose expression changed in the same direction across the three chemicals. The dose-response curve for gene expression changes was monotonic for each chemical, with both the number of genes significantly changed and the magnitude of change, for each gene, decreasing with decreasing dose. Using the available annotation of the gene expression changes induced by ER-agonist, our data suggest that a variety of cellular pathways are affected by estrogen exposure. These results indicate that gene expression data are diagnostic of mode of action and, if they are evaluated in the context of traditional toxicological end-points, can be used to elucidate dose-response characteristics.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Gary Overmann

PROVIDER: E-TABM-12 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene expression changes induced in the testis by transplacental exposure to high and low doses of 17{alpha}-ethynyl estradiol, genistein, or bisphenol A.

Naciff Jorge M JM Hess Karla A KA Overmann Gary J GJ Torontali Suzanne M SM Carr Gregory J GJ Tiesman Jay P JP Foertsch Leslie M LM Richardson Brian D BD Martinez Joel E JE Daston George P GP

Toxicological sciences : an official journal of the Society of Toxicology 20050518 2

The purpose of this study was to determine (1) the transcriptional program elicited by exposure to three estrogen receptor (ER) agonists: 17 alpha-ethynyl estradiol (EE), genistein (Ges), and bisphenol A (BPA) during fetal development of the rat testis and epididymis; and (2) whether very low dosages of estrogens (evaluated over five orders of magnitude of dosage) produce unexpected changes in gene expression (i.e., a non-monotonic dose-response curve). In three independently conducted experimen ...[more]

PMID: 15901920

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Project description:Genomic, proteomic, and metabolomic technologies continue to receive increasing interest from environmental toxicologists. This interest is due to the great potential of these technologies to identify detailed modes of action and to provide assistance in the evaluation of a contaminant?s risk to aquatic organisms. Our experimental model is the zebrafish (Danio rerio) exposed to reference endocrine disrupting compounds in order to investigate compound-induced changes in gene transcript profiles. Adult, female zebrafish were exposed to 0, 15, 40, and 100 ng/L of 17 alpha-ethynylestradiol (EE2) and concentration and time-dependent changes in hepatic gene expression were examined using Affymetrix GeneChip® Zebrafish Genome Microarrays. At 24, 48, and 168 hours, fish were sacrificed and liver mRNA was extracted for gene expression analysis (24 and 168 hours only). In an effort to link gene expression changes to effects on higher levels of biological organization, body and ovary weights were measured and blood was collected for measurement of plasma steroid hormones (17 beta-estradiol (E2), testosterone (T)) and vitellogenin (VTG) using ELISA. EE2 exposure significantly affected GSI, E2, T, VTG and gene expression. We observed 1575 genes that were significantly affected (up- or down-regulated by at least 1.5-fold (p ? 0.001) in a concentration-dependent manner by EE2 exposure at either 24 or 168 hours. EE2 exposure altered transcription of genes involved in steroid hormone homeostasis, cholesterol homeostasis, retinoic acid metabolism, and cell growth and proliferation. Plasma VTG was significantly increased at 24, 48, and 168 hours (p<0.05) at 40 and 100 ng/L and at 15 ng/L at 168 hours. E2 and T were significantly reduced following EE2 exposure at 48 and 168 hours. GSI was decreased in a dose-dependent manner at 168 hours. In this study, we identified genes involved in a variety of biological functions that have the potential to be used as markers of exposure to estrogenic substances. Future work will evaluate the use of these genes in zebrafish exposed to weak estrogens to determine if these genes are indicative of exposure to estrogens with varying potencies.

Dataset Information

Transcription profiling of rat testis by transplacental exposure to estrogen receptor (ER) agonists - high and low doses of 17a-Ethynyl estradiol, genistein or bisphenol A

Publications

Gene expression changes induced in the testis by transplacental exposure to high and low doses of 17{alpha}-ethynyl estradiol, genistein, or bisphenol A.

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