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Title: Interactions of methoxyacetic acid with androgen receptor

Abstract

Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC{sub 50} for androgen responsiveness, partially alleviating the antagonistic effect of the anti-androgens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by {approx} 90%. Deregulation of these genes may altermore » androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.« less

Authors:
;  [1]
  1. Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215 (United States)
Publication Date:
OSTI Identifier:
21272597
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 238; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2008.03.015; PII: S0041-008X(08)00144-0; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANDROGENS; DEREGULATION; ETHERS; GENES; GLYCOLS; INTERACTIONS; MICE; RECEPTORS; SPERMATOCYTES; TESTES; TOXICITY; TYROSINE

Citation Formats

Bagchi, Gargi, Hurst, Christopher H, and Waxman, David J. Interactions of methoxyacetic acid with androgen receptor. United States: N. p., 2009. Web. doi:10.1016/j.taap.2008.03.015.
Bagchi, Gargi, Hurst, Christopher H, & Waxman, David J. Interactions of methoxyacetic acid with androgen receptor. United States. https://doi.org/10.1016/j.taap.2008.03.015
Bagchi, Gargi, Hurst, Christopher H, and Waxman, David J. 2009. "Interactions of methoxyacetic acid with androgen receptor". United States. https://doi.org/10.1016/j.taap.2008.03.015.
@article{osti_21272597,
title = {Interactions of methoxyacetic acid with androgen receptor},
author = {Bagchi, Gargi and Hurst, Christopher H and Waxman, David J.},
abstractNote = {Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC{sub 50} for androgen responsiveness, partially alleviating the antagonistic effect of the anti-androgens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by {approx} 90%. Deregulation of these genes may alter androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.},
doi = {10.1016/j.taap.2008.03.015},
url = {https://www.osti.gov/biblio/21272597}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 238,
place = {United States},
year = {Wed Jul 15 00:00:00 EDT 2009},
month = {Wed Jul 15 00:00:00 EDT 2009}
}