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Complex modulation of androgen responsive gene expression by methoxyacetic acid

BACKGROUND: Optimal androgen signaling is critical for testicular development and spermatogenesis. Methoxyacetic acid (MAA), the primary active metabolite of the industrial chemical ethylene glycol monomethyl ether, disrupts spermatogenesis and causes testicular atrophy. Transcriptional trans-activa...

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Detalles Bibliográficos
Autores principales: Bagchi, Gargi, Zhang, Yijing, Stanley, Kerri A, Waxman, David J
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083340/
https://www.ncbi.nlm.nih.gov/pubmed/21453523
http://dx.doi.org/10.1186/1477-7827-9-42
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author Bagchi, Gargi
Zhang, Yijing
Stanley, Kerri A
Waxman, David J
author_facet Bagchi, Gargi
Zhang, Yijing
Stanley, Kerri A
Waxman, David J
author_sort Bagchi, Gargi
collection PubMed
description BACKGROUND: Optimal androgen signaling is critical for testicular development and spermatogenesis. Methoxyacetic acid (MAA), the primary active metabolite of the industrial chemical ethylene glycol monomethyl ether, disrupts spermatogenesis and causes testicular atrophy. Transcriptional trans-activation studies have indicated that MAA can enhance androgen receptor activity, however, whether MAA actually impacts the expression of androgen-responsive genes in vivo, and which genes might be affected is not known. METHODS: A mouse TM3 Leydig cell line that stably expresses androgen receptor (TM3-AR) was prepared and analyzed by transcriptional profiling to identify target gene interactions between MAA and testosterone on a global scale. RESULTS: MAA is shown to have widespread effects on androgen-responsive genes, affecting processes ranging from apoptosis to ion transport, cell adhesion, phosphorylation and transcription, with MAA able to enhance, as well as antagonize, androgenic responses. Moreover, testosterone is shown to exert both positive and negative effects on MAA gene responses. Motif analysis indicated that binding sites for FOX, HOX, LEF/TCF, STAT5 and MEF2 family transcription factors are among the most highly enriched in genes regulated by testosterone and MAA. Notably, 65 FOXO targets were repressed by testosterone or showed repression enhanced by MAA with testosterone; these include 16 genes associated with developmental processes, six of which are Hox genes. CONCLUSIONS: These findings highlight the complex interactions between testosterone and MAA, and provide insight into the effects of MAA exposure on androgen-dependent processes in a Leydig cell model.
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spelling pubmed-30833402011-04-28 Complex modulation of androgen responsive gene expression by methoxyacetic acid Bagchi, Gargi Zhang, Yijing Stanley, Kerri A Waxman, David J Reprod Biol Endocrinol Research BACKGROUND: Optimal androgen signaling is critical for testicular development and spermatogenesis. Methoxyacetic acid (MAA), the primary active metabolite of the industrial chemical ethylene glycol monomethyl ether, disrupts spermatogenesis and causes testicular atrophy. Transcriptional trans-activation studies have indicated that MAA can enhance androgen receptor activity, however, whether MAA actually impacts the expression of androgen-responsive genes in vivo, and which genes might be affected is not known. METHODS: A mouse TM3 Leydig cell line that stably expresses androgen receptor (TM3-AR) was prepared and analyzed by transcriptional profiling to identify target gene interactions between MAA and testosterone on a global scale. RESULTS: MAA is shown to have widespread effects on androgen-responsive genes, affecting processes ranging from apoptosis to ion transport, cell adhesion, phosphorylation and transcription, with MAA able to enhance, as well as antagonize, androgenic responses. Moreover, testosterone is shown to exert both positive and negative effects on MAA gene responses. Motif analysis indicated that binding sites for FOX, HOX, LEF/TCF, STAT5 and MEF2 family transcription factors are among the most highly enriched in genes regulated by testosterone and MAA. Notably, 65 FOXO targets were repressed by testosterone or showed repression enhanced by MAA with testosterone; these include 16 genes associated with developmental processes, six of which are Hox genes. CONCLUSIONS: These findings highlight the complex interactions between testosterone and MAA, and provide insight into the effects of MAA exposure on androgen-dependent processes in a Leydig cell model. BioMed Central 2011-03-31 /pmc/articles/PMC3083340/ /pubmed/21453523 http://dx.doi.org/10.1186/1477-7827-9-42 Text en Copyright ©2011 Bagchi et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Bagchi, Gargi
Zhang, Yijing
Stanley, Kerri A
Waxman, David J
Complex modulation of androgen responsive gene expression by methoxyacetic acid
title Complex modulation of androgen responsive gene expression by methoxyacetic acid
title_full Complex modulation of androgen responsive gene expression by methoxyacetic acid
title_fullStr Complex modulation of androgen responsive gene expression by methoxyacetic acid
title_full_unstemmed Complex modulation of androgen responsive gene expression by methoxyacetic acid
title_short Complex modulation of androgen responsive gene expression by methoxyacetic acid
title_sort complex modulation of androgen responsive gene expression by methoxyacetic acid
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083340/
https://www.ncbi.nlm.nih.gov/pubmed/21453523
http://dx.doi.org/10.1186/1477-7827-9-42
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