Complex Modulation of Androgen Responsive Gene Expression by Methoxyacetic Acid

Overview

Journal Reprod Biol Endocrinol

Publisher Biomed Central

Specialties Endocrinology
Reproductive Medicine

Date 2011 Apr 2

PMID 21453523

Citations 6

Authors

Gargi Bagchi

Yijing Zhang

Kerri A Stanley

David J Waxman

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Ca/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy.

Duran J, Lagos D, Pavez M, Troncoso M, Ramos S, Barrientos G Front Pharmacol. 2017; 8:604.

PMID: 28955223 PMC: 5601904. DOI: 10.3389/fphar.2017.00604.

Effects of the IGF-1/PTEN/Akt/FoxO signaling pathway on male reproduction in rats subjected to water immersion and restraint stress.

Huang P, Zhou Z, Shi F, Shao G, Wang R, Wang J Mol Med Rep. 2016; 14(6):5116-5124.

PMID: 27779666 PMC: 5355674. DOI: 10.3892/mmr.2016.5880.

Aminomethylphosphonic acid and methoxyacetic acid induce apoptosis in prostate cancer cells.

Parajuli K, Zhang Q, Liu S, You Z Int J Mol Sci. 2015; 16(5):11750-65.

PMID: 26006246 PMC: 4463728. DOI: 10.3390/ijms160511750.

Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis.

Parajuli K, Zhang Q, Liu S, Patel N, Lu H, Zeng S Am J Clin Exp Urol. 2015; 2(4):300-12.

PMID: 25606576 PMC: 4297326.

Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro.

Dayan C, Hales B Birth Defects Res B Dev Reprod Toxicol. 2014; 101(3):254-61.

PMID: 24798094 PMC: 4227605. DOI: 10.1002/bdrb.21108.

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