Complex modulation of androgen responsive gene expression by methoxyacetic acid

Department of Biology, Boston University, Boston, MA 02215, USA.
Reproductive Biology and Endocrinology (Impact Factor: 2.23). 03/2011; 9(1):42. DOI: 10.1186/1477-7827-9-42
Source: PubMed


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.
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.
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.
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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    • "Although 2-MAA is a well-established teratogen, its molecular mechanism of action is unclear. Disturbances in folate-dependent one-carbon transfer reactions (Welsch et al., 1987), chondrogenesis (Scofield et al., 2006), and apoptosis (Bagchi et al., 2011) have all been implicated in the teratogenicity induced by 2-MAA. An additional possibility is that the teratogenicity of 2-MAA is mediated by disturbances in acetylation programming. "
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    • "Spermatogenesis requires normal functions of AR [10] [11], ERα [12], and ERβ [13] and their disruption leads to testicular degradation after MAA exposure. In addition, MAA has been found to activate the tyrosine kinase – PI3K pathway and other pathways to enhance or antagonize androgen-induced gene expression [14] [15] [16]. Similarly, MAA can enhance the transcriptional activities of ERα and ERβ by activating MAPK and inhibiting histone deacetylases (HDACs) [17]. "
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    • "For example, exposure to high levels of genistein or fungicides, which may act as xenosteroids, are associated with a higher incidence of hypospadias in men. Methoxyacetic acid, the primary active metabolite of the industrial chemical ethylene glycol monomethyl ether, disrupts spermatogenesis, and causes testicular atrophy was shown to affect androgen sensitive HOX genes (Bagchi et al., 2011). "
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