Complex modulation of androgen responsive gene expression by methoxyacetic acid
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RESEARCH
Open Access
Complex modulation of androgen responsive gene expression by methoxyacetic acid Gargi Bagchi†, Yijing Zhang†, Kerri A Stanley and David J Waxman*
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.
Background Androgen signaling is critical for development of the male sexual phenotype, maturation of secondary sex characteristics and maintenance of muscle mass and bone density [1]. Disruption of androgen signaling can lead to a spectrum of developmental problems in male sexual characteristics and reproductive behavior [2]. Androgen action is mediated by androgen binding to androgen receptor (AR), a ligand-activated transcription factor that binds genomic regulatory elements associated with androgen responsive genes [3]. AR binding sites are often far (>10 kb) from transcription start sites of androgen-regulated genes, and many AR binding sites contain non-canonical androgen response elements [4-6]. Many transcription factors interact with AR, * Correspondence: [email protected] † Contributed equally Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
including GATA factors [7], STAT5 [8], NF1 and SP1 [9], which can increase AR transcriptional activity, as well as Forkhead proteins [10-12], P53 [13] and LEF/ TCF factors [14], which are reported to exert both repression and enhancement of AR transcriptional activity. Some of
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