Abstract
BackgroundOptimal 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.MethodsA 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.ResultsMAA 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.ConclusionsThese 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.
Highlights
Optimal androgen signaling is critical for testicular development and spermatogenesis
The androgen responsiveness of TM3-androgen receptor (AR) cells was confirmed by the ~5-fold increase in expression of Rhox5 (Pem) and by the ~10 fold decrease in expression of Igfbp3 following testosterone treatment; neither gene showed a significant response to testosterone in TM3 cells, but the repression of Igfbp3 by Methoxyacetic acid (MAA) [22] was evident in both cell lines (Figure 1B)
This study investigated on a genome-wide basis the impact of MAA on AR activity in a cultured Leydig cell model
Summary
Optimal androgen signaling is critical for testicular development and spermatogenesis. Many transcription factors interact with AR, including GATA factors [7], STAT5 [8], NF1 and SP1 [9], which can increase AR transcriptional activity, as well as Forkhead proteins [10,11,12], P53 [13] and LEF/ TCF factors [14], which are reported to exert both repression and enhancement of AR transcriptional activity Some of these effects may involve local interactions, as binding sites for GATA and Forkhead, as well as OCT family factors are often enriched nearby AR binding sites [4,5,6]. These findings suggest that physiological or pathophysiological conditions that affect the expression or activity of AR-interacting transcription factors such as these may impact AR activity
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