Abstract
BackgroundMethoxyacetic acid (MAA) is the active metabolite of the widely used industrial chemical ethylene glycol monomethyl ether, which is associated with various developmental and reproductive toxicities, including neural toxicity, blood and immune disorders, limb degeneration and testicular toxicity. Testicular toxicity is caused by degeneration of germ cells in association with changes in gene expression in both germ cells and Sertoli cells of the testis. This study investigates the impact of MAA on gene expression in testicular Leydig cells, which play a critical role in germ cell survival and male reproductive function.MethodsCultured mouse TM3 Leydig cells were treated with MAA for 3, 8, and 24 h and changes in gene expression were monitored by genome-wide transcriptional profiling.ResultsA total of 3,912 MAA-responsive genes were identified. Ingenuity Pathway analysis identified reproductive system disease, inflammatory disease and connective tissue disorder as the top biological functions affected by MAA. The MAA-responsive genes were classified into 1,366 early responders, 1,387 mid-responders, and 1,138 late responders, based on the time required for MAA to elicit a response. Analysis of enriched functional clusters for each subgroup identified 106 MAA early response genes involved in transcription regulation, including 32 genes associated with developmental processes. 60 DNA-binding proteins responded to MAA rapidly but transiently, and may contribute to the downstream effects of MAA seen for many mid and late response genes. Genes within the phosphatidylinositol/phospholipase C/calcium signaling pathway, whose activity is required for potentiation of nuclear receptor signaling by MAA, were also enriched in the set of early MAA response genes. In contrast, many of the genes responding to MAA at later time points encode membrane proteins that contribute to cell adhesion and membrane signaling.ConclusionsThese findings on the progressive changes in gene expression induced by MAA in a cultured Leydig cell model may help elucidate signaling pathways that lead to the testicular pathophysiological responses induced by MAA exposure and may identify useful biomarkers of MAA toxicity.
Highlights
Methoxyacetic acid (MAA) is the active metabolite of the widely used industrial chemical ethylene glycol monomethyl ether, which is associated with various developmental and reproductive toxicities, including neural toxicity, blood and immune disorders, limb degeneration and testicular toxicity
These findings on the progressive changes in gene expression induced by MAA in a cultured Leydig cell model may help elucidate signaling pathways that lead to the testicular pathophysiological responses induced by MAA exposure and may identify useful biomarkers of MAA toxicity
MAA did not cause any changes in TM3 cell viability over the course of at least 48 hr; we observed extensive changes in TM3 cell gene expression. 3,912 genes were altered in their expression by 5 mM MAA, the plasma MAA concentration associated with germ cell toxicity in mice [10]; 1,168 of these genes responded in 3 h MAA
Summary
Methoxyacetic acid (MAA) is the active metabolite of the widely used industrial chemical ethylene glycol monomethyl ether, which is associated with various developmental and reproductive toxicities, including neural toxicity, blood and immune disorders, limb degeneration and testicular toxicity. MAA was found to alter the expression of TM3 cell genes involved in testosterone biosynthesis (Cyp17a1) and androgen binding (Shbg) [9] We use this same Leydig cell model to characterize the sequential changes in gene expression that occur following MAA exposure. The early MAA-responsive genes include 106 genes involved in transcriptional regulation, whereas many of the genes responding to MAA at later time points encode membrane proteins that contribute to cell adhesion and membrane signaling These MAA-induced perturbations of cellular and biological functions may help elucidate the signaling pathways perturbed by this environmental toxicant and explain its mechanism of action at the gene level
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