Toxicity of ethylene glycol monomethyl ether: impact on testicular gene expression

Methoxyacetic acid (MAA), the active biological oxidation product of the industrial solvent ethylene glycol monomethyl ether (EGME), causes acute toxicity in several species including humans. MAA primarily affects tissues with rapidly dividing cells and high rates of energy metabolism, including testes, thymus and the fetus. Testicular toxicity, one of the most prominent consequences of EGME, and MAA, exposure, results from apoptosis of primary spermatocytes and is associated with changes in the expression of various genes and signalling pathways. This review of EGME metabolism and its organ-specific toxicities emphasizes genes and signalling pathways that are modulated by EGME exposure and their relevance to the molecular mechanisms underlying EGME and MAA toxicity. Of particular importance are the genes that code for oxidative stress response factors, protein kinases, and nuclear hormone receptors. Nuclear receptors and protein kinases regulate multiple cellular processes and are critical for signalling events required for spermatogenesis. De-regulation of their activity by EGME or MAA leads to inappropriate signalling in testicular cells. Oxidative stress in spermatocytes exposed to MAA triggers mitochondrial release of cytochrome C, activation of caspases and ultimately apoptosis. Detailed investigation of the molecular responses to MAA exposure may help elucidate the overall impact and extent of toxicity seen following EGME exposure. Finally, given the effects of EGME on multiple genes and signalling pathways in the testis, mixture studies combining EGME, or MAA, with other testicular toxicants may help identify toxicities that are aggravated by EGME exposure.