Ethylene Glycol Monomethyl Ether–Induced Toxicity Is Mediated through the Inhibition of Flavoprotein Dehydrogenase Enzyme Family
Open Access
- 8 July 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 118 (2), 643-652
- https://doi.org/10.1093/toxsci/kfq211
Abstract
Ethylene glycol monomethyl ether (EGME) is a widely used industrial solvent known to cause adverse effects to human and other mammals. Organs with high metabolism and rapid cell division, such as testes, are especially sensitive to its actions. In order to gain mechanistic understanding of EGME-induced toxicity, an untargeted metabolomic analysis was performed in rats. Male rats were administrated with EGME at 30 and 100 mg/kg/day. At days 1, 4, and 14, serum, urine, liver, and testes were collected for analysis. Testicular injury was observed at day 14 of the 100 mg/kg/day group only. Nearly 1900 metabolites across the four matrices were profiled using liquid chromatography-mass spectrometry/mass spectrometry and gas chromatography-mass spectrometry. Statistical analysis indicated that the most significant metabolic perturbations initiated from the early time points by EGME were the inhibition of choline oxidation, branched-chain amino acid catabolism, and fatty acid β-oxidation pathways, leading to the accumulation of sarcosine, dimethylglycine, and various carnitine- and glycine-conjugated metabolites. Pathway mapping of these altered metabolites revealed that all the disrupted steps were catalyzed by enzymes in the primary flavoprotein dehydrogenase family, suggesting that inhibition of flavoprotein dehydrogenase–catalyzed reactions may represent the mode of action for EGME-induced toxicity. Similar urinary and serum metabolite signatures are known to be the hallmarks of multiple acyl-coenzyme A dehydrogenase deficiency in humans, a genetic disorder because of defects in primary flavoprotein dehydrogenase reactions. We postulate that disruption of key biochemical pathways utilizing flavoprotein dehydrogenases in conjugation with downstream metabolic perturbations collectively result in the EGME-induced tissue damage.Keywords
This publication has 53 references indexed in Scilit:
- SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylationNature, 2010
- Metabolomic profiles delineate potential role for sarcosine in prostate cancer progressionNature, 2009
- Short-chain acyl-coenzyme A dehydrogenase deficiencyMolecular Genetics and Metabolism, 2008
- Methoxyacetic Acid-Induced Spermatocyte Death Is Associated with Histone Hyperacetylation in Rats1Biology of Reproduction, 2008
- Toxicity of ethylene glycol monomethyl ether: impact on testicular gene expressionInternational Journal of Andrology, 2007
- Choline: Critical Role During Fetal Development and Dietary Requirements in AdultsAnnual Review of Nutrition, 2006
- Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneitySeminars in Medical Genetics, Part C of the American Journal of Medical Genetics, 2006
- International industry initiatives to improve the glycol ether health effects knowledge baseToxicology Letters, 2005
- Methoxyacetic Acid Disregulation of Androgen Receptor and Androgen-Binding Protein Expression in Adult Rat Testis1Biology of Reproduction, 2003
- Clinical and biochemical characterization of short-chain acyl-coenzyme A dehydrogenase deficiencyThe Journal of Pediatrics, 1995