title: Ethylene glycol monomethyl ether-induced toxicity is mediated through the inhibition of flavoprotein dehydrogenase enzyme family.
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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ando
authors.forename: Wataru
authors.initials: W
authors.lastname: Saitoh
authors.forename: Tomoe
authors.initials: T
authors.lastname: Tanimoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Kiyosawa
authors.forename: Sunao
authors.initials: S
authors.lastname: Manabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
authors.forename: Haruo
authors.initials: H
authors.lastname: Iwabuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamoto
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Adam
authors.forename: James E
authors.initials: JE
authors.lastname: Weiel
authors.forename: John A
authors.initials: JA
authors.lastname: Ryals
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Lining
authors.initials: L
authors.lastname: Guo
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D044927:Electron-Transferring Flavoproteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects / Q000473:pathology; D005026:Ethylene Glycols / Q000378:metabolism / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D055432:Metabolomics; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013076:Sperm Count; D013094:Spermatozoa / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D044927:Electron-Transferring Flavoproteins; D004791:Enzyme Inhibitors; D005026:Ethylene Glycols; C005219:methyl cellosolve