Ethylene glycol monomethyl ether-induced toxicity is mediated through the inhibition of flavoprotein dehydrogenase enzyme family.
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.
Takei
Makoto
M
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co., Ltd, Shinagawa-ku, Tokyo 140-8710, Japan.
Ando
Yosuke
Y
Saitoh
Wataru
W
Tanimoto
Tomoe
T
Kiyosawa
Naoki
N
Manabe
Sunao
S
Sanbuissho
Atsushi
A
Okazaki
Osamu
O
Iwabuchi
Haruo
H
Yamoto
Takashi
T
Adam
Klaus-Peter
KP
Weiel
James E
JE
Ryals
John A
JA
Milburn
Michael V
MV
Guo
Lining
L
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
D044927:Electron-Transferring Flavoproteins; D004791:Enzyme Inhibitors; D005026:Ethylene Glycols; C005219:methyl cellosolve