Integrated NMR-based metabonomic investigation of early metabolic effects of ethylene glycol monomethyl ether (EGME) on male reproductive organs in rats.
High-resolution Magic Angle Spinning (Hr-MAS) (1)H-NMR spectroscopy was used to analyze intact testicular tissues ex vivo and to investigate the toxicological effects of ethylene glycol monomethyl ether (EGME), a well-known spermatocytes toxicant, on male reproductive organs by NMR-based metabonomic analysis. Especially, we reported the first Hr-MAS (1)H-NMR spectra of epididymis. Sexually matured male rats were treated with 50 and 2,000 mg/kg EGME, and body weight, reproductive organs weight, histopathology and plasma biochemistry were examined at 6 and 24 hr after administration. Two multivariate statistical methods, namely, unsupervised PCA and supervised PLS-DA, indicated that the balance of endogenous metabolites was perturbed in both reproductive organs and biofluids. In the testes, lactate, creatine and glutathione were mainly affected by EGME treatment. In urine and plasma, altered excretions of the TCA cycle intermediates (2-oxoglutarate, citrate and succinate) and the ketone-bodies (acetoacetate and beta-hydroxybutyrate) were also observed. The finding in current integrated metabonomic analysis of both intact tissues and biofluids suggested that EGME-induced testicular toxicity was attributed to perturbation of the energy supply processes, suppression of the TCA cycle, or oxidative stress. Furthermore, Hr-MAS (1)H-NMR proved useful to investigate the molecular snapshot of biological tissues and the mechanism of toxicity.
Yamamoto
Toshinori
T
Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc., Aichi, Japan. Toshinori.Yamamoto@pfizer.com
Horii
Ikuo
I
Yoshida
Takemi
T
D000818:Animals; D054316:Biomarkers, Pharmacological / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001835:Body Weight / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003401:Creatine / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004822:Epididymis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005026:Ethylene Glycols / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000633:toxicity*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014116:Toxicology / Q000379:methods*
D054316:Biomarkers, Pharmacological; D005026:Ethylene Glycols; D007657:Ketone Bodies; D012997:Solvents; D019344:Lactic Acid; D005978:Glutathione; C021296:2-ethoxyethanol; D003401:Creatine