The role of metabolism in 2-methoxyethanol-induced testicular toxicity.
The role of metabolism in 2-methoxyethanol (ME)-induced testicular toxicity has been investigated with Sprague-Dawley rats. Following administration of [14C]ME (250 mg/kg, ip) to a group of animals, there was evidence of testicular damage, identified as depletion of the spermatocyte population. Radioactivity detected in urine over 48 hr after treatment accounted for 55% of the dose. The major urinary metabolites were identified by HPLC and isotope dilution analysis, as methoxyacetic acid (MAA) and methoxyacetylglycine (accounting for 50 to 60% and 18 to 25%, respectively, of urinary radioactivity). Analysis of plasma revealed a rapid conversion of ME to MAA (t1/2 for disappearance of ME = 0.6 +/- 0.03 hr) and gradual clearance of radioactivity (t1/2 = 19.7 +/- 2.3 hr). Pretreatment of animals with pyrazole (400 mg/kg, ip) 1 hr prior to [14C]ME dosing gave complete protection against the testicular toxicity of ME. Radioactivity detected in the urine from the pyrazole-pretreated groups over 48 hr (18%) was significantly lower than in the ME-only group. The major radioactive peak co-chromatographed with ME (30 to 36% of the total urinary radioactivity). MAA and methoxyacetylglycine were not major metabolites. Analysis of plasma revealed almost complete inhibition of the conversion of ME to MAA (t1/2 for disappearance of ME = 42.6 +/- 5.6 hr, clearance of radioactivity t1/2 = 51.0 +/- 7.8 hr). The results demonstrate that metabolic activation is required for 2-methoxyethanol to exert toxicity to the male reproductive system.
D000085:Acetates / Q000652:urine; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004221:Disulfiram / Q000494:pharmacology; D005026:Ethylene Glycols / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D013058:Mass Spectrometry; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012671:Seminiferous Tubules / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000473:pathology
D000085:Acetates; D005026:Ethylene Glycols; D011720:Pyrazoles; C031280:pyrazole; C005219:methyl cellosolve; C013598:methoxyacetic acid; D004221:Disulfiram