Testicular toxicity produced by ethylene glycol monomethyl and monoethyl ethers in the rat.
Ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) were administered orally to young male rats at doses varying from 50 to 500 mg/kg/day and 250 to 1000 mg/kg/day for EGME and EGEE, respectively, for 11 days. At sequential times animals were killed and testicular histology examined. The initial and major site of damage following EGME treatment was restricted to the primary spermatocytes undergoing postzygotene meiotic maturation and division. EGEE produced damage of an identical nature, but a larger dose was required to elicit equivalent severity (500 mg EGEE/kg being approximately equivalent to 100 mg EGME/kg). Additionally, within the spermatocyte population, differential sensitivity was observed depending on the precise stage of meiotic maturation: dividing (stage XIV) and early pachytene (stages I-II) greater than late pachytene (stages VIII-XIII) greater than mid-pachytene (stages III-VII). Equivalent doses of methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) gave injury similar to the corresponding glycol ether. When animals were pretreated with inhibitors of alcohol metabolism followed by a testicular toxic dose of EGME (500 mg/kg), an inhibitor of alcohol dehydrogenase (pyrazole) offered complete protection. Pretreatment with the aldehyde dehydrogenase inhibitors disulfiram or pargyline did not ameliorate the testicular toxicity of EGME. In mixed cultures of Sertoli-germ cells, MAA and not EGME produced effects on spermatocytes analogous to that seen in vivo, at concentrations approximately equivalent to steady-state plasma levels after a single oral dose of EGME (500 mg/kg). It would seem likely that a metabolite (MAA or possibly methoxyacetaldehyde) and not EGME is responsible for the production of testicular damage.
D000085:Acetates / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D004221:Disulfiram / Q000494:pharmacology; D005026:Ethylene Glycols / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010293:Pargyline / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D012671:Seminiferous Tubules / Q000473:pathology; D013733:Testicular Diseases / Q000139:chemically induced*; D013737:Testis / Q000187:drug effects*; D013997:Time Factors; D014018:Tissue Distribution
D000085:Acetates; D005026:Ethylene Glycols; D011720:Pyrazoles; C031280:pyrazole; C034096:ethoxyacetic acid; D010293:Pargyline; C005219:methyl cellosolve; C013598:methoxyacetic acid; C021296:2-ethoxyethanol; D004221:Disulfiram