Modulation of m-dinitrobenzene and m-nitrosonitrobenzene toxicity in rat Sertoli--germ cell cocultures.
Previous work has shown that m-dinitrobenzene is a testicular toxicant in rats in vivo, and in vitro produces comparable morphological changes in rat testicular Sertoli-germ cell cocultures. m-Dinitrobenzene is metabolized both in vivo and in the in vitro system to m-nitroaniline m-nitroaniline and m-nitroacetanilide. These metabolites do not provoke testicular toxicity in vivo or in vitro. We have therefore proposed a pathway for the metabolism of m-dinitrobenzene to m-nitroaniline and m-nitroacetanilide, which involved the intermediate m-nitrosonitrobenzene (1-nitroso-3-nitrobenzene, NNB). When tested, m-nitrosonitrobenzene, at equimolar doses to m-dinitrobenzene, produced similar morphological changes in the culture system to those exhibited by m-dinitrobenzene. However, m-nitrosonitrobenzene produced a greater toxicity than did m-dinitrobenzene (as measured by germ cell detachment). When the intracellular thiol levels were reduced in the cocultures pretreated with diethyl maleate, the toxicity of both m-dinitrobenzene and m-nitrosonitrobenzene was enhanced. In contrast, pretreatment of cocultures with agents known to increase cellular thiol (cysteamine) or scavenge reactive intermediates (cysteamine or ascorbate) reduced the toxicity of m-dinitrobenzene and m-nitrosonitrobenzene. We propose that m-dinitrobenzene requires metabolic activation before it can exert its toxicity to Sertoli cells, and it appears that the toxic species is m-nitrosonitrobenzene or a further metabolite of m-nitrosonitrobenzene.
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Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.
Foster
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D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D003543:Cysteamine / Q000494:pharmacology; D004136:Dinitrobenzenes / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D008297:Male; D008298:Maleates / Q000494:pharmacology; D009578:Nitrobenzenes / Q000633:toxicity*; D009603:Nitroso Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism; D013094:Spermatozoa / Q000187:drug effects*
D004136:Dinitrobenzenes; D008298:Maleates; D009578:Nitrobenzenes; D009603:Nitroso Compounds; C063131:1-nitro-3-nitrosobenzene; D003543:Cysteamine; C017906:3-dinitrobenzene; C014476:diethyl maleate; D005978:Glutathione; D001205:Ascorbic Acid