© 1990 Oxford University Press
other |
Modulation of m-Dinitrobenzene and m-Nitrosonitrobenzene Toxicity in Rat Sertoli-Germ Cell Cocultures
Central Toxicology Laboratory Alderley Park, Macclesfield, Cheshire, United Kingdom SK10 4TJ
Received April 13, 1989; accepted June 29, 1989
Modulation of m-Dinitrobenzene and m-Nitrosonitrobenzene Toxicity in Rat Sertoli-Germ Cell Cocultures. CAVE, D. A., AND FOSTER, P. M. D. (1990). Fundam. Appl. Toxicol. 14, 199–207. 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-nitroani-line 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 (cyste-amine 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.