Modulation of m-Dinitrobenzene and m-Nitrosonitrobenzene Toxicity in Rat Sertoli-Germ Cell Cocultures

Modulation of m-Dinitrobenzene and m-Nitrosonitrobenzene Toxicityin Rat Sertoli-Germ Cell Cocultures. CAVE, D. A., AND FOSTER,P. M. D. (1990). Fundam. Appl. Toxicol. 14, 199–207. Previouswork has shown that m-dinitrobenzene is a testicular toxicantin rats In vivo, and in vitro produces comparable morphologicalchanges in rat testicular Sertoli-germ cell cocultures. m-Dinitrobenzeneis metabolized both In vivo and in the in vitro system to m-nitroani-lineand m-nitroacetanilide. These metabolites do not provoke testiculartoxicity In vivo or in vitro. We have therefore proposed a pathwayfor the metabolism of m-dinitrobenzene to m-nitroaniline andm-nitroacetanilide, which involved the intermediate m-nitrosonitrobenzene(1 -nitroso-3-nitrobenzene, NNB). When tested, m-nitrosonitrobenzene,at equimolar doses to m-dinitrobenzene, produced similar morphologicalchanges in the culture system to those exhibited by m-dinitrobenzene.However, m-nitrosonitrobenzene produced a greater toxicity thandid m-dinitrobenzene (as measured by germ cell detachment).When the intracellular thiol levels were reduced in the coculturespretreated with diethyl maleate, the toxicity of both m-dinitrobenzeneand m-nitrosonitrobenzene was enhanced. In contrast, pretreatmentof 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 activationbefore it can exert its toxicity to Sertoli cells, and it appearsthat the toxic species is m-nitrosonitrobenzene or a furthermetabolite of m-nitrosonitrobenzene.