-Exposure to 2,4,6-trinitrotoluene (TNT) causes methemoglobin (metHb) formation, hemolysis and negative heme balance in vivo, but the mechanistic details are poorly understood. In the present study, we examined the participation of metabolic activation in TNT-mediated hematotoxicity. Exposure of rats with TNT (300 mg/kg, i.p.) for 4 days resulted in a decrease of hematocrit value coupled to an increase in metHb formation. The red blood cells treated with 4-hydroxylamino-2,6-dinitrotoluene (HADNT), a metabolite of TNT, underwent readily hemolysis in vitro, whereas such a phenomenon was not seen with TNT. Consistent with this, HADNT is active toward metHb formation and the decrease in thiol content of the globin moiety compared with TNT and its metabolites 4-amino-2,6-dinitrotoluene (ADNT) and 4-acetylamino-2,6-dinitrotoluene (AADNT). Furthermore, interaction of purified rat oxyhemoglobin (oxyHb) with HADNT, but not TNT, ADNT, and AADNT, caused a concentration-dependent production of H 2 O 2 and ferrylhemoglobin (ferrylHb) which is a highly oxidizing state formed by reaction of oxyHb with H 2 O 2 . Notably, hemin was released during interaction of oxyHb with HADNT. Taken together, these findings suggest that HADNT is an active metabolite that mediates TNT-induced hematotoxicity via formation of prooxidants such as H 2 O 2 and ferrylHb.

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-2,4,6-Trinitrotoluene (TNT) is a serious occupational and environmental pollutant. We conducted a cross-sectional health survey of workers in a TNT explosives factory in Fuxin, China. For each subject, we determined their blood pressure, hematotoxicity parameters, glutathione concentration, lipid hydroperoxide concentration, superoxide dismutase activity, and nitrite/nitrate (NOx) concentration in serum. Significantly fewer white blood cells were found in samples from male workers exposed to TNT than in samples from control male workers, but hematological parameters (such as the amount of hemoglobin present, the hematocrit value, and the formation of methemoglobin) varied little between the exposed and control workers. Exposure of male workers to TNT was found to cause their blood pressure to decrease significantly, concomitant with a tendency towards increased NOx concentrations in serum. On the other hand, lipid hydroperoxide (an oxidative stress marker) concentrations were significantly higher in female workers exposed to TNT than in control female workers. Our results suggest that TNT has different, deleterious effects in males and females, causing hematotoxic stress in males and oxidative stress in females.