2,4,6-Trinitrotoluene-induced Reproductive Toxicity via Oxidative DNA Damage by its Metabolite

Abstract

Several epidemiological studies and animal experiments showed that 2,4,6-trinitrotoluene (TNT), a commonly used explosive, induced reproductive toxicity. To clarify whether the toxicity results from the interference of endocrine systems or direct damage to reproductive organs, we examined the effects of TNT on the male reproductive system in Fischer 344 rats. TNT administration induced germ cell degeneration, the disappearance of spermatozoa in seminiferous tubules, and a dramatic decrease in the sperm number in both the testis and epididymis. TNT increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in sperm whereas plasma testosterone levels did not decrease. These results suggest that TNT-induced toxicity is derived from direct damage to spermatozoa rather than testosterone-dependent mechanisms. To determine the mechanism of 8-oxodG formation in vivo, we examined DNA damage induced by TNT and its metabolic products in vitro. 4-Hydroxylamino-2,6-dinitrotoluene, a TNT metabolite, induced Cu(II)-mediated damage to 32P-labeled DNA fragments and increased 8-oxodG formation in calf thymus DNA, although TNT itself did not. DNA damage was enhanced by NADH, suggesting that NADH-mediated redox reactions involving TNT metabolites enhanced toxicity. Catalase and bathocuproine inhibited DNA damage, indicating the involvement of H2O2 and Cu(I). These findings suggest that TNT induces reproductive toxicity through oxidative DNA damage mediated by its metabolite. We propose that oxidative DNA damage in the testis plays a role in reproductive toxicity induced by TNT and other nitroaromatic compounds.

Multiple environmental stressors elicit complex interactive effects in the western fence lizard (Sceloporus occidentalis)

“…An earlier study investigating TNT effects in WFL also demonstrated the slight increase, then a decrease, in testes mass over the range of TNT (McFarland et al 2008). The testes as a TNT target organ has been reported in other species and included atrophy with a decrease in mass (Dilley et al 1982;Levine et al 1990;Homma-Takeda et al 2002). When examining the stressors food and TNT (Table 2), the testes were the only organ that experienced a loss in mass due to both a decrease in food intake (p = 0.012) and TNT exposure (p \ 0.001), increasing the potential significance of this organ as a sensitive target organ for other environmental stressors.…”

Changes to the rumen bacterial population of sheep with the addition of 2,4,6-trinitrotoluene to their diet

“…According to the Environmental Protection Agency (EPA), TNT affects human, aquatic, and terrestrial life forms and lists it as a class C potential human carcinogen (Smets et al 2007). TNT metabolites induce reproductive toxicity through oxidative DNA damage as shown by animal models and epidemiological studies (Homma-Takeda et al 2002).…”

Microbial Degradation of 2,4,6-Trinitrotoluene In Vitro and in Natural Environments

“…Possible application areas are not only restricted to bioremediation (Hannink et al 2001), but also to specific biocatalysis (Kadiyala et al 2003) and cancer therapy (Denny 2002;Knox et al 2003). Through their activity, they decisively determine the toxicity of nitroaromatic compounds (Homma-Takeda et al 2002;Padda et al 2003), although their physiological relevance is still largely unknown. Nitroreductases may be classified into two types.…”