Characterization of the Testicular Toxicity of 3

Nitrotriazolone (3-nitro-1,2,4-triazol-5-one; NTO) and dinitroanisole (2,4-dinitroanisole; DNAN), insensitive energetic materials used in explosive formulations, have induced testicular toxicity and oligospermia in repeated-dose oral toxicity tests. To identify the target site of testicular toxicity of NTO and DNAN, Sprague Dawley rats were orally dosed with NTO (500 mg/kg/d) or DNAN (50 or 100 mg/kg/d) in corn oil for 1, 3, 7, or 14 days. Degeneration of germinal epithelium occurred in multiple tubule stages on days 7 and 14 in treated rats. Degeneration increased in severity with time and was characterized by degeneration/apoptosis of pachytene spermatocytes and round and elongating spermatids, depletion of step 19 spermatids, luminal spermatogenic cell sloughing, multinucleate cells, and pronounced Sertoli cell vacuolation. Serum luteinizing hormone and follicle-stimulating hormone did not differ between NTO- and DNAN-treated and control rats on any sampling day. Serum testosterone levels reduced only in rats given 50 mg/kg/d DNAN for 7 days. These results suggest that the initial site of testicular injury for both NTO and DNAN is the Sertoli cell