Potential new targets involved in 1,3-dinitrobenzene induced testicular toxicity

1,3-Dinitrobenzene (DNB) causes testicular injury, particularly to Sertoli cells, and induces apoptosis in the surrounding germinal cells in rodents; however, the mechanisms causing this toxicity are poorly understood. Our studies, using standard and molecular tools, were conducted to better understand the pathogenesis of the testicular effects. Four daily oral doses of 0.1–8 mg/kg/day caused marked testicular lesions in rats from 4 mg/kg/day. Global transcriptomics revealed cell cycle and cell death as the major biological processes affected with the expression of genes associated with cell cycle progression (“mitotic roles of polo-like kinase”) being particularly altered. In a single dose time course study (4 mg/kg), no adverse changes were recorded; however, in contrast to the data from the multiple dose study, plasma testosterone and testicular steroidogenesis-related gene expression were affected. These steroid hormone effects were confirmed in vitro using the H295R steroidogenesis assay. With this global approach we show that DNB not only induces apoptosis and interferes with cell cycle in the testes but that DNB can also modulate steroid hormone biosynthesis, suggesting an interference with the endocrine system. However, the contribution of the endocrine changes to the severe testicular lesions is presently unknown and requires further investigation.

► DNB induces rat testicular lesions after 4 days gavage but not after a single dose.
► Genes associated with mitosis, particularly polo-like kinase, were deregulated.
► Steroidogenesis (hormone and genes) was perturbed in vivo after a single dose.
► Sex hormone secretion affected in vitro in the H295R adrenal steroidogenesis assay.
► Contribution of endocrine disruption to testicular toxicity of DNB is discussed.