Overexpression of glutathione peroxidase-1 attenuates cocaine-induced reproductive dysfunction in male mice by inhibiting nuclear factor κB

초록

Since reproductive toxicity is associated with oxidative stress, nuclear factor kappa B (NF kappa B), a redox-sensitive transcription factor, may be involved in the reproductive dysfunction induced by the abusive drug, such as cocaine. In the present study, we investigated whether NF kappa B mediates cocaine-induced reproductive dysfunction in male mice, and whether glutathione peroxidase (GPx)-1, a well-known enzymatic antioxidant, modulates NF kappa B activity to affect this reproductive dysfunction. Cocaine treatment significantly increased nuclear translocation of NF kappa B and its DNA binding activity in the testis of mice. Treatment with cocaine resulted in a significant increase in sperm abnormality, and in significant decreases in the sperm viability and sperm level. Furthermore, cocaine significantly reduced hypothalamic gonadotropin-releasing-hormone expression and plasma testosterone level. These alterations were more pronounced in the GPx-1 knockout (GPx-1 KO) than wild type (WT) mice, and they were less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than in non-transgenic (non-TG) mice. Pyrrolidine dithiocarbamate (PDTC), an NF kappa B inhibitor, was more effective in attenuating cocaine-induced reproductive toxicity in GPx-1 KO than in WT mice. Although PDTC treatment was also significantly protective against the reproductive toxicity in non-TG mice, PDTC did not show additional positive effects against the protective potential mediated by GPx-1 overexpression in mice. Therefore, our results suggest that GPx-1 gene is a protective factor in response to reproductive dysfunction induced by cocaine in male mice, and that NF kappa B is a critical mediator of protective activity of GPx-1 gene in our experimental conditions.

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