Deciphering the molecular mechanism during doxorubicin-mediated oxidative stress, apoptosis through Nrf2 and PGC-1α in a rat testicular milieu

Abstract

Doxorubicin is an extensively applied anti-cancerous drug since 1950's and its usage is constrained because of its accumulation in a non-cancerous organ. Many studies have proven that doxorubicin causes reproductive toxicity depends on its dosage, particularly due to increased oxidative stress and apoptosis. A number of the researches have been carried out concerning its prevention. But there is a need to recognize the mechanism at the back of its toxicity to get better and improved method of treatment. To clarify the feasible mechanism of doxorubicin-mediated reproductive toxicity in rats, we have administrated doxorubicin at distinct dosages inclusive of low dosage (male rats that are at 230-250 g acquired cumulatively 1.5 mg/kg; ip; once per week for five weeks) and high dosage (male rats which are at 230-250 grams obtained cumulatively 15 mg/kg; ip; once every week for five weeks). Doxorubicin decreases antioxidant level such as GSH, Cu/Zn SOD, Mn SOD both in serum and testes. Increased oxidative stress is considered via elevated MDA level both in serum and testes. The level of ROS is measured via the DCFDA method in testes. Apoptosis become found through DNA fragmentation assay and quantification of Caspase 3, Caspase 9, Bcl2 and Cytochrome C. Doxorubicin mediated oxidative stress and apoptosis in testicular milieu is through deregulation of Nrf2, PGC-1α, AHR, ARNT, PXR, SUMO-1, UCP2, UCP3, ANX A5, Caspase 3, Caspase 9, Bcl2, Cytochrome C, GR, and GPX. In end, doxorubicin-mediated oxidative stress and apoptosis is through diverse transcriptional factors and genes with respect to decreased antioxidant level, augmented ROS level and Annexin A5 in the testicular milieu.

Keywords: Antioxidants; Apoptosis; Doxorubicin; Male reproductive toxicity; Oxidative stress; Transcription factors.