Crosstalk between E2F1 and P53 transcription factors in doxorubicin-induced DNA damage: evidence for preventive/protective effects of silymarin

Abstract

Objectives: To study the effects of silymarin in various forms of applications on the molecular mechanism(s) of doxorubicin-induced testicular toxicity in male rats.

Methods: Following DOX administration with or without SMN in male rats, sperm quality assays were conducted. Moreover, total antioxidant capacity and nitric oxide content of testis were determined. Expression profile of p53 and E2F1 was analysed by PCR technique. Ultimately, the rate of DNA fragmentation in the testes was quantitatively measured.

Key findings: P53 and E2F1 expression in DOX-received animals at mRNA level showed a revers profile of an up- and down-regulation, respectively. Administration of SMN in preventive and protective forms resulted in a significant (P < 0.05) reduction in DOX-induced sperm abnormalities, DNA fragmentation, nitric oxide concentration and a marked increase in total antioxidant power, rate of sperm motility and viability. SMN lowered the DOX-up-regulated expression of p53 at mRNA level.

Conclusions: DOX-induced testicular toxicity was characterized by lowering sperm quality values, induction of oxidative and nitrosative stress and DNA fragmentation. Preventive and protective effects of SMN on DOX-induced testicular toxicity may attribute to its antioxidant property. DOX-induced testicular damages and SMN preventive/protective effects might be mediated via up- and down-regulation of p53 and E2F1 transcription factors.

Keywords: DNA fragmentation; chemotherapy; silymarin; testicular toxicity; transcription factor.