Effect of troxerutin on the expression of genes regulating mitochondrial biogenesis and microRNA?140 in doxorubicin?induced testicular toxicity

Behnaz Mokhtari Mokhtari, Arezou Abdi, Seyed Zanyar Athari, Hojjatollah Nozad Charoudeh, Alireza Alihemmati, Reza Badalzadeh

Abstract


Background: Application of doxorubicin (DOX) in cancer patients is limited due to its dose?dependent toxicity to nontarget tissues such as testis and subsequent infertility. Due to limitation of our knowledge about the mechanisms of DOX toxicity in the reproductive system, reduction of DOX?induced testicular toxicity remains an actual and primary clinical challenge. Considering the potentials of troxerutin (TXR) in generating a protective phenotype in many tissues, we aimed to examine the effect of TXR on DOX?induced testicular toxicity by evaluating the histological  hanges and the expression of mitochondrial biogenesis genes and microRNA?140 (miR?140).

Materials and Methods: Twenty?four adult male Wistar rats (250–300 g) were divided in groups with/ without DOX and/or TXR. DOX was injected intraperitoneally at 6 consecutive doses over 12 days (cumulative dose: 12 mg/kg). TXR (150 mg/kg/day; orally) was administered for 4 weeks before DOX challenge. One week after the last injection of DOX, testicular histopathological changes, spermatogenesis activity, and expression of mitochondrial biogenesis genes and miR?140 were determined.

Results: DOX challenge significantly increased  esticular histopathological changes, decreased testicular expression profiles of sirtuin 1 (SIRT?1) and nuclear respiratory factor?2 (NRF?2), and increased expression of miR?140 (P < 0.05 to P < 0.01). Pretreatment of DOX?received rats with TXR significantly reversed testicular  istopathological changes, spermatogenesis activity index, and the  xpression levels of SIRT?1, peroxisome proliferator?activated receptor?? coactivator 1?alpha (PGC?1?), NRF?2, and miR?140 (P < 0.05 to P < 0.01).

Conclusion: Reduction of DOX?induced testicular toxicity following TXR pretreatment was associated with upregulation of SIRT?1/PGC?1?/NRF?2 profiles and better regulation of miR?140 expression. It seems that improving microRNA?mitochondrial biogenesis network can play a role in the beneficial effect of TXR on DOX?induced testicular toxicity.


Keywords


Doxorubicin, microRNA?140, mitochondrial biogenesis, testicular toxicity, troxerutin

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