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

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

doi:10.4103/jrms.jrms_120_22

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

J Res Med Sci. 2023 Apr 21:28:35. doi: 10.4103/jrms.jrms_120_22. eCollection 2023.

Authors

Behnaz Mokhtari^{1

2}, Arezou Abdi^{2

3

4}, Seyed Zanyar Athari^{2

3}, Hojjatollah Nozad-Charoudeh⁴, Alireza Alihemmati^{1

4}, Reza Badalzadeh^{4

5}

Affiliations

¹ Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
² Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
³ Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
⁴ Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
⁵ Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

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 changes 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 testicular 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 histopathological changes, spermatogenesis activity index, and the expression levels of SIRT-1, peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), 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-1α/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.