Isorhamnetin: a flavonoid, attenuated doxorubicin-induced testicular injury via regulation of steroidogenic enzymes and apoptotic signaling gene expression in male rats

Shama Mustafa; Muhammad Umar Ijaz; Qurat Ul Ain; Tayyaba Afsar; Ali Almajwal; Huma Shafique; Suhail Razak

doi:10.1093/toxres/tfac024

Isorhamnetin: a flavonoid, attenuated doxorubicin-induced testicular injury via regulation of steroidogenic enzymes and apoptotic signaling gene expression in male rats

Toxicol Res (Camb). 2022 May 23;11(3):475-485. doi: 10.1093/toxres/tfac024. eCollection 2022 Jun.

Authors

Shama Mustafa¹, Muhammad Umar Ijaz, Qurat Ul Ain², Tayyaba Afsar³, Ali Almajwal³, Huma Shafique⁴, Suhail Razak³

Affiliations

¹ Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad 38040, Pakistan.
² Department of Zoology, Government College Women University, Sialkot 51310, Pakistan.
³ Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia.
⁴ Institute of cellular medicine, Newcastle University Medical School, Newcastle University, Newcastle NE17RU, United Kingdom.

Abstract

Background: Male reproductive damage is one of the most adverse side effects of doxorubicin (DOX). Isorhamnetin is a natural flavonoid, which displays remarkable antioxidant potential.

Objective: The current research was designed to assess the protective effects of Isorhamnetin against DOX-instigated testicular damages.

Methods: Adult male Wistar rats (n=32) were divided into 4 groups: control, DOX (3 mg/kg i.p. 3 doses each after 1 week), DOX + Isorhamnetin (3 mg/kg 3 doses each after 1 week +10 mg/kg i.p. daily for 28 days, respectively), and Isorhamnetin (10 mg/kg i.p. per day). After 28 days of treatment, biochemical, spermatogenic, steroidogenic, hormonal, proapoptotic, antiapoptotic, and histopathological parameters were estimated.

Results: DOX exposure significantly decreased the activity of acid phosphatase, lactate dehydrogenase, and gamma-glutamyl transferase. Furthermore, DOX substantially decreased the activities of antioxidant enzymes, i.e. catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase along with protein content, whereas it increased the malondialdehyde level. It also reduced sperm progressive motility, viability, the number of hypoosmotic tail swelled spermatozoa, and epididymis sperm count and increased the sperm morphological anomalies (head, midpiece, and tail). Besides, it decreased the levels of follicle-stimulating hormone, luteinizing hormone, and plasma testosterone and lowered the expression of steroidogenic enzymes (3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, and steroidogenic acute regulatory protein) and testicular antiapoptotic marker (B-cell lymphoma 2) but increased the expression of proapoptotic markers (BCL2-associated X protein and caspase-3) along with histopathological impairments. However, isorhamnetin prevented all the damages caused by DOX.

Conclusion: Conclusively, Isorhamnetin can be used as a powerful mitigating agent to avert DOX-induced testicular damages.

Keywords: antioxidant; doxorubicin; isorhamnetin; oxidative stress; testicular damage.