Mechanisms of doxorubicin-mediated reproductive toxicity - A review

Uma Priya Mohan; Tirupathi Pichiah P B; Syeda Thabassum Akhtar Iqbal; Sankarganesh Arunachalam

doi:10.1016/j.reprotox.2021.04.003

Mechanisms of doxorubicin-mediated reproductive toxicity - A review

Reprod Toxicol. 2021 Jun:102:80-89. doi: 10.1016/j.reprotox.2021.04.003. Epub 2021 Apr 18.

Authors

Uma Priya Mohan¹, Tirupathi Pichiah P B², Syeda Thabassum Akhtar Iqbal³, Sankarganesh Arunachalam⁴

Affiliations

¹ Centre for Cardiovascular and Adverse Drug Reactions, Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Tamil Nadu, PIN 626126, India.
² Department of Animal Science, Bharathidasan University, Tiruchirappalli, India.
³ School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, PIN 632014, India.
⁴ Centre for Cardiovascular and Adverse Drug Reactions, Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, Tamil Nadu, PIN 626126, India. Electronic address: sankarganesh@gmail.com.

PMID: 33878324
DOI: 10.1016/j.reprotox.2021.04.003

Abstract

The anticancer drug doxorubicin has been associated with several adverse side-effects including reproductive toxicity in both genders. The current review has complied the mechanisms of doxorubicin induced reproductive toxicity. The articles cited in the review were searched using Google Scholar, PubMed, Scopus, Science Direct. Doxorubicin treatment has been found to cause a decrease in testicular mass along with histopathological deformities, oligospermia and abnormalities in sperm morphology. Apart from severely affecting the normal physiological role of both Leydig cells and Sertoli cells, doxorubicin also causes chromosome abnormalities and affects DNA methylase enzyme. Testicular lipid metabolism has been found to be negatively affected by doxorubicin treatment resulting in altered profile of sphingolipids glycerophospholipids and neutral lipids. Dysregulation of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β- hydroxysteroid dehydrogenase (17β-HSD) are strongly linked to testicular exposure to doxorubicin. Further, oxidative stress along with endoplasmic reticulum stress are also found to aggravate the male reproductive functioning in doxorubicin treated conditions. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase (GPx) are downregulated by doxorubicin. It also disturbs the hormones of the hypothalamic-pituitary-gonadal (HPG)-axis including testosterone, luteinizing hormone, follicle stimulating hormone etc. In females, the drug disturbs folliculogenesis and oogenesis leading to failure of ovulation and uterine cycle. In rodent model the drug shortens pro-estrous and estrous phases. It was also found that doxorubicin causes mitochondrial dysfunction in oocytes with impaired calcium signaling along with ER stress. The goal of the present review is to comprehends various pathways due to which doxorubicin treatment promotes toxicity in male and female reproductive system.

Keywords: Adriamycin; Doxorubicin; Folliculogenesis; Leydig cells; Reproductive toxicity; Sertoli cells; Spermatogenesis; Testicular toxicity.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

17-Hydroxysteroid Dehydrogenases
Animals
Antioxidants
Doxorubicin / toxicity*
Female
Follicle Stimulating Hormone
Leydig Cells / drug effects
Lipid Peroxidation / drug effects
Luteinizing Hormone
Male
Oxidative Stress
Reproduction / drug effects*
Testis / drug effects
Testosterone / metabolism

Substances

Antioxidants
Testosterone
Doxorubicin
Luteinizing Hormone
Follicle Stimulating Hormone
17-Hydroxysteroid Dehydrogenases
3 (or 17)-beta-hydroxysteroid dehydrogenase