Hepatitis C virus infection is endemic in Egypt with the highest prevalence rate in the world. Without treatment, most acute infections lead to chronic, followed by cirrhosis and hepatocellular carcinoma. Sofosbuvir acts like a nucleos(t)ide analogue that specifically inhibits hepatitis C virus replication. Our study aimed to explore the molecular mechanisms and the possible side effects of the therapeutic dose of sofosbuvir on mitochondrial biogenesis and functions of liver, muscle and ovary tissues of young normal female rats and explore the possible prenatal effect of Sofosbuvir on the embryos of the exposed mother. The study was conducted on female albino rats 2 months old that was classified into 2 groups. Group I (Control group): 20 healthy female rats and Group II (exposed group): 20 female rats that was supplemented with 4 mg/kg of sofosbuvir drug for 3 months. At the end of the treatment period, 10 normal and 10 exposed female rats will be sacrificed and dissected out to obtain blood, ovary, liver and muscles. Pregnancy will be induced in 10 control females and 10 exposed females by mating with healthy male rats overnight. At gestational day 17 (GD 17) pregnant control females and pregnant exposed females will be sacrificed by cervical dislocation. The embryos with their membranes and placentas will be quickly dissected out of the uterine horns. Each embryo will be dissected to obtain the fetal liver, and muscles. The reported toxicity was mediated through suppression of Peroxisome proliferator-activated receptor gamma coactivator- 1alpha (PGC-1α), mitochondria transcription factor A that impair mitochondrial biogenesis that manifested a decline in mitochondrial DNA copy number. Also, sofosbuvir suppresses the expression of DNA polymerase γ and declines the mitochondrial NADH dehydrogenase subunit-5 content that impair the mitochondrial functions. According to our results, the ovarian tissue is the most affected organ followed by the liver and placenta while muscle tissue appears to resist sofosbuvir-induced mitochondrial toxicity. In conclusion, the effects of sofosbuvir on the ovarian mitochondrial biogenesis and functions was found to not just affect the exposed females but unfortunately may have long-lasting consequences by impairing the embryonic development and transfer these mitochondrial abnormalities to next generations.
Dr. Rana Hassan Mahmoud Hassan Khafaga, born on 4\11\1989.She completed her graduation, Class of 2012, Alexandria University, Faculty of science, Biochemistry Department,currently she is Assistant lecturer at Biochemistry department at Medical Research Institute (MRI), Alexandria University, Egypt and she is a student in Ph.D degree in MRI Alexandria University since February 2018 and Working on a Project accepted by STDF organization titled by: Short-term and long-term trans-generational side effects of Sofosbuvir: Experimental study on female rats, 2019. She has attended many international conferences and has many awards.