The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats

Abstract

Background Hepatitis C virus (HCV) infection is a global public health problem and Egypt has the highest HCV prevalence worldwide. Hence, global efforts target to eliminate HCV by 2030. Sofosbuvir is a nucleotide analogue inhibitor of HCV polymerase essential for viral replication. Animal studies prove that Sofosbuvir metabolites cross the placenta and are excreted in the milk of nursing animals. We aimed to investigate the possible effects of preconception maternal exposure to Sofosbuvir on mitochondrial biogenesis in prenatal fetal liver, skeletal muscle, and placental tissues. Methods The study was conducted on 20 female albino rats divided into a control group receiving a placebo and an exposed group receiving 4 mg/kg orally/day for 3 months of Sofosbuvir. At the end of the treatment period, pregnancy was induced in both groups by mating with healthy male rats overnight. At gestational day 17, all pregnant female rats were sacrificed. Each fetus was dissected to obtain the fetal liver, skeletal muscle, and placental tissues. Results The results of our study indicated that the exposure of young female rats to Sofosbuvir affects pregnancy outcomes. Fetal liver and muscle showed lower mitochondrial DNA-copy number (mtDNA-CN) by about 24% and 29% respectively, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and its downstream targets; nuclear respiratory factor-1 and mitochondrial transcription factor A. While the placental tissues showed different patterns, particularly elevated in mtDNA-CN by about 43%. Conclusions The study provides preliminary evidence of the detrimental effects of Sofosbuvir on the pregnancy outcomes of the exposed females and may impair the placental and fetal organs’ development. These effects may be mediated through modulating mitochondrial homeostasis and functions.

The Intergeneration Long-Lasting Consequences of Pre-Conceptional Exposure to Sofosbuvir on the Ovarian Tissues of F1 Offspring: Experimental Study on Rats

“…Our recent study provided preliminary evidence for the detrimental effects of SOF on the pregnancy outcomes of exposed female rats [ 17 ], and in the present study, we extend our finding to the intergenerational detrimental effects of maternal SOF exposure on the ovarian tissues of the female rat postnatal offspring. The ovarian tissues of the F1 female offspring of mothers pre-conceptionally exposed to SOF showed an imbalance in mitochondrial homeostasis, which was associated with shifting in the redox status, oxidative DNA damage, inflammation, and modulation of estrogen receptors and Kiss1 expression and its receptor.…”

“…Sofosbuvir ((SOF), a product of Pharco Pharmaceuticals, Alexandria, Egypt), was available in the form of tablets with the trade name ‘Gratisovir’. Each tablet contains 400 mg of sofosbuvir; these tablets were dissolved in distilled water and given to rats orally by gastric tube at a dose of 4 mg/kg per day for 3 months [ 17 , 42 ].…”

“…The isolated DNA samples from the ovarian tissues were enzymatically digested as described previously [ 17 ] and used to assess the content of 8-OHdG using an ELISA kit (Chongqing Biospes Co., Ltd., Catalog number BYEK3439) according to the manufacturer’s instructions.…”

“…Furthermore, mitochondrial toxicity is one possible mechanism of nucleoside analog toxicity [ 16 ]. Our previous studies indicated that pre-conceptional SOF exposure in young female rats affected mitochondrial biogenesis and function in the ovaries, among other tissues, of the young females and their fetuses [ 17 ].…”

Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats

“…Sofosbuvir (SOF) (a drug produced by Pharco Pharmaceuticals in Alexandria, Egypt), was available in the form of tablets with the commercial name 'Gratisovir'. Each tablet containing 400 mg of SOF was dissolved in distilled water and administrated orally to the rats via a gastric tube at a dose of 4 mg/kg/day for 3 months [37,38].…”