Effects of Sex and Androgenic Drugs on the Expression of Angiotensin-Converting Enzyme 2 Receptor, Cathepsin l and Transmembrane Serine Protease in Mouse Lungs

Introduction: Although males and females have the same prevalence of COVID-19, a variation in the severity of symptoms between males and females has been observed. We hypothesize that this variation can partly be explained by the effect of androgens on the infectious activity of the SARS-Cov2 virus.
Aims: This study investigated the effect of sex and two androgenic drugs testosterone and oxandrolone on the mRNA expression of several SARS-Cov2 entry genes: angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and cathepsin l (CatL) in mouse lungs.
Methods: Twenty-eight BALB/c mice were divided into four groups; the first three groups (all male mice) were treated with the vehicle, testosterone, and oxandrolone, respectively, while the fourth group consisted of untreated female mice. The androgenic drugs were administered for 21 days in doses equivalent to the human one. Accordingly, the expressions of ACE2, TMPRESS2, and CatL genes were measured using real-time PCR assay. In addition, the histopathological alterations in the lungs and the levels of total serum testosterone were analyzed.
Results: We found that the expression of ACE2 was significantly upregulated in the lungs of the testosterone-treated group by 2.5 times. The expression of TMPRSS2 was also significantly upregulated in the lungs of oxandrolone-treated mice by 6.6 times. Moreover, these molecular alterations were associated with a high elevation of the serum testosterone and the induction of inflammation and oxidative stress. In addition, we found that the mRNA levels of ACE2, TMPRSS2, and CatL were significantly higher in the lungs of the female compared to male mice.
Conclusion: We found several significant differences between the mRNA expression of ACE2, TMPRSS2, and CatL genes in the lungs of male and female mice. We showed how the administration of testosterone and oxandrolone to male mice upregulated the lungs’ mRNA expression of ACE2 and TMPRSS2, respectively. These results can expand our molecular understanding of the roles of sex and androgenic drugs on the expression of SARS-Cov2 entry genes.