What Did Animal Model Studies Give us about The Varicocele-Induced Pathogenesis both at Testicular and Sperm Levels: A Fact or Fiction

The varicocele (VCL), as inevitable fact of infertility reason, hasbeen reported in ۱۰-۲۰% of infertile individuals. The VCL is categorizedinto three different grades, initiation from faint to moresevere conditions, which is able to potentially result in competeinfertility. Indeed, diminished venous drainage, retrograde bloodflow-down to pampiniform plexus, and increased temperatureof testicles have been illustrated as prevailing reasons of VCLinducedpathogenesis in testicular tissue, leading to detrimentalimpact on spermatogenesis and spermiogenesis. Additional theories,which explain the testicular effects of VCL are suboptimaldrainage of testicular gonadotoxins due to venous dilatation, refluxof renal and adrenal metabolites contributing to venous dilatation,testicular hypoxia, higher levels of oxidants in the semen,and anti-sperm antibodies. In line with this issue, several studieshave shown that, the VCL adversely affects the germinal epitheliumand sperm cells on a cellular and molecular level, includingdiminished testicular DNA polymerase activity, enhancedgerm and sperm cells apoptosis, elevated reactive oxygen species(ROS, named as VCL-induced oxidative stress), altered Sertolicell niche and network with Leydig cells, and finally decreasedLeydig cell testosterone secretion. Among all these hypothesis,those trials performed using animal models established the VCLinducedpathogenesis mechanistically. Accordingly, it has beencame clear that, the VCL-induced testosterone withdrawal resultsin a cascade of evidences, leading to impaired chaperonesrelatedtesticular homeostasis, including DNA fragmentation,and protein degradation, and negatively affects the Sertoli cellsrelatedmicroenvironment and/or niche, resulting in suppressedspermatogonial stem cells self-renewal process. Moreover, theanimal model-based trials have illustrated that, the VCL-inducedoxidative stress results in severe DNA damage at precursor germcell level, and negatively affects the cell cycle machinery duringmitosis and meiosis, resulting in spermatogenesis arrest. Inline with these findings, using animal models, demonstrated that,the VCL-induced oxidative stress down-regulates the potentialin stabilizing mRNA content of haploid germ cells, and via thismechanism it negatively affects the essential protein synthesis.Moreover, it came clear that, the progressive oxidative stress inassociation with overexpression/synthesis of inflammatory mediators(such as TNF-α, IL-۱, IL-۶, IL-۱۰, iNOS, ALP, AST) inVCL-induced testicles negatively affects the testicular endocrinestatus, resulting in arrested/delayed spermatogenesis and spermiogenesis.In addition, the animal model studies showed the crosslinkbetween oxidative stress, hypoxia, and suppressed endocrinestatus with epigenetic alterations during histone-protamine replacementprocess. Finally, using animal model studies made itclear that, the long-time VCL is able to result in pre-implantationembryo arrest at very early stages, and diminishes the blastocystratio. Thus, considering all these findings, it would be more logicto conclude that, the animal model trials could successfully helpthe researchers and clinicians to understand the molecular, bio chemical and histological changes during VCL in more detail.However, the species-specific differences between animal modelsand VCL patients should be considered, and more trials areneeded to come close the fact that, how actually VCL affects thehuman fertilization potential.

کلیدواژه ها:

Varicocele ، Animal Models ، Spermatogenesis ، Fertilization potential