[Impact of reverse transcriptase inhibitors on sperm mitochondrial and genomic DNA in assisted reproduction techniques]

Abstract

For the last ten years, antiretroviral therapy (ARV) has improved the prognosis in HIV-1 infection and showed a better control of the viral excretion by reducing viral shedding in semen. However, nucleoside analogues reverse transcriptase inhibitors (NRTI) therapy reported important adverse effects. Most of these side effects observed seem to be linked with a common mechanism: mitochondrial activity alteration. Since the introduction of protocols for HIV-1 serodiscordant couples, with male infected partners under NRTI therapy, many results in the literature such as: semen characteristics and pregnancies, drew the attention of research teams. Many studies have suggested that NRTI has an affect on semen parameters, but proposed mechanisms of these effects have rarely been discussed. NRTI have a great affinity for the reverse transcriptase of HIV-1. Because many NRTI are not only inhibitors of reverse transcriptase but also inhibitors of the DNA polymerase beta and gamma, several toxic effects can be considered. Nevertheless, this specificity is not absolute and "accidental" incorporations of NRTI can occur on genomic sperm DNA. Only one study on genomic sperm DNA with patients under NRTI therapy was published without concluding results. Recently, studies have suggested that NRTI exposure could induce an alteration on mitochondrial energy-generating ability of spermatozoa. NRTI are known to induce an increase in the generation of reactive oxygen species, which results in the degradation of mitochondrial transmembrane potential (Deltapsim). This loss of Deltapsim can tend to release some specific apoptosis factors, such as cytochrome c, that initiates programmed cell death. Sperm DNA fragmentation, associated to apoptosis, was reported as a possible cause of recurrent pregnancy loss. If the incorporation of NRTI was reported in genomic DNA of somatic cells, the absence of data on the genomic sperm DNA justifies further studies concerning the effects of paternal exposure to NRTI on the genomic material of the male gamete, in particular because of its implication in the zygote development after fertilization.