The Quest for the Origin of Male Infertility

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In men that have apparently normal semen parameters, the inability to support a successful pregnancy indicates a concealed abnormality that may impair gamete competence. In these 113 men with a normal peripheral karyotype and a chromatin fragmentation of 18.2 ± 8% (range 8.6 – 32.4%), the quest for the origin of male infertility can be initiated with the assessment of the gamete chromosomal status. Interestingly, there was a progressive increase in aneuploidy of the gonosomes but most importantly of the autosomes in relation to advancing male age. While this appears more dramatic for specific chromosomes like Chr 15 and 17, we noticed that Chr 21 abnormalities appeared higher in younger men.

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These findings were better evaluated by determining specific copy number variants of sequenced DNA in individual spermatozoa. Indeed, with this approach all chromosomes were sequenced, resulting in a more accurate aneuploidy assessment. Semen specimens of men unable to conceive (n=10) were compared to infertile individuals (n=6). In order to provide an appropriate control, the genetic profile of proven fertile donors (n=2) was also assessed. The group defined as infertile retained the ability to achieve fertilization and support the development of conceptuses capable of implanting, but resulted in pregnancy loss). While the standard FISH technique was unable to disclose differences among the groups of men studied, whole chromosome sequencing evidenced that overall aneuploidy was increased in men successfully treated by ART and even higher in infertile men (P<0.0001) when compared to control. Once the chromosome types were queried, both autosomal and the sex chromosomes appeared to be affected. An advantage of sequencing technology is the ability to identify specific genes and whether there are mutations involved. According to the highest CNV observed, we depicted 10 genes and an additional 4 pseudogenes. Their action ranged from general ancillary cellular function in the testis to meiotic crossing-over regulation, sperm development, involvement in sperm-egg fusion, and nucleus-cytoplasmic transport of RNA. When considering couples treated by different assisted reproduction techniques, we identified gene mutation commonalities arising from gene deletions and duplications. Indeed, in couples that were treated by IUI, only pseudogenes were involved (TPTE2P4), while for the couples treated by in vitro insemination (IVF) a gene involved in spermatogenesis was imbalanced (RBMY1F). In men requiring ICSI, genes (DPY19L2) involved in supporting specific functional components of the male gamete such as the acrosome were mutated. For men treated by testicular biopsy, a larger number of genes were involved in contributing to basic cellular functions (ANKRD36B), androgen production modulation (SIRPB1), or activation of germ stem cells (CSF2RA). Interestingly, men treated by IVF or ICSI shared in common imbalance of a gene involved in meiotic crossing-over. Finally, all couples requiring some forms of assisted conception had mutations in ADAM3A and NXF2, genes responsible for supporting sperm-egg fusion and RNA nucleus-cytoplasmic transport, respectively.

An analysis of gene duplications and deletions confirmed a progressive increase in genomic mutations (P<0.05) for men with a reduced or compromised ability to generate offspring when compared to the fertile individuals and control.

Age also can affect fertility, even if it is not clear whether the culprit is cell aging itself or the consequence of an environmental insult that has become manifested with the advancing aging process of the individual. These epigenetic insults vary, particularly regarding the male gamete, from the ability of the spermatozoon to carry a cytosolic factor capable of activating the oocyte to the ability to provide a functional centrosome that will ordain the chromosomal segregation at the first mitotic division of the conceptus. Our goal, in this study, is to query the expression of specific genes involved in meiotic spermatogenesis and of those involved in supporting the formation of the sperm cell in its fully functional form. We assessed gene expression on 10 individuals by isolating RNA from their semen specimens. Among them, we specifically compared men treated by ART but unable to conceive versus men that successfully achieved a pregnancy through assisted reproduction in comparison to donor control. Sequencing the extracted spermatozoa RNA of about 23,260 genes, we identified 86 of them as imbalanced compared to donor controls, 24 of which were actually overexpressed while predominantly 62 were indeed under-expressed. The overall function of the under-expressed genes involved nuclear compaction, centrosomal development, mitochondrial activity, as well as flagellar development and function. Moreover, 7 genes were significantly under-expressed (P<0.001). Activity of these genes, mainly involved in apoptosis (MORC1/TNFRSF21/ZFAND6) and DNA repair mechanisms (APLF/ERCC4), appeared to decrease with male age (P<0.05) and inversely correlated with sperm DNA fragmentation (P<0.05). In addition, the corresponding gene products localized within specific components of the spermatozoon, were predictive of the proficiency of the spermatozoon in displaying proper motility (P<0.01) and bearing the ability to fertilize an oocyte (P<0.05).

Among all genes assessed, we evidenced 28 (0.1%) ncRNAs that were differently expressed (P<0.0005) between the control cohort (n=3) and men (n=5) treated by ICSI achieving a fertilization of 71.4% (30/42) but not capable of sustaining a pregnancy. Of these transcripts, 21/28 (75.0%) were long non-coding RNA and 7/21 (25.0%) were attributed as small non-coding RNA. Additionally, 16 ncRNA genes were completely unexpressed in the cohort of men unable to conceive. In relation to their function, most of these (11/16, 68.8%) non-protein-coding RNA appeared to guide chemical modification of other RNAs, influence methylation, and modulate stability and translation of messenger RNA. Interestingly, 13/16 (81.3%) ncRNA were located on autosomes, while only three genes were located on the sex chromosomes, following a similar distribution of spermatogenesis related genes.

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