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Idiopathic Infertility and Genome Instability
Infertility (defined as the inability to conceive within a year of unprotected coitus) is a global health and social issue affecting close to 15% of couples. In half of the couples seeking medical treatment for infertility, male factor infertility is identified together with abnormal semen characteristics. The focus of current clinical practice is laid on the presence of sufficient sperm count in the ejaculated specimen with adequate motility and morphology of spermatozoa capable of giving fertilization a chance (conventional semen analysis).
Genome instability may play a role in severe cases of male infertility, with disrupted spermatogenesis being just one manifestation of decreased general health and increased morbidity. Here, we review the data on the association of male infertility with genetic, epigenetic, and environmental alterations, the causes and consequences, and the methods for assessment of genome instability. Male infertility research has provided evidence that spermatogenic defects are often not limited to testicular dysfunction. An increased incidence of urogenital disorders and several types of cancer, as well as overall reduced health (manifested by decreased life expectancy and increased morbidity) have been reported in infertile men. The pathophysiological link between decreased life expectancy and male infertility supports the notion of male infertility being a systemic rather than an isolated condition. It is driven by the accumulation of DNA strand breaks and premature cellular senescence. We have presented extensive data supporting the notion that genome instability can lead to severe male infertility termed “idiopathic oligo-astheno-teratozoospermia.” We have detailed that genome instability in men with oligo-astheno-teratozoospermia (OAT) might depend on several genetic and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic mutations, RT, PIWI/piRNA regulatory pathway, pathogenic allelic variants in repair system genes, DNA methylation, environmental aspects, and lifestyle factors.
In summary, there are extensive data supporting the notion that genome instability may lead to severe male infertility (OAT), whereas genetic tests recommended for routine clinical investigation (such as testing for karyotype, Y chromosome AZF region microdeletions) provide a diagnosis in only 15–25% of cases. We have detailed that genome instability in men with OAT depends on several other genetic and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic mutations, RT, PIWI/piRNA regulatory pathway, pathogenic allelic variants in repair system genes, DNA methylation, and environmental aspects (e.g., smoking, alcohol).
The entry is from 10.3390/life11070628
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