Decreased fertility is becoming an important social and medical problem and the male factor is involved in at least half of infertility cases. Since conventional semen analysis provides limited prediction of male fertility, in this work we evaluated the potential use of seminal small RNAs (sRNA) as markers of semen quality in ART. Our bioinformatic analyses of available sRNA-seq databases showed that the most abundant sRNA species in seminal plasma of normozoospermic men are tRNA-derived fragments (tRFs), a novel class of regulatory sRNAs. These molecules not only exert their function within cells but also are released into the extracellular environment where they could carry out signaling functions. To evaluate whether the assessment of seminal tRFs in normozoospermic men has a predictive value for the clinical outcome in ART, we performed a prospective study with couples who underwent ICSI cycles with donated oocytes. The results obtained demonstrated that levels of 5’tRF-Glu-CTC, 5’tRF-Lys-CTT, and 5’tRF-Gly-GCC are significantly elevated in seminal samples from cases with repeated failed ICSI cycles, suggesting a potential association between increased seminal tRFs and unexplained male infertility. Interestingly, these tRFs showed a negative association with seminal testosterone, highlighting their involvement in male endocrinology. Our findings also suggest that tRFs could play a role in modulating male reproductive function in response to physiological stress since they showed significant associations with the levels of sperm DNA fragmentation in couples that achieved pregnancy but not in cases with failed ICSI cycles where seminal cortisol levels correlate with sperm quality.
The human adrenal cortex, involved in adaptive responses to stress, fluid homeostasis, and secondary sexual characteristics, arises from a tightly regulated development of a zone and cell type-specific secretory pattern. However, the molecular mechanisms governing adrenal zonation, particularly postnatal ZR development, which produces adrenal androgens in a life-time-specific manner, remain poorly understood. The hallmark of ZR is the low expression of type 2 3β-hydroxysteroid dehydrogenase (HSD3B2). However, the mechanisms underlying HSD3B2 downregulation in the ZR remain unknown. MiRNAs are seen as regulators of cell phenotypes. The objective of the study was to compare miRNA expression profiles in human adrenal ZR and zona fasciculata (ZF). ZF and ZR were microdissected from human adrenals tissues (n=5, from boys aged 16, 17 and 19 yr and girls aged 12 and 16 yr) by laser capture microdissection (LCM). Total RNA was extracted from 5 ZF/ZR pairs and next-generation sequencing (NGS) was used to perform the microRNA expression profiling. 281 mature microRNAs were identified in human adrenal cortex. Among them, 7 microRNAs were significantly differentially expressed between ZF and ZR. The expression of miR-375-3p, miR-483-3p and miR-7-5p was higher in ZR compared with its paired ZF by 2-fold or greater. Multiple available bioinformatic algorithms (TargetScan, miRanda, DianaLab and PicTar) were employed to search for its target genes. Among predicted target genes, several genes (GATA-6, GATA-4, SF1, NR4A2, and IGF-1) are known to be involved in HSD3B2 regulation. In summary, LCM combined with NGS provided a robust approach to explore the adrenal zone-specific micro-RNA profiling. Our data gave first hints that miRNAs might be novel regulatory modules associated with human adrenal ZR cell-specific transcript regulation underlying developmental androgen production.
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