CircRNA Role and circRNA-Dependent Network (ceRNET) in Asthenozoospermia

Abstract

The role of circRNA in reproduction is under investigation. CircRNAs are expressed in human testis, spermatozoa (SPZ), and seminal plasma. Their involvement in embryo development has also been suggested. Asthenozoospermia, a common cause of male infertility, is characterized by reduced or absent sperm motility in fresh ejaculate. While abnormal mitochondrial function, altered sperm tail, and genomic causes have been deeply investigated, the epigenetic signature of asthenozoospermic derived SPZ still remains unexplored. CircRNAs may take part in the repertoire of differentially expressed molecules in infertile men. Considering this background, we carried out a circRNA microarray, identifying a total of 9,138 transcripts, 22% of them novel based and 83.5% with an exonic structure. Using KEGG analysis, we evaluated the circRNA contribution in pathways related to mitochondrial function and sperm motility. In order to discriminate circRNAs with a differential expression in SPZ with differential morphological parameters, we separated sperm cells by Percoll gradient and analyzed their differential circRNA payload. A bioinformatic approach was then utilized to build a circRNA/miRNA/mRNA network. With the aim to demonstrate a dynamic contribution of circRNAs to the sperm epigenetic signature, we verified their modulation as a consequence of an oral amino acid supplementation, efficacious in improving SPZ motility.

Environmental Impact on Male (In)Fertility via Epigenetic Route

“…Accordingly, tsRNAs, rsRNAs, and miRNAs show a differential expression, linked to sperm quality, according to embryo quality, regardless traditional semen-parameter assessment [ 137 ]. This result is perfectly in line with evidence about circRNA content, much richer in asthenozoospermic patients, in comparison to normozoospermic individuals [ 105 , 111 ]. Unlike what has been thought for decades, sperm RNAs provide crucial information on sperm competence, embryo development and infertility etiology [ 138 , 139 ].…”

“…CircRNAs have been discovered in human embryos [ 109 , 110 ] and are potentially involved in chromosome organization, cell cycle regulation and DNA repair. First considered a maternal contribution to the embryonic inheritance, they have been now characterized in mouse and in human SPZ, collected from both normozoospermic and asthenozoospermic subjects [ 105 , 106 , 111 ]. Indeed, due to the differential pattern of expression observed, circRNAs have been suggested as a possible sperm quality markers [ 105 , 111 ].…”

“…First considered a maternal contribution to the embryonic inheritance, they have been now characterized in mouse and in human SPZ, collected from both normozoospermic and asthenozoospermic subjects [ 105 , 106 , 111 ]. Indeed, due to the differential pattern of expression observed, circRNAs have been suggested as a possible sperm quality markers [ 105 , 111 ]. Interestingly, paternal circRNAs may be transferred from SPZ into the oocyte during fertilization as in the case of SPZ-derived circNAPEPLDiso1, a circRNA of NAPEPLD, the enzyme involved in the biosynthesis of the endocannabinoid anandamide (AEA) [ 112 ], which has key roles in reproductive functions [ 113 , 114 , 115 , 116 , 117 , 118 ].…”

Screening, Identification and Interaction Analysis of Key MicroRNAs and Genes in Asthenozoospermia

“…Abnormal sperm morphology, poor sperm motility and low sperm count are identi ed as common causes of male infertility. According to the criteria reported by the World Health Organization, asthenozoospermia is characterized by total motility < 40% and progressive motility < 32% in fresh semen samples [3]. Several factors have been con rmed to be associated with asthenozoospermia, as shown in Fig.…”

CircRNA hsa_circ_0008500 Acts as a miR-1301-3p Sponge to Promote Osteoblast Mineralization by Upregulating PADI4

“…With accumulating knowledge of features and functions of circRNAs, these are now regarded as pivotal regulators in various biological processes. Interestingly, circRNAs modulation downstream oral amino acid supplementation improves sperm vitality and motility, showing the relationship between differentially expressed circRNAs and drug therapy (Manfrevola et al, 2020). To date, only a small number of circRNAs have been functionally characterized.…”