Increased N6-methyladenosine in Human Sperm RNA as a Risk Factor for Asthenozoospermia

Abstract

Male infertility is a worldwide medical problem. Asthenozoospermia is a common cause of infertility. Epigenetic modifications of DNA and histones have been shown to influence human infertility, but no research has explored whether N6-methyladenosine (m6A) level in RNA is associated with asthenozoospermia. Here, we collected a total of 52 semen samples, including 20 asthenozoospermia patients and 32 healthy controls. An LC-ESI-MS/MS method was used to detect m6A contents in sperm RNA, and real-time PCR was performed to determine the mRNA expression of demethylase (FTO, ALKBH5), methyltransferase (METTL3, METTL14, WTAP) and an m6A-selective-binding protein (YTHDF2). We found that m6A content (p = 0.033) and the mRNA expression of METTL3 (p = 0.016) and METTL14 (p = 0.025) in asthenozoospermia patients were significantly higher than those of controls. Increased m6A content was a risk factor for asthenozoospermia (odds ratio (OR) 3.229, 95% confidence interval (CI) 1.178 – 8.853, p = 0.023). Moreover, m6A content was correlated with the expression of METTL3 (r = 0.303, p = 0.032) and with sperm motility (progressive motility: r = −0.288, p = 0.038; non-progressive motility: r = −0.293, p = 0.037; immotility: r = 0.387, p = 0.005). Our data suggest that increased m6A content is a risk factor for asthenozoospermia and affects sperm motility. Methyltransferases, particularly METTL3, play key roles in increasing m6A contents in sperm RNA.

Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice

“…In humans, increased expression of FTO, METTL3 and METTL14 , as well as levels of m 6 A, have been identified in the sperm of infertile men (Yang et al . ), in addition to significant changes in both histone modification and DNA methylation status (Rahiminia et al . ).…”

The RNA Modification N 6-Methyladenosine and Its Implications in Human Disease

“…While Alkbh5 null mice are viable and appear anatomically normal, they exhibit impaired fertility due to the apoptosis of meiotic metaphase-stage spermatocytes [39]. A study of human asthenozoospermia patients found a correlation between elevated METTL3 and m 6 A levels, and sperm motility [49]. ALKBH5 localizes to the nucleus, and loss of ALKBH5 impairs mRNA export, RNA metabolism, and assembly of mRNA processing factors in nuclear speckles [39].…”

METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N 6‐methyladenosine‐dependent primary MicroRNA processing

“…Perturbations of the regulatory machinery of m 6 A modification might be associated with human diseases or cancers. For example, METTL3 and METTL14 increase m 6 A levels of sperm in asthenozoospermia . FTO expression inversely correlates with m 6 A levels during adipogenesis, and ALKBH5 deficiency reduces m 6 A levels and leads to compromised spermatogenesis in mice .…”