Oxidative Stress Mediated by N6-Methyladenosine Methylation Contributes to High-Fat Diet Induced Male Reproductive Dysfunction

Abstract

Objective: To determine the mechanism of oxidative stress mediated by N6-methyladenosine (m6A) methylation contributing to high fat diet-induced reproductive dysfunction.

Results: In vivo, compared with those in the Control group, the sperm count and sperm motility decrease significantly; the testosterone, luteinizing hormone levels, hyaluronidase, acrosomal enzyme levels, and total antioxidant capacity decrease significantly; malondialdehyde increases significantly in the DIO and DIO-R groups. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 1 (SOD1), and NAD(P)H quinone dehydrogenase 1 (NQO1) decreases significantly in the DIO and DIO-R groups; m6A levels in testis tissue in the DIO and DIO-R groups increase; the enrichment of m6A-modified Nrf2 mRNA in testis in the DIO group and DIO-R group increases significantly. Also the m6A regulatory proteins increase significantly in the DIO group and DIO-R group. In vitro, compared to palmitic acid treated cells, the reactive oxygen species (ROS) level significantly decreases in STM2457, S-Adenosylhomocysteine treated cells and YTHDC2, YTHDF2 gene silence cells; however, Nrf2 expression increases in all treated cells. In addition, m6A expression decreases.

Conclusions: Oxidative stress mediates by methylation of m6A may contribute to high fat diet-induced male reproductive dysfunction.

Keywords: Nrf2; high fat diet; m6A; male reproduction; oxidative stress.