N6-Methyladenosine and 5-Methylcytosine Epitranscriptomic Regulation of Male Reproduction and Fertility

Functional spermatozoa production depends on spermatogenesis, a complex developmental process that requires precise regulation of gene expression at multiple levels. Although considerable progress has been made in understanding the transcriptional and epigenetic mechanisms governing germ cell development, post-transcriptional regulation mediated by RNA modifications has recently emerged as an important component of male fertility regulation. Epitranscriptomics, the study of chemical RNA modifications and their associated regulatory proteins, has revealed diverse roles for RNA modifications in spermatogenesis, sperm maturation, fertilization, and early embryonic development. Among more than 170 RNA modifications identified to date, N6-methyladenosine (m6A) and 5-methylcytosine (m5C) are well characterized in the male reproductive system. Distinct groups of regulatory proteins function to deposit, remove, and recognize these modifications, thereby controlling RNA fate and metabolism. Functional studies in genetic knockout animal models show that disrupting key epitranscriptomic regulators contributes to abnormal germ cell development at multiple developmental stages. Notably, adverse environmental exposure reprograms the germ cell epitranscriptome, leading to abnormal spermatogenesis and male infertility. In light of recent advances, this narrative review summarizes current progress in male fertility, with particular emphasis on m6A and m5C RNA modifications. Finally, it outlines future perspectives on RNA modification studies in male fertility. Deeper mechanistic insights into male infertility can contribute to the development of new targeted therapies.