miR-125a-5p increases cellular DNA damage of aging males and perturbs stage-specific embryo development via Rbm38-p53 signaling

An increasing number of men are fathering children at an older age than in the past. While advanced maternal age has long been recognized as a risk factor for adverse reproductive outcomes, the influence of paternal age on reproduction is incompletely comprehended. Herein, we found that miR-125a-5p was upregulated in the sperm of aging males and was related to inferior sperm DNA integrity as an adverse predictor. Moreover, we demonstrated that miR-125a-5p suppressed mitochondrial function and increased cellular DNA damage in GC2 cells. We also found that miR-125a-5p perturbed embryo development at specific morula/blastocyst stages. Mechanistically, we confirmed that miR-125a-5p disturbed the mitochondrial function by targeting Rbm38 and activating the p53 damage response pathway, and induced a developmental delay in a p21-dependent manner. Our study revealed an important role of miR-125a-5p in sperm function and early embryo development of aging males, and provided a fresh view to comprehend the aging process in sperm.

Automated summary

This study identified that miR-125a-5p is upregulated in the sperm of aging males and is associated with inferior sperm DNA integrity, suppressed mitochondrial function, increased cellular DNA damage, and perturbed embryo development. Mechanistically, miR-125a-5p targets Rbm38 and activates the p53 damage response pathway, leading to a developmental delay in a p21-dependent manner. This research provides important insights into the role of miR-125a-5p in sperm function and early embryo development in aging males.