Abstract
The elderly males undergo degenerative fertility and testicular endocrine function that jeopardize the reproductive health and well-being. However, the mechanisms underlying reproductive aging are unclear. Here, we tried to address this by investigating the phenotypes and transcriptomes of seven regions of the male mouse reproductive tract: the testis, efferent ductules, initial segment, caput, corpus and cauda epididymidis, and vas deferens, in adult (3 months) and aged (21 months) mice. Quantitative PCR, immunohistochemistry, immunofluorescent staining, and enzyme-linked immunosorbent assay were performed for the analysis of gene expression in mice, human tissues, and semen samples. Aged male mice showed both systematic and reproductive changes, and remarkable histological changes were detected in the testis and proximal epididymis. Transcriptomes of the male reproductive tract were mapped, and a series of region-specific genes were identified and validated in mouse and/or human tissues, including Protamine 1 (Prm2), ADAM metallopeptidase domain 28 (Adam28), Ribonuclease A family member 13 (Rnase13), WAP four-disulfide core domain 13 (Wfdc13), and Wfdc9. Meanwhile, age-related transcriptome changes of different regions of the male reproductive tract were characterized. Notably, increased immune response was functionally related to the male reproductive aging, especially the T cell activation. An immune response-associated factor, phospholipase A2 group IID (Pla2g2d), was identified as a potential biomarker for reproductive aging in mice. And the PLA2G2D level in human seminal plasma surged at approximately 35 years of age. Furthermore, we highlighted Protein tyrosine phosphatase receptor type C (Ptprc), Lymphocyte protein tyrosine kinase (Lck), Microtubule associated protein tau (Mapt), and Interferon induced protein with tetratricopeptide repeats 3 (Ifit3) as critical molecules in the aging of initial segment, caput, caput, and cauda epididymidis, respectively. This study provides an RNA-seq resource for the male reproductive system during aging in mice, and is expected to improve our understanding of male reproductive aging and infertility.
Highlights
Aging is a progressive process involving gradual declines in the functions of multiple organs and cells
To determine whether 21-month-old male mice are a suitable model for the natural reproductive aging, we comprehensively studied phenotypes associated with reproductive aging as well as systemic aging
We identified a series of region-specific genes of male mouse reproductive tract (Figures 2B,C), which were in broad agreement with those of previous RNA-seq and microarray analyses of murine transcriptome profiles, such as ADAM metallopeptidase domain 28 (Adam28) in initial segment, Transmembrane Epididymal Protein 1 (Teddm1b) in caput, and serine peptidase inhibitor, Kunitz type 3 (Spint3) in corpus epididymis (Johnston et al, 2005; Shi et al, 2021)
Summary
Aging is a progressive process involving gradual declines in the functions of multiple organs and cells. A delay in the age of paternity due to social factors has resulted in aging-related fertility concerns (Sharma et al, 2015). Advanced age is negatively correlated with sperm concentration, motility, normal morphological changes, serum testosterone concentration, and reproductive outcomes (Sharma et al, 2015; Gunes et al, 2016). The sperm of elderly men are more likely to bear genetic and epigenetic defects, leading to an elevated risk of pregnancy loss and birth defects in offspring (Yoon et al, 2009; Kong et al, 2012; Paoli et al, 2019; Potabattula et al, 2020). The exact mechanisms underlying male reproductive aging remain largely unclear
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