Abstract
The d-galactose (d-gal)-injected animal model, which is typically established by administering consecutive subcutaneous d-gal injections to animals for approximately six or eight weeks, has been frequently used for aging research. In addition, this animal model has been demonstrated to accelerate aging in the brain, kidneys, liver and blood cells. However, studies on aging in male reproductive organs that have used this animal model remain few. Therefore, the current study aimed to optimize a model of male reproductive aging by administering d-gal injections to male mice and to determine the possible mechanism expediting senescence processes during spermatogenesis. In this study, C57Bl/6 mice were randomized into five groups (each containing 8–10 mice according to the daily intraperitoneal injection of vehicle control or 100 or 200 mg/kg dosages of d-gal for a period of six or eight weeks). First, mice subjected to d-gal injections for six or eight weeks demonstrated considerably decreased superoxide dismutase activity in the serum and testis lysates compared to those in the control group. The lipid peroxidation in testis also increased in the d-gal-injected groups. Furthermore, the d-gal-injected groups exhibited a decreased ratio of testis weight/body weight and sperm count compared to the control group. The percentages of both immotile sperm and abnormal sperm increased considerably in the d-gal-injected groups compared to those of the control group. To determine the genes influenced by the d-gal injection during murine spermatogenesis, a c-DNA microarray was conducted to compare testicular RNA samples between the treated groups and the control group. The d-gal-injected groups exhibited RNA transcripts of nine spermatogenesis-related genes (Cycl2, Hk1, Pltp, Utp3, Cabyr, Zpbp2, Speer2, Csnka2ip and Katnb1) that were up- or down-regulated by at least two-fold compared to the control group. Several of these genes are critical for forming sperm-head morphologies or maintaining nuclear integration (e.g., cylicin, basic protein of sperm head cytoskeleton 2 (Cylc2), casein kinase 2, alpha prime interacting protein (Csnka2ip) and katanin p80 (WD40-containing) subunit B1 (Katnb1)). These results indicate that d-gal-injected mice are suitable for investigating male reproductive aging.
Highlights
To optimize a model of male reproductive aging, a total of 50 mice were divided into five groups according to the administered D-gal dosage and injection period (Figure 1A): Group 1 (G1; a D-gal dosage of 100 mg/kg administered daily over six weeks), Group 2 (G2; a D-gal dosage of 100 mg/kg administered over eight weeks), Group 3 (G3; a D-gal dosage of 200 mg/kg administered over six weeks ), Group 4 (G4; a D-gal dosage of 200 mg/kg administered over eight weeks) and the vehicle group (control group; Phosphate-buffered saline (PBS) administered over eight weeks)
By conducting cDNA microarray analyses, we identified several spermatogenic genes affected by reproductive aging
These results reveal the possible mechanisms of male reproductive aging
Summary
The increasing trend of delayed parenthood in developed countries is accompanied by an increase in couples with reduced fertility [1,2]. In approximately 50% of couples with reduced fertility, fertility defects can be traced to male partners [3]. Several large-scale clinical studies have indicated that male aging is accompanied by decreased semen quality (e.g., reduced total sperm count, concentration and motility), a decrease in the normal morphological sperm ratio and DNA-fragmented sperm [4,5]. The major reason for diminished semen quality is the accumulation of reactive oxygen species (ROS) and the loss of telomerase activity that accompanies aging [6,7]. Reactive Oxygen Species (ROS) Generation in Testes
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