In Western society, couples increasingly delay parenthood until later in life. Overall, studies have focused on the reproductive performance of older parents or the impact of advanced maternal age on pregnancy outcomes, but few studies have examined how advanced paternal age (APA) affects offspring health. The aim of this study was to investigate the impact of increasing paternal age on offspring reproductive performance and long-term metabolic health in a mouse model. Here, the same adult B6D2F1/J male mice were mated at 4, 12, and 18 months of age with 6- to 10-week-old naturally cycling CF1 females to generate 3 offspring cohorts conceived at increasing paternal ages PA4, PA12, and PA18. The offspring resulting from mating the same fathers at different ages (n = 20 per age; 10 males and 10 females) were maintained up to 20 weeks of age and morphometric parameters, growth curve, and glucose tolerance were measured. We found that increasing paternal age was associated with a trend toward longer time to conception. Litter sizes were not significantly different. Reassuringly, metabolic parameters and growth curve were not different in the 3 cohorts of offspring. Most importantly, increased paternal age (PA4 vs PA18) was associated with a statistically significant decrease in sperm concentration, sperm motility, and anogenital distance in offspring. These changes raise concerns about the potential impact of APA on the reproductive fitness in males of the next generation.

Although recent evidence indicates that several chemokines and defensins, well-known as inflammatory mediators, are expressed in the male and female reproductive tracts, the location and functional significance of chemokine networks in sperm physiology and sperm reproductive tract interactions are poorly understood. To address this deficiency in our knowledge, we examined the expression and function in sperm of CCR6, a receptor common to several chemoattractant peptides, and screened several reproductive tract fluids for the presence of specific ligands. CCR6 protein is present in mouse and human sperm and mainly localized in the sperm tail with other minor patterns in sperm from mice (neck and acrosomal region) and men (neck and midpiece regions). As expected from the protein immunoblotting and immunofluorescence results, mouse Ccr6 mRNA is expressed in the testis. Furthermore, the Defb29 mRNA encoding the CCR6 ligand, β-defensin DEFB29, is expressed at high levels in the epididymis. As determined by protein chip analysis, several chemokines (including some that act through CCR6, such as CCL20/MIP-3α (formerly macrophage inflammatory protein 3α) and protein hormones were present in human follicular fluid, endometrial secretions, and seminal plasma. In functional chemotaxis assays, capacitated human sperm exhibited a directional movement towards CCL20, and displayed modifications in motility parameters. Our data indicate that chemokine ligand/receptor interactions in the male and female genital tracts promote sperm motility and chemotaxis under non-inflammatory conditions. Therefore, some of the physiological reactions mediated by CCR6 ligands in male reproduction extend beyond a pro-inflammatory response and might find application in clinical reproduction and/or contraception.