NCOA5 Haplo-insufficiency Results in Male Mouse Infertility through Increased IL-6 Expression in the Epididymis

Male infertility might be caused by genetic and/or environmental factors that impair spermatogenesis and epididymal sperm maturation. Here we report that heterozygous deletion of the nuclear receptor coactivator-5 (Ncoa5) gene resulted in decreased motility and progression of spermatozoa in the cauda epididymis, leading to infertility in male mice. Light microscopic and ultrastructural analysis revealed morphological defects in the spermatozoa collected from the cauda epididymis of Ncoa5^+/- mice. Immunohistochemistry showed that interleukin-6 (IL-6) expression in epithelial cells of Ncoa5^+/- epididymis was higher than wild type counterparts. Furthermore, heterozygous deletion of Il-6 gene in Ncoa5^+/- male mice partially improved spermatozoa motility and moderately rescued infertility phenotype. Our results uncover a previously unknown physiological role of NCOA5 in the regulation of epididymal sperm maturation and suggest that NCOA5 deficiency could cause male infertility through increased IL-6 expression in epididymis.