Deficiency in mouse Y chromosome long arm gene complement is associated with sperm DNA damage

We observed that epididymal sperm from mice with severe NPYq deficiency (that is, deletion of nine-tenths or the entire NPYq gene complement) are impaired in oocyte activation ability following ICSI and there is an increased incidence of oocyte arrest and paternal chromosome breaks. Comet assays revealed increased DNA damage in both epididymal and testicular sperm from these mice, with epididymal sperm more severely affected. In all mice the level of DNA damage was increased by freezing. Epididymal sperm from mice with severe NPYq deficiencies also suffered from impaired membrane integrity and abnormal chromatin condensation and suboptimal chromatin protamination. It is therefore likely that the increased DNA damage associated with NPYq deficiency is a consequence of disturbed chromatin remodeling.This study provides the first evidence of DNA damage in sperm from mice with NPYq deficiencies and indicates that NPYq-encoded gene/s may play a role in processes regulating chromatin remodeling and thus in maintaining DNA integrity in sperm.The DNA of the male specific region of the mouse Y chromosome long arm (NPYq) is highly repetitive and includes multiple copies of at least five distinct genes: Ssty1, Ssty2, Sly, Asty, and Orly [1,2] (J Alfoldi and DC Page, personal communication). These genes are exclusively expressed in spermatids during the final stages of spermatogenesis [1-3]. NPYq deficiency leads to teratozoospermia, subfertility with progeny sex ratio skewed towards females, or to complete infertility [4-8]. We have previously shown that infertility of mice with severe NPYq deficiencies can be overcome with intracytoplasmic sperm injection (ICSI) [8,9]; however, the overall efficiency of ICSI was unsatisfactory. This was particularly marked in further ICSI trials with frozen epididymal sperm from males lacking NPYq; despite using artificial oocyte activation, a total of 287 oocytes injected and 101 embryos transferred into 7 surrogates yielded only 1 pregnancy