The knockout mice models of

The knockout mice models of the DNMTs gene shed light on understanding the molecular background of male infertility development. Dnmt1−/− causes demethylation of the genome (Lei et al, 1996, Li et al, 1992) (). The Dnmt3a conditional knockout mouse models exhibit spermatogenic arrest at the spermatogonial stage (Kaneda et al., 2004) and also Dnmt3a knockout male mice have azoospermia (Bourc'his, Bestor, 2004, Kaneda et al, 2004) whereas the Dnmt3b conditional knockout mice shows no infertile phenotype (Kaneda et al, 2004, Okano et al, 1999) (). The Dnmt3L knockout () mice are viable, but female mice fail to create viable pups (Saitou et al., 2012); however, the males are infertile showing the characteristic features of azoospermia (Bourc'his et al, 2001, Hata et al, 2002) (). Additionally, lack of the Dnmt3L gene causes loss of paternal methylation imprints, especially on the H19 locus (Bourc'his, Bestor, 2004, Kaneda et al, 2004, Webster et al, 2005). As is known, although DNMT3L does not include any catalytic activity, it plays an important role in normal spermatogenesis (Vlachogiannis et al., 2015). Hata et al. (2006) examined histological structures of the testes at 7 weeks after birth (Hata et al., 2006). They found that the testes involve no spermatids and consist of only pre-leptotene or leptotene spermatocytes and Sertoli cells, meaning that there is no development pachytene spermatocytes or subsequent cell types. Furthermore, the expression of sex-chromosome-linked genes and gonad-specific genes are prominently decreased in the testes when compared with wild type counterparts (Hata et al., 2006). In another work, disruption of the Dnmt3a or Dnmt3L gene functioning in de novo methylation, causes H19 hypomethylation in the prospermatogonial clobetasol price mg in mice (Kato et al., 2007). Recently, Urdinguio et al. (2015) indicated that DNA methylation levels in the sperm cells obtained from patients with unexplained infertility exhibited different methylation patterns compared with the spermatozoa from fertile men: 2752 CpG sites exhibited abnormal DNA methylation patterns (Urdinguio et al., 2015) (). Of the total CpG sites analysed here, 1305 CpG sites were found to be hypomethylated, whereas 1447 of them underwent hypermethylation in the infertile patients. The data suggested that the significant changes of DNA methylation may be due to the presence of sperm specific methylation regions, which show predominant differences between fertile and infertile groups (Urdinguio et al., 2015). In recently published studies, researchers found that some demographic factors such as cigarette smoking and ageing may negatively affect DNA methylation establishment during spermatogenesis. For example, cigarette smoking causes an increased DNA methylation at the promoter region of the Pebp1 (Phosphatidylethanolamine binding protein 1) gene in mice testis, and some of the distinctly methylated genes are known to be closely associated with spermatogenesis (Xu et al., 2013) and the remaining genes function in other somatic tissues (Scoccianti et al, 2011, Wangsri et al, 2012, Word et al, 2013). In a study evaluating the effect of ageing on DNA methylation, sperm cells from old mice possessed remarkably lower global DNA methylation levels in comparison with the sperm cells from young ones (Milekic et al., 2015). In addition, environmental stress also induces alterations in DNA methylation status of mammalian cells (Elhamamsy, 2016). Environmental factors such as cadmium exposure (Virani et al., 2016) and tobacco smoking can cause DNA methylation changes (Ambatipudi et al., 2016), and maternal smoking during pregnancy leads to DNA methylation impairments in the newborns (Joubert et al., 2016). In a recent study by Radford et al. (2014), they revealed that the in-utero nutritional environment potentially affects the male germ cell methylome, which may have an association with improving metabolic diseases in offspring (Radford et al., 2014). On the other hand, in females, aging is capable of altering global DNA methylation levels and expression profile of DNMT1, DNMT3A, DNMT3B and DNMT3L in MII oocytes and preimplantation embryos (except blastocyst). The global DNA methylation and expression of the DNMT proteins were predominantly reduced in the MII oocytes and preimplantation embryos from old mice when compared with young mice (Yue et al., 2012).