Decreased expression of DNA methyltransferases in the testes of patients with non-obstructive azoospermia leads to changes in global DNA methylation levels
Fatma Uysal A B , Gokhan Akkoyunlu A and Saffet Ozturk
A C
+ Author Affiliations
- Author Affiliations
A Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey.
B Department of Histology and Embryology, Ankara University School of Medicine, 06100, Ankara, Turkey.
C Corresponding author. Email: sozturk@akdeniz.edu.tr
Reproduction, Fertility and Development 31(8) 1386-1394 https://doi.org/10.1071/RD18246
Submitted: 27 June 2018 Accepted: 13 February 2019 Published: 29 April 2019
Abstract
DNA methylation plays key roles in epigenetic regulation during mammalian spermatogenesis. DNA methyltransferases (DNMTs) function in de novo and maintenance methylation processes by adding a methyl group to the fifth carbon atom of the cytosine residues within cytosine–phosphate–guanine (CpG) and non-CpG dinucleotide sites. Azoospermia is one of the main causes of male infertility, and is classified as obstructive (OA) or non-obstructive (NOA) azoospermia based on histopathological characteristics. The molecular background of NOA is still largely unknown. DNA methylation performed by DNMTs is implicated in the transcriptional regulation of spermatogenesis-related genes. The aim of the present study was to evaluate the cellular localisation and expression levels of the DNMT1, DNMT3A and DNMT3B proteins, as well as global DNA methylation profiles in testicular biopsy samples obtained from men with various types of NOA, including hypospermatogenesis (hyposperm), round spermatid (RS) arrest, spermatocyte (SC) arrest and Sertoli cell-only (SCO) syndrome. In the testicular biopsy samples, DNMT1 expression and global DNA methylation levels decreased gradually from the hyposperm to SCO groups (P < 0.05). DNMT3A expression was significantly decreased in the RS arrest, SC arrest and SCO groups compared with the hyposperm group (P < 0.05). DNMT3B expression was significantly lower in the RS arrest and SCO groups than in the hyposperm group (P < 0.05). Although both DNMT1 and DNMT3A were localised in the cytoplasm and nucleus of the spermatogenic cells, staining for DNMT3B was more intensive in the nucleus of spermatogenic cells. In conclusion, the findings suggest that significant changes in DNMT expression and global DNA methylation levels in spermatogenic cells may contribute to development of male infertility in the NOA groups. Further studies are needed to determine the molecular biological effects of the altered DNMT expression and DNA methylation levels on development of male infertility.
Additional keywords: DNMTs, male infertility, spermatogenesis, testis.
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