Human Molecular Genetics Advance Access originally published online on July 17, 2007
Human Molecular Genetics 2007 16(21):2542-2551; doi:10.1093/hmg/ddm187
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Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients
1 Department of Obstetrics, 2 Department of Gynecology, and 3 The 21st Century COE Program, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan, 4 St Luke Clinic, Oita, Japan, 5 Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Japan and 6 Department of Genetics, The Graduate University for Advanced Studies (Sokendai), Mishima, Japan
* To whom correspondence should be addressed. Tel: +81 227177844; Fax: +81 227177872; Email: tarima{at}mail.tains.tohoku.ac.jp
Received May 17, 2007; Accepted July 11, 2007
Recent studies suggest that assisted reproductive technologies (ART), which involve the isolation, handling and culture of gametes and early embryos, are associated with an increased incidence of rare imprinting disorders. Major epigenetic events take place during this time and the process of ART may expose the epigenome to external influences, preventing the proper establishment and maintenance of genomic imprints. However, the risks of ART cannot be simply evaluated because the patients who receive ART may differ both demographically and genetically from the general population at reproductive age. In this study, we examined the DNA methylation status of seven imprinted genes using a combined bisulphite-PCR restriction analysis and sequencing technique on sperm DNA obtained from 97 infertile men. We found an abnormal paternal methylation imprint in 14 patients (14.4%) and abnormal maternal imprint in 20 patients (20.6%). The majority of these doubly defective samples were in men with moderate or severe oligospermia. These abnormalities were specific to imprinted loci as we found that global DNA methylation was normal in these samples. The outcome of ART with sperm shown to have an abnormal DNA methylation pattern was generally poor. However, one sample of sperm with both paternal and maternal methylation errors used in ICSI produced a child of normal appearance without any abnormalities in their imprinted methylation pattern. Our data suggest that sperm from infertile patients, especially those with oligospermia, may carry a higher risk of transmitting incorrect primary imprints to their offspring, highlighting the need for more research into ART.
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