Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression

M. H. Milekic, Y. Xin, A. O'Donnell, K. K. Kumar, M. Bradley-Moore, D. Malaspina, H. Moore, D. Brunner, Y. Ge, J. Edwards, S. Paul, F. G. Haghighi, J. A. Gingrich

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.

Original languageEnglish
Pages (from-to)995-1001
Number of pages7
JournalMolecular Psychiatry
Volume20
Issue number8
DOIs
StatePublished - Aug 25 2015

Fingerprint

Dive into the research topics of 'Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression'. Together they form a unique fingerprint.

Cite this