title: Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.
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.
authors.affiliation: Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Milekic
authors.affiliation: Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: O'Donnell
authors.affiliation: Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Kumar
authors.affiliation: Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bradley-Moore
authors.affiliation: 1] Department of Psychiatry, New York University, New York, NY, USA [2] Department of Psychiatry, New York University, and The NY OMH Creedmoor Psychiatric Center, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Malaspina
authors.affiliation: Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Moore
authors.affiliation: 1] Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA [2] PsychoGenics, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Brunner
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Helen & Robert Appel Institute for Alzheimer's Research, Mind and Brain Institute, Weill Cornell Medical School, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Haghighi
authors.affiliation: Department of Psychiatry, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gingrich
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D019175:DNA Methylation; D005220:Fathers; D015870:Gene Expression / Q000235:genetics; D008297:Male; D057507:Mice, 129 Strain; D009043:Motor Activity / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics; D013094:Spermatozoa
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