title: Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility.
abstract: Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9-19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists.
authors.affiliation: Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Jenkins
authors.affiliation: Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Aston
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Pflueger
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Cairns
authors.affiliation: Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America; Department of Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America; Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Carrell
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010331:Paternal Age; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology; D013094:Spermatozoa / Q000378:metabolism / Q000473:pathology*