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.

Effects of aging on the male reproductive system

“…These aberrations in DNA methylation were transmitted to the offspring although some of them are known to be reset during prenatal life. The results have shown that both CGI regions and splice junctions are abnormally methylated in older fathers' offspring and these genomic regions correspond to neurodevelopmental genes implicated in autism and schizophrenia [130].…”

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress

“…Posttranslational histone modifications, DNA methylation patterns, and populations of small noncoding RNAs in sperm have been implicated in the transgenerational transmission of paternal experience, with changes in these epigenetic marks observed following male exposure to such diverse stimuli as stress, malnutrition, and drugs of abuse (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In particular, the role of sperm RNA as a mechanistic link between paternal experience and its consequences on offspring behavior and physiology has been emphasized by recent studies that characterize offspring phenotypes following in vitro fertilization and/or the experimental manipulation of total sperm RNA content (12,20).…”

“…Rodent models examining paternal transmission have identified epigenetic signatures in mature sperm as possible substrates of transgenerational programming, namely patterns of retained histone modifications, DNA methylation, and/or populations of small noncoding RNAs (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). RNA populations are of primary interest, as they may be altered through intercellular communication via epididymosomes even in transcriptionally inert mature sperm, where DNA condensation impedes other epigenetic change (22)(23)(24).…”

Sperm DNA Methylation, Infertility and Transgenerational Epigenetics

“…Furthermore, Milekic et al, found that mice born to older males had DNA methylation abnormalities in the brain, which were similar to abnormalities seen in the paternal sperm of old mice but not in young mice. The off spring also exhibited behavioural differences that illustrate the effects of this aberrant methylation [86]. These studies indicate age-related DNA methylation changes in sperm may be retained in the embryo.…”