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A team of Japanese scientists have revealed a mechanism associated with an increased risk of behavioural defects among offspring of older fathers in a mouse study, with strong indications similar processes are involved in humans. The researchers examined the link between behavioural defects in mice, specifically animal communication, and lack of DNA methylation - a major process controlling the expression of genes with a critical role in cell development, ageing and diseases such as cancer. Attachment of methyl groups to the DNA (DNA methylation) is a major epigenetic mechanism that plays an important part in neurological development by ensuring that particular proteins are expressed by their coding genes in specific brain tissues, while being suppressed in tissue where their presence would be damaging.

In the study, whole-genome analysis of sperm from old mice (more than one year of age) identified reduced levels of DNA methylation in genomic regions with specific binding sites for a transcriptional repressor called REST. In young male mice (three months of age), DNA methylation was present at REST target sites allowing normal neuron tissue development. In the older mice, reduced methylation levels at REST binding sites in the sperm genome might impact gene expression in the developing embryonic brain of the offspring, leading to behavioural defects, whereas brains among offspring of younger mouse fathers develop normally.

Further evidence that this process plays a key role in reducing neural tissue development was obtained by administering young male mice with a DNA de-methylation drug to emulate reduced methylation in the older animals. Importantly, their offspring exhibited a similarly reduced vocal communication range.

The researchers went on to observe that mice exhibiting this vocal impairment also tended to have smaller brains, a thinner primary motor cortex and fewer neurons in one of the deep layers. Smaller brains are common in both humans and mice with impairments in the REST pathway.

The findings are relevant in the wider context of the Developmental Origin of Health and Disease (DOHaD) concept. First proposed in the 1980s, this approach links the health status and risk of disease in later childhood and adult life with environmental conditions in early life. This concept was originally associated mostly with maternal influence on offspring, but has more recently been expanded to include paternal influence. This study adds further weight to accumulating evidence that besides exposure to environmental contaminants, advanced paternal age also may have negative effects on the health of the next generation, including low birth weight, psychiatric disorders such as schizophrenia and autism spectrum disorder (ASD).

Further research is needed to establish the direct connections between reduced DNA methylation of these genomic regions in sperm and expression of key target genes in the embryonic brain linking to subsequent behavioural abnormalities. While the degree of DNA methylation now appears quite clear through correlation, molecular mechanisms underlying the developmental and causal events remain to be elucidated. There is also further work to be done determining whether the same mechanisms are implicated in developmental consequences from paternal exposure to environmental contamination.

Publication Details:

Title: Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF
Authors: Kaichi Yoshizaki, Ryuichi Kimura, Hisato Kobayashi, Shinya Oki, Takako Kikkawa, Lingling Mai, Kohei, Koike, Kentaro Mochizuki, Hitoshi Inada, Yasuhisa Matsui, Tomohiro Kono, Noriko Osumi
DOI: 10.15252/embr.202051524