Using MethylC capture sequencing, the authors identified over 38,000 differentially methylated CpGs in the sperm of men with an elevated BMI, overlapping with regions associated with advanced paternal age, enriched for neural gene and disease ontologies and localized to transposable elements and early lineage-specification promoters, suggesting sperm methylome alterations linked to elevated BMI may influence key embryonic transcriptional processes, notably those associated with trophectoderm and placental development.
Men with elevated BMI have over 38,000 differentially methylated CpGs in their sperm compared with other men.
Sperm methylation changes linked to elevated BMI overlap with regions associated with advanced paternal age.
Differentially methylated regions are enriched for neural genes and disease ontologies.
Differentially methylated regions localize to transposable elements that can act as active enhancers during human zygotic genome activation.
Differentially methylated regions are also found at gene promoters involved in early lineage specification.
This study examined sperm from men with different body mass index (BMI) and ages to see whether the chemical tags on DNA, called DNA methylation, differ. These tags help control which genes are switched on or off. The researchers found more than 38,000 spots in the sperm DNA of men with higher BMI where the methylation pattern was different, and some of these overlapped with regions known to change with a man's age. Many of the altered regions were near genes involved in brain development and neurological disease. Others were in DNA elements and gene control regions that become active in the very early embryo, including those important for forming the placenta. This suggests a possible biological route by which a father's weight and age could influence his child's development, which may help explain epidemiological links to childhood neurodevelopmental disorders. The abstract describes associations in sperm only and does not show that these changes cause disease in children. The findings suggest that sperm methylation could influence early embryonic gene activity, but further research would be needed to confirm any effect on offspring health.
Schulz M, Shao X, Lambrot R, Lafleur C, Chan D, Dumargne M, et al.. (2026). Altered sperm DNA methylation provides an epigenetic route from overweight and older men to intergenerational disease transmission.. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2534171123