Altered sperm DNA methylation provides an epigenetic route from overweight and older men to intergenerational disease transmission.

Creator(s)

• Mathieu Schulz
• Xiaojian Shao
• Romain Lambrot
• Christine Lafleur
• Donovan Chan
• Marie-Charlotte Dumargne
• Amanda J. MacFarlane
• Sergey Moskovtsev
• Guillaume Bourque
• Tomi Pastinen, Children's Mercy HospitalFollow
• Clifford Librach
• Hope Weiler
• Jacquetta Trasler
• Sarah Kimmins

Document Type

Article

Publication Date

10-20-2026

Identifier

DOI: 10.1073/pnas.2534171123; PMCID: PMC13684213

Abstract

The occurrence of childhood neurodevelopmental disorders has been steadily increasing for decades, yet we have little understanding of modes of inheritance implicated in these diseases. Epidemiology studies have revealed an association between an elevated paternal Body Mass Index (BMI) and age as factors implicated in increased risk for neurodevelopmental disorders in children. Epigenetic regulation of gene expression by DNA methylation at cytosines is susceptible to environmental, diet, and lifestyle changes. Yet, whether a man's BMI and age influence the sperm methylome and potentially impact offspring development remains unresolved. Using MethylC capture sequencing, we identified over 38,000 differentially methylated CpGs in the sperm of men with an elevated BMI, with overlap occurring in regions associated with advanced paternal age. These were enriched for neural gene and disease ontologies. Differentially methylated regions localized to transposable elements that can act as active enhancers during human zygotic genome activation, and at gene promoters for early lineage specification. These results suggest that sperm methylome alterations that are linked to an elevated BMI may influence key embryonic transcriptional processes, notably those associated with trophectoderm and placental development.

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

123

Issue

42

First Page

2534171123

Last Page

2534171123

MeSH Keywords

Humans; Male; Spermatozoa; DNA Methylation; Neurodevelopmental Disorders; Paternal Inheritance; Paternal Age; Overweight; Epigenomics; Body Mass Index; DNA-Cytosine Methylases; Embryonic Development; Aging; Epigenetic Memory

PubMed ID

42886706

Keywords

Humans; Male; Spermatozoa; DNA Methylation; Neurodevelopmental Disorders; Paternal Inheritance; Paternal Age; Overweight; Epigenomics; Body Mass Index; DNA-Cytosine Methylases; Embryonic Development; Aging; Epigenetic Memory

Comments

Grants and funding

• 341268/Canadian Institutes of Health Research (CIHR)
• 180414/Canadian Institutes of Health Research (CIHR)
• 358654/Canadian Institutes of Health Research (CIHR)
• 148425/Canadian Institutes of Health Research (CIHR)
• 191775/Canadian Institutes of Health Research (CIHR)

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

Publisher's Link: https://doi.org/10.1073/pnas.2534171123

Recommended Citation

Schulz M, Shao X, Lambrot R, et al. Altered sperm DNA methylation provides an epigenetic route from overweight and older men to intergenerational disease transmission. Proc Natl Acad Sci U S A. 2026;123(42):e2534171123. doi:10.1073/pnas.2534171123