Altered sperm DNA methylation provides an epigenetic route from overweight and older men to intergenerational disease transmission
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.
Authors
- Xiaojian Shao (ORCID: https://orcid.org/0000-0002-3044-621X)
- Romain Lambrot (ORCID: https://orcid.org/0000-0003-2025-0974)
- Mathieu Schulz (ORCID: https://orcid.org/0000-0003-0373-4264)
- Marie-Charlotte Dumargne (ORCID: https://orcid.org/0000-0001-7009-9104)
- Tomi Pastinen (ORCID: https://orcid.org/0000-0003-4016-5021)
- Hope Alberta Weiler (ORCID: https://orcid.org/0009-0001-6753-9364)
- Guillaume Bourque (ORCID: https://orcid.org/0000-0002-3933-9656)
- Donovan Chan (ORCID: https://orcid.org/0000-0002-6860-8384)
- Christine Lafleur (ORCID: https://orcid.org/0000-0001-7714-3243)
- Sarah Kimmins (ORCID: https://orcid.org/0000-0002-0168-7233)
- Jacquetta M. Trasler (ORCID: https://orcid.org/0000-0002-4830-042X)
- Sergey I. Moskovtsev (ORCID: https://orcid.org/0000-0003-1303-6048)
- Amanda J MacFarlane (ORCID: https://orcid.org/0000-0002-3208-3483)
- Clifford L. Librach (ORCID: https://orcid.org/0000-0002-1226-560X)
Institutions
- Health Canada (CA)
- University of Ottawa (CA)
- University of Toronto (CA)
- McGill University Health Centre (CA)
- Mercy Children's Hospital (US)
- McGill Genome Centre (CA)
- Mercy Research (US)
- CReATe Fertility Centre (CA)
- National Research Council Canada (CA)
- Research Institute of the McGill University Health Centre (CA)
- McGill University (CA)
- Université de Montréal (CA)
- Ottawa University (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-10-16
- DOI
- https://doi.org/10.1073/pnas.2534171123
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Canadian Institutes of Health Research