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Peer-reviewedCC BY-NC-NDProceedings of the National Academy of Sciences of the United States of America

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

  • Mathieu Schulz1
  • Xiaojian Shao2,3
  • Romain Lambrot1
  • Christine Lafleur1
  • Donovan Chan4
  • Marie-Charlotte Dumargne5
  • Amanda J MacFarlane6
  • Sergey Moskovtsev7,8
  • Guillaume Bourque9
  • Tomi Pastinen9,10
  • Clifford Librach7,11
  • Hope Weiler12
2 more authors
  • Jacquetta Trasler4,13
  • Sarah Kimmins1,14
14 affiliations
  1. 1Department of Pathology and Cell Biology, University of Montreal Hospital Research Center, Montreal, QC H2X 0A9, Canada.
  2. 2Digital Technologies Research Center, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.
  3. 3Ottawa Institute of Systems Biology, Department of Biochemistry Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
  4. 4Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
  5. 5Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK-2200, Denmark.
  6. 6Nutrition Research Division, Health Canada, Ottawa, Ottawa, ON K1A 0K9, Canada.
  7. 7CReATe Fertility Clinic Center, Toronto, ON M5G 1N8, Canada.
  8. 8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  9. 9McGill Genome Center, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
  10. 10Genomic medicine Center, Children's Mercy Hospital, Kansas City, MO 64108.
  11. 11Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada.
  12. 12Nutrition Research Division, Bureau of Nutritional Sciences, Food and Nutrition Directorate, Health Products and Food Branch, Health Canada, Ottawa K1A 0K9, Canada.
  13. 13Departments of Pediatrics, Human Genetics, Pharmacology and Therapeutics, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada.
  14. 14Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada.
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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.

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Cite

BibTeXRIS
BibTeX
@article{schulz2026altered,
  title = {{Altered sperm DNA methylation provides an epigenetic route from overweight and older men to intergenerational disease transmission.}},
  author = {Mathieu Schulz and Xiaojian Shao and Romain Lambrot and Christine Lafleur and Donovan Chan and Marie-Charlotte Dumargne and Amanda J MacFarlane and Sergey Moskovtsev and Guillaume Bourque and Tomi Pastinen and Clifford Librach and Hope Weiler and Jacquetta Trasler and Sarah Kimmins},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2534171123},
  url = {https://europepmc.org/article/MED/42886706},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Altered sperm DNA methylation provides an epigenetic route from overweight and older men to intergenerational disease transmission.
AU  - Mathieu Schulz
AU  - Xiaojian Shao
AU  - Romain Lambrot
AU  - Christine Lafleur
AU  - Donovan Chan
AU  - Marie-Charlotte Dumargne
AU  - Amanda J MacFarlane
AU  - Sergey Moskovtsev
AU  - Guillaume Bourque
AU  - Tomi Pastinen
AU  - Clifford Librach
AU  - Hope Weiler
AU  - Jacquetta Trasler
AU  - Sarah Kimmins
PY  - 2026
DA  - 2026/10/16
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2534171123
UR  - https://europepmc.org/article/MED/42886706
AB  - 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.
SN  - 0027-8424
SN  - 1091-6490
ER  -