Poster Presentation Australian Epigenetics Alliance Conference 2022

Exposure of Grenlandic Inuit and South African VhaVenda men to the toxicant DDT is implicated in paternal epigenetic transmission of developmental disease (#119)

Ariane Lismer 1 , Xiaojian Shao 2 , Marie-Charlotte Dumargne 3 , Christine Lafleur 3 , Romain Lambrot 3 , Donovan Chan 4 , Gunnar Toft 5 , Jens Peter Bonde 6 7 , Amanda MacFarlane 8 , Riana Bornman 9 , Natalie Aneck-Hahn 9 , Sean Patrick 9 , Janice Bailey 10 , Cristiaan de Jaager 9 , Vanessa Dumeaux 11 , Jacquetta Trasler 1 4 12 13 , Sarah Kimmins 1 3
  1. Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada
  2. Digital Technologies Research Centre, National Research Council Canada, Ottawa, ON, Canada
  3. Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada
  4. Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
  5. Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
  6. Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, Copenhagen, Denmark
  7. Institute of Public Health, University of Copenhagen, Copenhagen, Denmark
  8. Nutrition Research Division, Health Canada, Ottawa, ON, Canada
  9. University of Pretoria Institute for Sustainable Malaria Control, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
  10. Research Centre on Reproduction and Intergenerational Health, Department of Animal Sciences, Université Laval, Quebec, QC, Canada
  11. Department of Anatomy and Cell Biology and Department of Oncology, Western University, London, ON, Canada
  12. Department of Human Genetics, McGill University, Montreal, QC, Canada
  13. Department of Paediatrics, McGill University, Montreal, QC, Canada

Humans are exposed to a myriad of toxicants that have negative health consequences on generations to come. These generational effects first described in animal models and epidemiological studies, implicated germline epigenetic factors. Nonetheless, the molecular mechanisms mediating epigenetic inheritance remains almost entirely unexplored in humans. Exposure to the insecticide dichlorodiphenyltrichloroethane (DDT) is linked to birth defects, cancer, and neurodevelopmental delays. Although DDT has been banned world-wide since the 1970s, it is still sanctioned for indoor residual spraying to control malarial disease vectors in Sub-Saharan Africa. The impacts of DDT on human health are not only restricted to regions of use since DDT is transported over long distances to Arctic regions by ocean currents. Here, we studied two geographically diverse DDT-exposed populations, Greenlandic Inuit and South African VhaVenda men, and aimed to determine whether sperm DNAme and chromatin enrichments were associated with levels of DDT exposures and could be implicated in epigenetic inheritance. To quantitatively identify regions that were altered in DNAme and histone enrichment of exposed men, we used a sperm customized methyl-capture approach followed by sequencing (MCC-seq), and chromatin immunoprecipitation targeting histone H3K4me3 followed by sequencing (ChIP-seq). We then performed differential and functional analyses to investigate the relationship between DDT-associated alterations in the sperm epigenome, their predicted transmission to the embryo at fertilization, and persistence throughout development. We identified regions with altered DNAme (DNAme) and differential enrichment of H3K4me3 that were dose-like responsive to serum DDE levels. Altered sperm DNAme and H3K4me3 occurred at regulatory regions involved in fertility, disease, development and neurofunction. A subset of regions with altered sperm DNAme and H3K4me3 occurred at transposable elements and were predicted to persist in the pre-implantation embryo. These findings suggest that DDT exposure in men may negatively impact embryo development and the health of future generations through epigenetic mechanisms.