Sanaz Keyhan1, Emily Burke2, Rose Schrott3,4, Zhiqing Huang3, Carole Grenier3, Thomas Price1, Doug Raburn1, David L Corcoran5, Adelheid Soubry6, Catherine Hoyo7, Susan K Murphy8,9. 1. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, 27713, USA. 2. Department of Biostatistics, Duke University, Durham, 27710, USA. 3. Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Duke University Medical Center, 501 W. Main Street, Suite 510, The Chestefield Building, PO Box 90534, Durham, NC, 27701, USA. 4. Duke University Integrated Toxicology and Environmental Health Program, The Nicholas School of the Environment, Duke University, Durham, NC, 27708, USA. 5. Center for Genomics and Computational Biology, Duke University Medical Center, Durham, NC, 27710, USA. 6. Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, KU Leuven University, 2000, Leuven, Belgium. 7. Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27633, USA. 8. Division of Reproductive Sciences, Department of Obstetrics and Gynecology, Duke University Medical Center, 501 W. Main Street, Suite 510, The Chestefield Building, PO Box 90534, Durham, NC, 27701, USA. susan.murphy@duke.edu. 9. Duke University Integrated Toxicology and Environmental Health Program, The Nicholas School of the Environment, Duke University, Durham, NC, 27708, USA. susan.murphy@duke.edu.
Abstract
BACKGROUND: Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the next generation. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n = 20) is associated with differences in mature spermatozoa DNA methylation profiles relative to controls with normal BMI (n = 47). RESULTS: We identified 3264 CpG sites in human sperm that are significantly associated with BMI (p < 0.05) using Infinium HumanMethylation450 BeadChips. These CpG sites were significantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfite sequencing of cloned alleles revealed that the methylation differences are present in a subset of sperm rather than being randomly distributed across all sperm. CONCLUSIONS: Male obesity is associated with altered sperm DNA methylation profiles that appear to affect reprogramming fidelity in a subset of sperm, suggestive of an influence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the potential to impede normal development.
BACKGROUND: Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the next generation. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n = 20) is associated with differences in mature spermatozoa DNA methylation profiles relative to controls with normal BMI (n = 47). RESULTS: We identified 3264 CpG sites in human sperm that are significantly associated with BMI (p < 0.05) using Infinium HumanMethylation450 BeadChips. These CpG sites were significantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfite sequencing of cloned alleles revealed that the methylation differences are present in a subset of sperm rather than being randomly distributed across all sperm. CONCLUSIONS: Male obesity is associated with altered sperm DNA methylation profiles that appear to affect reprogramming fidelity in a subset of sperm, suggestive of an influence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the potential to impede normal development.
Entities:
Keywords:
Epigenetics; Methylation; Obesity; Reprogramming; Sperm; TIEGER study
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