Male obesity impacts DNA methylation reprogramming in sperm.
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2021-01-25
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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.Type
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Keyhan, Sanaz, Emily Burke, Rose Schrott, Zhiqing Huang, Carole Grenier, Thomas Price, Doug Raburn, David L Corcoran, et al. (2021). Male obesity impacts DNA methylation reprogramming in sperm. Clinical epigenetics, 13(1). p. 17. 10.1186/s13148-020-00997-0 Retrieved from https://hdl.handle.net/10161/22564.
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Scholars@Duke
Thomas Michael Price
Dr. Price is involved in both clinical and basic science research. The main focus of the basic science molecular endocrinology laboratory is the study of novel sex steroid receptors. Currently, the work focuses on a novel progesterone receptor that localizes to the mitochondrion. Studies including RNAi in cell models and creation of transgenic mice are ongoing to discover the function of this receptor. The overall hypothesis is that progesterone modulates mitochondrial activity to meet the increased cellular energy demands of pregnancy via this receptor.
Dr. Price also participates in clinical research endeavors. These projects are constantly changing and focus on many aspects of reproductive endocrinology including ovarian preservation during chemotherapy, treatments for menorrhagia, endometriosis, leiomyomata and infertility.
Douglas Joe Raburn
Dr. Raburn is the Director of the Assisted Reproductive Technology Laboratories at the Duke Fertility Center. As part of the multidisciplinary team within the Reproductive Endocrinology and Infertility division, he specializes in optimizing outcomes for patients who require assisted reproduction for current and future family building. His research focuses on gamete, embryo and reproductive tissue biology.
Susan Kay Murphy
Dr. Murphy is a tenured Associate Professor in the Department of Obstetrics and Gynecology and serves as Chief of the Division of Reproductive Sciences. As a molecular biologist with training in human epigenetics, her research interests are largely centered around the role of epigenetic modifications in health and disease.
Dr. Murphy has ongoing projects on gynecologic malignancies, including approaches to eradicate ovarian cancer cells that survive chemotherapy and later give rise to recurrent disease. Dr. Murphy is actively involved in many collaborative projects relating to the Developmental Origins of Health and Disease (DOHaD).
Her lab is currently working on preconception environmental exposures in males, particularly on the impact of cannabis on the sperm epigenome and the potential heritability of these effects. They are also studying the epigenetic and health effects of in utero exposures, with primary focus on children from the Newborn Epigenetics STudy (NEST), a pregnancy cohort she co-founded who were recruited from central North Carolina between 2005 and 2011. Dr. Murphy and her colleagues continue to follow NEST children to determine relationships between prenatal exposures and later health outcomes.
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