Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study

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Abstract

Background

Epigenetic reprogramming in mammalian gametes resets methylation marks that regulate monoallelic expression of imprinted genes. In males, this involves erasure of the maternal methylation marks and establishment of paternal-specific methylation to appropriately guide normal development. The degree to which exogenous factors influence the fidelity of methylation reprogramming is unknown. We previously found an association between paternal obesity and altered DNA methylation in umbilical cord blood, suggesting that the father’s endocrine, nutritional, or lifestyle status could potentiate intergenerational heritable epigenetic abnormalities. In these analyses, we examine the relationship between male overweight/obesity and DNA methylation status of imprinted gene regulatory regions in the gametes.

Methods

Linear regression models were used to compare sperm DNA methylation percentages, quantified by bisulfite pyrosequencing, at 12 differentially methylated regions (DMRs) from 23 overweight/obese and 44 normal weight men. Our study population included 69 volunteers from The Influence of the Environment on Gametic Epigenetic Reprogramming (TIEGER) study, based in NC, USA.

Results

After adjusting for age and fertility patient status, semen from overweight or obese men had significantly lower methylation percentages at the MEG3 (β = −1.99; SE = 0.84; p = 0.02), NDN (β = −1.10; SE = 0.47; p = 0.02), SNRPN (β = −0.65; SE = 0.27; p = 0.02), and SGCE/PEG10 (β = −2.5; SE = 1.01; p = 0.01) DMRs. Our data further suggest a slight increase in DNA methylation at the MEG3-IG DMR (β = +1.22; SE = 0.59; p = 0.04) and H19 DMR (β = +1.37; SE = 0.62; p = 0.03) in sperm of overweight/obese men.

Conclusions

Our data support that male overweight/obesity status is traceable in the sperm epigenome. Further research is needed to understand the effect of such changes and the point of origin of DNA methylation differences between lean and overweight/obese men. Together with our earlier reports on paternal obesity and epigenetic shifts in the offspring, our studies set the groundwork for future studies investigating male gametic methylation aberrations due to paternal lifestyle factors such as obesity.

Electronic supplementary material

The online version of this article (doi:10.1186/s13148-016-0217-2) contains supplementary material, which is available to authorized users.

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Most cited references 34

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Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms.

Pathik D Wadhwa, Claudia Buss, Sonja Entringer … (2009)

"Barker's hypothesis" emerged almost 25 years ago from epidemiological studies of birth and death records that revealed a high geographic correlation between rates of infant mortality and certain classes of later adult deaths as well as an association between birthweight and rates of adult death from ischemic heart disease. These observations led to a theory that undernutrition during gestation was an important early origin of adult cardiac and metabolic disorders due to fetal programming that permanently shaped the body's structure, function, and metabolism and contributed to adult disease. This theory stimulated interest in the fetal origins of adult disorders, which expanded and coalesced approximately 5 years ago with the formation of an international society for developmental origins of health and disease (DOHaD). Here we review a few examples of the many emergent themes of the DOHaD approach, including theoretical advances related to predictive adaptive responses of the fetus to a broad range of environmental cues, empirical observations of effects of overnutrition and stress during pregnancy on outcomes in childhood and adulthood, and potential epigenetic mechanisms that may underlie these observations and theory. Next, we discuss the relevance of the DOHaD approach to reproductive medicine. Finally, we consider the next steps that might be taken to apply, evaluate, and extend the DOHaD approach. Thieme Medical Publishers.

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Obesity: overview of an epidemic.

Nia Mitchell, Victoria A Catenacci, Holly Wyatt … (2011)

The obesity epidemic in the United States has proven difficult to reverse. We have not been successful in helping people sustain the eating and physical activity patterns that are needed to maintain a healthy body weight. There is growing recognition that we will not be able to sustain healthy lifestyles until we are able to address the environment and culture that currently support unhealthy lifestyles. Addressing obesity requires an understanding of energy balance. From an energy balance approach it should be easier to prevent obesity than to reverse it. Further, from an energy balance point of view, it may not be possible to solve the problem by focusing on food alone. Currently, energy requirements of much of the population may be below the level of energy intake than can reasonably be maintained over time. Many initiatives are underway to revise how we build our communities, the ways we produce and market our foods, and the ways we inadvertently promote sedentary behavior. Efforts are underway to prevent obesity in schools, worksites, and communities. It is probably too early to evaluate these efforts, but there have been no large-scale successes in preventing obesity to date. There is reason to be optimistic about dealing with obesity. We have successfully addressed many previous threats to public health. It was probably inconceivable in the 1950s to think that major public health initiatives could have such a dramatic effect on reducing the prevalence of smoking in the United States. Yet, this serious problem was addressed via a combination of strategies involving public health, economics, political advocacy, behavioral change, and environmental change. Similarly, Americans have been persuaded to use seat belts and recycle, addressing two other challenges to public health. But, there is also reason to be pessimistic. Certainly, we can learn from our previous efforts for social change, but we must realize that our challenge with obesity may be greater. In the other examples cited, we had clear goals in mind. Our goals were to stop smoking, increase the use of seatbelts, and increase recycling. The difficulty of achieving these goals should not be minimized, but they were clear and simple goals. In the case of obesity, there is no clear agreement about goals. Moreover, experts do not agree on which strategies should be implemented on a widespread basis to achieve the behavioral changes in the population needed to reverse the high prevalence rates of obesity. We need a successful model that will help us understand what to do to address obesity. A good example is the recent HEALTHY study. This comprehensive intervention was implemented in several schools and aimed to reduce obesity by concentrating on behavior and environment. This intervention delivered most of the strategies we believe to be effective in schools. Although the program produced a reduction in obesity, this reduction was not greater than the reduction seen in the control schools that did not receive the intervention. This does not mean we should not be intervening in schools, but rather that it may require concerted efforts across behavioral settings to reduce obesity. Although we need successful models, there is a great deal of urgency in responding to the obesity epidemic. An excellent example is the effort to get menu labeling in restaurants, which is moving rapidly toward being national policy. The evaluation of this strategy is still ongoing, and it is not clear what impact it will have on obesity rates. We should be encouraging efforts like this, but we must evaluate them rigorously. Once we become serious about addressing obesity, it will likely take decades to reverse obesity rates to levels seen 30 years ago. Meanwhile, the prevalence of overweight and obesity remains high and quite likely will continue to increase.

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Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Adelheid Soubry, Joellen Schildkraut, Amy Murtha … (2013)

Background Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Methods We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m2. Results Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome. Conclusions While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.

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Author and article information

Contributors

Adelheid Soubry: adelheid.soubry@hotmail.com

Susan K. Murphy: susan.murphy@duke.edu

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 6 May 2016

Publication date PMC-release: 6 May 2016

Publication date Collection: 2016

Volume: 8

Electronic Location Identifier: 51

Affiliations

[ ]Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, KU Leuven University, 3000 Leuven, Belgium

[ ]Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC 27708 USA

[ ]Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27633 USA

[ ]Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Fertility, Duke University Medical Center, Durham, NC 27713 USA

[ ]Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710 USA

Article

Publisher ID: 217

DOI: 10.1186/s13148-016-0217-2

PMC ID: 4859994

PubMed ID: 27158277

SO-VID: e265c49c-e346-4829-ab7d-a9b82b3533b7

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 February 2016

Date accepted : 28 April 2016

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ScienceOpen disciplines: Genetics

Keywords: epigenetics,sperm,obesity,tieger study,imprinted gene,methylation

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ScienceOpen disciplines: Genetics

Keywords: epigenetics, sperm, obesity, tieger study, imprinted gene, methylation

Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study

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Conclusions

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Most cited references 34

Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms.

Obesity: overview of an epidemic.

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

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