Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study (original) (raw)
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Male obesity impacts DNA methylation reprogramming in sperm
Clinical Epigenetics, 2021
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 associate...
Obesity-induced sperm DNA methylation changes at satellite repeats are reprogrammed in rat offspring
Asian Journal of Andrology, 2015
methylation state of regulatory regions in spermatozoa (and oocytes) controls gene transcription in offspring. 7 Like many other cell types, mature spermatozoa in humans and rodents have high methylation levels at most repetitive elements and intergenic regions that transcriptionally repress these regions. Gene-specific hyper-or hypo-methylation is found at promoters, with a general observation of decreasing methylation with increasing CpG density. 8-12 Furthermore, the promoters of genes involved in early development are more likely to be hypo-methylated, suggesting that they are primed for activation in offspring. 10,12 Several studies have described alteration of normal sperm DNA methylation patterns, due to genotype, environmental exposure or disease. These include methylation changes associated with mutations in DNA methyltransferases, 13 reduced fertility, 14-17 toxin and drug exposure, 18-20 dietary alterations, 21,22 and stress exposure. 23,24 There is no sign of a "standard epigenetic response" to these insults, as increases and decreases in global and locus-specific DNA methylation have all been reported. An obstacle to the persistence of sperm methylation states in offspring is the extensive demethylation of the paternally-inherited chromosomes after fertilisation in humans and rodents. 25,26 Therefore,
Newborns of obese parents have altered DNA methylation patterns at imprinted genes
2013
BACKGROUND: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity. OBJECTIVE: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT). METHODS: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI X30 kg m À 2 , was ascertained through standardized questionnaires. RESULTS: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST
Male Obesity: Epigenetic Origin and Effects in Sperm and Offspring
Current Molecular Biology Reports, 2017
Purpose of Review The prevalence of obesity has increased substantially in the current generations of Western countries, and the burden of obesity-related complications has been growing steadily. In men, obesity is not only a major risk factor for serious chronic diseases, concern is growing that the reproductive capacity, and more particularly, their offspring’s health may be affected. Obesity-related impaired spermatogenesis is associated with a decrease in microscopic and molecular sperm characteristics and pregnancy success. We hypothesize that epigenetics is an important mediator explaining interactions between an obesogenic environment and sperm/offspring outcomes. Recent Findings Recent studies have explored inter- and transgenerational epigenetic effects in sperm cells and in offspring. Father-to-child effects have been reported in relation to preconceptional nutritional and life-style related factors. Summary Here, we summarize the current understanding about obesity and mo...
Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans
Highlights d Distinct sncRNA expression and DNA methylation profiles in sperm from obese humans d Differentially methylated genes are related to brain function d The spermatozoal epigenome is dynamically remodeled after bariatric surgery d Differential methylation clusters with known SNPs of obesity SUMMARY Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity. Comprehensive profiling of the epigenome of sperm from lean and obese men showed similar histone positioning, but small noncoding RNA expression and DNA methylation patterns were markedly different. In a separate cohort of morbidly obese men, surgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite. Our data provide evidence that the epigenome of human spermatozoa dynamically changes under environmental pressure and offers insight into how obesity may propagate metabolic dysfunction to the next generation.
Clinical epigenetics, 2018
This study assessed the associations between nine differentially methylated regions (DMRs) of imprinted genes in DNA derived from umbilical cord blood leukocytes in males and females and (1) birth weight for gestational age score, (2) weight-for-length (WFL) score at 1 year, and (3) body mass index (BMI) score at 3 years. We conducted multiple linear regression in = 567 infants at birth, = 288 children at 1 year, and = 294 children at 3 years from the Newborn Epigenetics Study (NEST). We stratified by sex and adjusted for race/ethnicity, maternal education, maternal pre-pregnancy BMI, prenatal smoking, maternal age, gestational age, and paternal race. We also conducted analysis restricting to infants not born small for gestational age. We found an association between higher methylation of the sequences regulating paternally expressed gene 10 () and anthropometric scores at 1 year ( = 0.84; 95% CI = 0.34, 1.33; = 0.001) and 3 years ( = 1.03; 95% CI = 0.37, 1.69; value = 0.003) in...
BMC Medicine, 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/m 2 . 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.
BACKGROUND: Recent technological advances in epigenome profiling have led to an increasing number of studies investigating the role of the epigenome in obesity. There is also evidence that environmental exposures during early life can induce persistent alterations in the epigenome, which may lead to an increased risk of obesity later in life. METHOD: This paper provides a systematic review of studies investigating the association between obesity and either global, sitespecific or genome-wide methylation of DNA. Studies on the impact of pre-and postnatal interventions on methylation and obesity are also reviewed. We discuss outstanding questions, and introduce EpiSCOPE, a multidisciplinary research program aimed at increasing the understanding of epigenetic changes in emergence of obesity. RESULTS: An electronic search for relevant articles, published between September 2008 and September 2013 was performed. From the 319 articles identified, 46 studies were included and reviewed. The studies provided no consistent evidence for a relationship between global methylation and obesity. The studies did identify multiple obesity-associated differentially methylated sites, mainly in blood cells. Extensive, but small, alterations in methylation at specific sites were observed in weight loss intervention studies, and several associations between methylation marks at birth and later life obesity were found. CONCLUSIONS: Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Eventually this may help in predicting an individual's obesity risk at a young age and opens possibilities for introducing targeted prevention strategies. It has also become clear that several epigenetic marks are modifiable, by changing the exposure in utero, but also by lifestyle changes in adult life, which implies that there is the potential for interventions to be introduced in postnatal life to modify unfavourable epigenomic profiles.