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

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          Abstract

          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.

          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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          Most cited references39

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          Role of insulin-like growth factors in embryonic and postnatal growth.

          A developmental analysis of growth kinetics in mouse embryos carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF1R), alone or in combination, defined the onset of mutational effects leading to growth deficiency and indicated that between embryonic days 11.0 and 12.5, IGF1R serves only the in vivo mitogenic signaling of IGF-II. From E13.5 onward, IGF1R interacts with both IGF-I and IGF-II, while IGF-II recognizes an additional unknown receptor (XR). In contrast with the embryo proper, placental growth is served exclusively by an IGF-II-XR interaction. Additional genetic data suggested that the type 2IGF/mannose 6-phosphate receptor is an unlikely candidate for XR. Postnatal growth curves indicated that surviving Igf-1(-/-) mutants, which are infertile and exhibit delayed bone development, continue to grow with a retarded rate after birth in comparison with wild-type littermates and become 30% of normal weight as adults.
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            Obesity in young men after famine exposure in utero and early infancy.

            In a historical cohort study of 300,000 19-year-old men exposed to the Dutch famine of 1944-45 and examined at military induction, we tested the hypothesis that prenatal and early postnatal nutrition determines subsequent obesity. Outcomes were opposite depending on the time of exposure. During the last trimester of pregnancy and the first months of life, exposure produced significantly lower obesity rates (P less than 0.005). This result is consistent with the inference that nutritional deprivation affected a critical period of development for adipose-tissue cellularity. During the first half of pregnancy, however, exposure resulted in significantly higher obesity rates (P less than 0.0005). This observation is consistent with the inference that nutritional deprivation affected the differentiation of hypothalamic centers regulating food intake and growth, and that subsequent increased food availability produced an accumulation of excess fat in an organism growing to its predetermined maximum size.
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              Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses

              Objective To determine the relation between overweight and obesity in mothers and preterm birth and low birth weight in singleton pregnancies in developed and developing countries. Design Systematic review and meta-analyses. Data sources Medline and Embase from their inceptions, and reference lists of identified articles. Study selection Studies including a reference group of women with normal body mass index that assessed the effect of overweight and obesity on two primary outcomes: preterm birth (before 37 weeks) and low birth weight (<2500 g). Data extraction Two assessors independently reviewed titles, abstracts, and full articles, extracted data using a piloted data collection form, and assessed quality. Data synthesis 84 studies (64 cohort and 20 case-control) were included, totalling 1 095 834 women. Although the overall risk of preterm birth was similar in overweight and obese women and women of normal weight, the risk of induced preterm birth was increased in overweight and obese women (relative risk 1.30, 95% confidence interval 1.23 to 1.37). Although overall the risk of having an infant of low birth weight was decreased in overweight and obese women (0.84, 0.75 to 0.95), the decrease was greater in developing countries than in developed countries (0.58, 0.47 to 0.71 v 0.90, 0.79 to 1.01). After accounting for publication bias, the apparent protective effect of overweight and obesity on low birth weight disappeared with the addition of imputed “missing” studies (0.95, 0.85 to 1.07), whereas the risk of preterm birth appeared significantly higher in overweight and obese women (1.24, 1.13 to 1.37). Conclusions Overweight and obese women have increased risks of preterm birth and induced preterm birth and, after accounting for publication bias, appeared to have increased risks of preterm birth overall. The beneficial effects of maternal overweight and obesity on low birth weight were greater in developing countries and disappeared after accounting for publication bias.
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                Author and article information

                Contributors
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central
                1741-7015
                2013
                6 February 2013
                : 11
                : 29
                Affiliations
                [1 ]Duke Cancer Institute, Duke University Medical Center 2715, Durham, NC 27710, USA
                [2 ]Department of Community and Family Medicine, Duke University Medical Center 104006, Durham, NC 27710, USA
                [3 ]Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, Duke University Medical Center, 4022 Hospital South, Durham, NC 27705, USA
                [4 ]Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center 91012, Durham, NC 27708, USA
                [5 ]Department of Radiation Oncology, Duke University Medical Center 3433, Durham, NC 27710, USA
                [6 ]Department of Pediatrics, Duke University Medical Center 3350, Durham, NC 27710, USA
                [7 ]Department of Obstetrics and Gynecology, Division of Clinical Epidemiology, Duke University Medical Center 2914, Durham, NC 27710, USA
                Article
                1741-7015-11-29
                10.1186/1741-7015-11-29
                3584733
                23388414
                9e4f3a7d-d5f4-4a19-9189-2da1e433783b
                Copyright ©2013 Soubry et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research Article

                Medicine
                epigenetics,dna methylation,igf2,obesity,offspring,newborn epigenetics study,epidemiology
                Medicine
                epigenetics, dna methylation, igf2, obesity, offspring, newborn epigenetics study, epidemiology

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