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      Maternal Genistein Alters Coat Color and Protects A vy Mouse Offspring from Obesity by Modifying the Fetal Epigenome

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          Abstract

          Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti ( A vy / a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine–guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome.

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          Most cited references 43

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          The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.

          In this article, we attempt to distinguish between the properties of moderator and mediator variables at a number of levels. First, we seek to make theorists and researchers aware of the importance of not using the terms moderator and mediator interchangeably by carefully elaborating, both conceptually and strategically, the many ways in which moderators and mediators differ. We then go beyond this largely pedagogical function and delineate the conceptual and strategic implications of making use of such distinctions with regard to a wide range of phenomena, including control and stress, attitudes, and personality traits. We also provide a specific compendium of analytic procedures appropriate for making the most effective use of the moderator and mediator distinction, both separately and in terms of a broader causal system that includes both moderators and mediators.
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            DNA methylation patterns and epigenetic memory.

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              Epigenetic programming by maternal behavior.

              Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                April 2006
                26 January 2006
                : 114
                : 4
                : 567-572
                Affiliations
                [1 ]Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
                [2 ]University Program in Genetics and Genomics and
                [3 ]Integrated Toxicology Program, Duke University, Durham, North Carolina, USA
                [4 ]Department of Pediatrics and
                [5 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
                Author notes
                Address correspondence to R.L. Jirtle, Box 3433, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 684-2770. Fax: (919) 684-5584. E-mail: jirtle@radonc.duke.edu

                The authors declare they have no competing financial interests.

                Article
                ehp0114-000567
                10.1289/ehp.8700
                1440782
                16581547
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                Categories
                Research

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