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      Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys

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          Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10 –15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure ( r S -values>−0.62), but in girls only 207 (41%) showed inverse correlation ( r S -values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.

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          The fundamental role of epigenetic events in cancer.

          Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.
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            Increased methylation variation in epigenetic domains across cancer types

            Summary Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal, in colon, lung, breast, thyroid, and Wilms tumors, with intermediate variation in adenomas. Whole genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. These data suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer and could contribute to tumor heterogeneity.
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              Epigenetic epidemiology of the developmental origins hypothesis.

              Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying this "developmental origins hypothesis" are poorly understood. This review focuses on the likely involvement of epigenetic mechanisms in the developmental origins of health and disease (DOHaD). We describe permanent effects of transient environmental influences on the developmental establishment of epigenetic gene regulation and evidence linking epigenetic dysregulation with human disease. We propose a definition of "epigenetic epidemiology" and delineate how this emerging field provides a basis from which to explore the role of epigenetic mechanisms in DOHaD. We suggest strategies for future human epidemiologic studies to identify causal associations between early exposures, long-term changes in epigenetic regulation, and disease, which may ultimately enable specific early-life interventions to improve human health.

                Author and article information

                [1 ]Institute of Environmental Medicine , Unit of Metals and Health, Karolinska Institutet, Stockholm, Sweden
                [2 ]Department of Laboratory Medicine, Section of Occupational and Environmental Medicine, Lund University , Lund, Sweden
                [3 ]International Centre for Diarrhoeal Disease Research Bangladesh (ICDDR,B), Dhaka, Bangladesh
                [4 ]Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana , Ljubljana, Slovenia
                [5 ]Unit of Biostatistics, Institute of Environmental Medicine , Karolinska Institutet, Stockholm, Sweden
                Author notes
                [* ]Address for correspondence: K. Broberg, Institute of Environmental Medicine, Unit of Metals and Health, Karolinska Institutet, 17177 Stockholm, Sweden. (Email karin.broberg@ )
                J Dev Orig Health Dis
                J Dev Orig Health Dis
                Journal of Developmental Origins of Health and Disease
                Cambridge University Press (Cambridge, UK )
                14 April 2014
                August 2014
                : 5
                : 4
                : 288-298
                S2040174414000221 00022
                © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2014

                The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution licence <

                Figures: 2, Tables: 4, Pages: 11
                Original Article

                fetal, epigenetic, development, cpg, cancer, 450 k


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