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      Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation

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          Abstract

          <p id="d5468194e275">Endocrine disrupting chemicals (EDCs) pose a public health risk through disruption of normal biological processes. Identifying toxicoepigenetic mechanisms of developmental exposure-induced effects for EDCs, such as phthalates or bisphenol A (BPA), is essential. Here, we investigate whether maternal exposure to EDCs is predictive of infant DNA methylation at candidate gene regions. In the Michigan Mother-Infant Pairs (MMIP) cohort, DNA was extracted from cord blood leukocytes for methylation analysis by pyrosequencing (n = 116) and methylation changes related to first trimester levels of 9 phthalate metabolites and BPA. Growth and metabolism-related genes selected for methylation analysis included imprinted ( <i>IGF2</i>, <i>H19</i>) and non-imprinted ( <i>PPARA</i>, <i>ESR1</i>) genes along with LINE-1 repetitive elements. Findings revealed decreases in methylation of LINE-1, <i>IGF2</i>, and <i>PPARA</i> with increasing phthalate concentrations. For example, a log unit increase in ΣDEHP corresponded to a 1.03 [95% confidence interval (CI): −1.83, −0.22] percentage point decrease in <i>PPARA</i> methylation. Changes in DNA methylation were also inversely correlated with <i>PPARA</i> gene expression determined by RT-qPCR (r = −0.34, <i>P</i> = 0.02), thereby providing evidence in support of functional relevance. A sex-stratified analysis of EDCs and DNA methylation showed that some relationships were female-specific. For example, urinary BPA exposure was associated with a 1.35 (95%CI: −2.69, −0.01) percentage point decrease in <i>IGF2</i> methylation and a 1.22 (95%CI: −2.27, −0.16) percentage point decrease in <i>PPARA</i> methylation in females only. These findings add to a body of evidence suggesting epigenetically labile regions may provide a conduit linking early exposures with disease risk later in life and that toxicoepigenetic susceptibility may be sex specific. </p>

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          A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements.

          We report a method for studying global DNA methylation based on using bisulfite treatment of DNA and simultaneous PCR of multiple DNA repetitive elements, such as Alu elements and long interspersed nucleotide elements (LINE). The PCR product, which represents a pool of approximately 15 000 genomic loci, could be used for direct sequencing, selective restriction digestion or pyrosequencing, in order to quantitate DNA methylation. By restriction digestion or pyrosequencing, the assay was reproducible with a standard deviation of only 2% between assays. Using this method we found that almost two-thirds of the CpG methylation sites in Alu elements are mutated, but of the remaining methylation target sites, 87% were methylated. Due to the heavy methylation of repetitive elements, this assay was especially useful in detecting decreases in DNA methylation, and this assay was validated by examining cell lines treated with the methylation inhibitor 5-aza-2'deoxycytidine (DAC), where we found a 1-16% decrease in Alu element and 18-60% LINE methylation within 3 days of treatment. This method can be used as a surrogate marker of genome-wide methylation changes. In addition, it is less labor intensive and requires less DNA than previous methods of assessing global DNA methylation.
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            Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms.

            "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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              Bisulfite genomic sequencing: systematic investigation of critical experimental parameters.

              Bisulfite genomic sequencing is the method of choice for the generation of methylation maps with single-base resolution. The method is based on the selective deamination of cytosine to uracil by treatment with bisulfite and the sequencing of subsequently generated PCR products. In contrast to cytosine, 5-methylcytosine does not react with bisulfite and can therefore be distinguished. In order to investigate the potential for optimization of the method and to determine the critical experimental parameters, we determined the influence of incubation time and incubation temperature on the deamination efficiency and measured the degree of DNA degradation during the bisulfite treatment. We found that maximum conversion rates of cytosine occurred at 55 degrees C (4-18 h) and 95 degrees C (1 h). Under these conditions at least 84-96% of the DNA is degraded. To study the impact of primer selection, homologous DNA templates were constructed possessing cytosine-containing and cytosine-free primer binding sites, respectively. The recognition rates for cytosine (>/=97%) and 5-methylcytosine (>/=94%) were found to be identical for both templates.
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                Author and article information

                Journal
                Epigenetics
                Epigenetics
                Informa UK Limited
                1559-2294
                1559-2308
                May 10 2018
                March 04 2018
                April 18 2018
                March 04 2018
                : 13
                : 3
                : 301-309
                Affiliations
                [1 ] Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA
                [2 ] Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
                [3 ] Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA
                [4 ] Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA
                Article
                10.1080/15592294.2018.1448680
                5997152
                29513082
                972c9f7d-1538-429c-9037-27fa889c3bd1
                © 2018
                History

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