Molecular Mechanisms of Obesity in Children Exposed to Phthalates in Utero

子宫内接触邻苯二甲酸盐的儿童肥胖的分子机制

• 批准号: 9210551
• 负责人: Nina T Holland
• 金额: $ 57万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210551
• 关键词: 14 year old; 9 year old; Address; Adolescence; Adolescent; Adult; Affect; Age; Agriculture; Animal Model; Animals; Bioinformatics; Biological; Biological Markers; Birth; Blood; Body mass index; Candidate Disease Gene; Cell model; Child; Child health care; Childhood; Collection; Cosmetics; DNA Methylation; Data; Development; Diet; Disease; Elderly; Endocrine Disruptors; Energy Intake; Energy Metabolism; Enrollment; Environmental Exposure; Epidemic; Epigenetic Process; Etiology; Exposure to; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic Predisposition to Disease; Goals; Growth; Health; High Prevalence; Hormones; Human; In Vitro; Interdisciplinary Study; Isoprostanes; Latino; Lead; Leptin; Link; Measures; Mediating; Metabolic; Metabolic syndrome; Methodology; Methylation; Mexican Americans; Minority; Modification; Molecular; Mothers; National Health and Nutrition Examination Survey; Not Hispanic or Latino; Obesity; Outcome; Overweight; Oxidative Stress; Participant; Pattern; Peroxisome Proliferator-Activated Receptors; Physical activity; Plasticizers; Plastics; Policies; Population; Pregnancy; Pregnant Women; Prevalence; Proteins; Puberty; Race; Rat Cell Line; Research; Role; Salinas Valley; Sampling; Site; United States; Untranslated RNA; Urine; adipokines; adiponectin; bead chip; bisulfite sequencing; cohort; critical period; early adolescence; early life exposure; energy balance; environmental chemical; epidemiology study; epigenetic marker; genome-wide; high risk; histone modification; improved; in utero; lifestyle factors; lipid biosynthesis; methylation pattern; methylome; next generation; obesity in children; obesity risk; obesogen; obesogenic; phthalates; predictive marker; prenatal; prenatal exposure; prevent; programs; public health relevance; response; sex; social; waist circumference

DESCRIPTION (provided by applicant): In the last 30 years, the prevalence of obesity has risen sharply among children, and minority populations are particularly vulnerable. In the CHAMACOS birth cohort, a Mexican-American population from the agricultural Salinas Valley, CA, children have a particularly high prevalence of obesity (>39% at age 9) compared to both Mexican-American children (25%) and children of all races (20%) in the United States. Changes in diet and physical activity patterns do not completely explain the current obesity epidemic. Recent research suggests that exposure to environmental obesogens, particularly during the prenatal period, may also contribute to increases in obesity. Evidence from animals and epidemiologic studies suggests that phthalates, components of plastics and cosmetics ubiquitously found in humans, may be obesogenic. For instance, as shown in animals, they can change levels of biomarkers of obesity such as adipokines, protein hormones that regulate adipogenesis. There is also growing evidence that environmental exposures can influence DNA methylation (one of the main types of epigenetic markers) and result in adverse health outcomes. However, to date, no data are available on the effects of prenatal phthalate exposure on the molecular mechanisms of obesity in children or the potential role of epigenetic dysregulation. The overall goal of this proposal is to determine whether prenatal phthalate exposure contributes to the development of childhood obesity and metabolic syndrome (MetS) and to examine whether epigenetic changes mediate this relationship. We hypothesize that in utero phthalate exposure alters DNA methylation and leads to changes in adipokines (adiponectin and leptin), oxidative stress (isoprostanes), and higher risk of obesity and metabolic MetS in children. First, we will assess whether early and/or late pregnancy exposures are associated with a) biomarkers (adiponectin, leptin and isoprostane) and b) parameters of obesity and MetS in children at 5, 9 and 14 years of age. Second, we will characterize DNA methylation patterns in children at birth and 9 years of age, and examine whether site-specific changes in the methylome (by 450K array) are associated with a) prenatal phthalate exposure and b) biomarkers and parameters of obesity and MetS. Finally, we will validate 450K array data using next generation bisulfite sequencing and the most advanced expression and bioinformatic methodologies. The proposed research utilizes the rich collection of biological samples and data on exposures, diet, activities, and health outcomes in CHAMACOS participants. By extending assessment of children to age 14, this study will include critical periods of obesity development spanning pregnancy through adolescence. Our results will help elucidate the longitudinal effects of phthalates on obesity, explore the role of epigenetics and adipokines in the development of obesity and MetS, and address important gaps in our understanding of obesity. They will also inform policies aimed at improving children's health and preventing child obesity.

描述（由申请人提供）：在过去的30年里，儿童肥胖症的患病率急剧上升，少数民族人口特别容易受到影响。在CHAMACOS出生队列中，来自农业Salinas Valley，CA的墨西哥裔美国人，与墨西哥裔美国人儿童（25%）和美国所有种族的儿童（20%）相比，儿童的肥胖患病率特别高（9岁时>39%）。饮食和体育活动模式的变化并不能完全解释目前的肥胖流行病。最近的研究表明，暴露于环境中的致肥胖物质，特别是在产前期间，也可能导致肥胖的增加。来自动物和流行病学研究的证据表明，邻苯二甲酸酯，塑料和化妆品的成分，在人类中无处不在，可能是致肥胖的。例如，如在动物中所示，它们可以改变肥胖生物标志物的水平，如脂肪因子，调节脂肪形成的蛋白质激素。越来越多的证据表明，环境暴露会影响DNA甲基化（表观遗传标记的主要类型之一），并导致不良的健康结果。然而，到目前为止，还没有关于产前邻苯二甲酸酯暴露对儿童肥胖分子机制的影响或表观遗传失调的潜在作用的数据。 该提案的总体目标是确定产前邻苯二甲酸酯暴露是否有助于儿童肥胖和代谢综合征（MetS）的发展，并检查表观遗传变化是否介导了这种关系。我们假设，在子宫内邻苯二甲酸酯暴露改变DNA甲基化，并导致脂肪因子（脂联素和瘦素），氧化应激（异前列腺素）的变化，以及儿童肥胖和代谢代谢MetS的风险增加。首先，我们将评估妊娠早期和/或晚期暴露是否与a）生物标志物（脂联素、瘦素和异前列烷）和B）5、9和14岁儿童肥胖和代谢综合征参数相关。其次，我们将描述出生时和9岁儿童的DNA甲基化模式，并检查甲基化组（通过450 K阵列）的位点特异性变化是否与a）产前邻苯二甲酸酯暴露和B）肥胖和MetS的生物标志物和参数相关。最后，我们将使用下一代亚硫酸氢盐测序和最先进的表达和生物信息学方法验证450 K阵列数据。 拟议的研究利用了CHAMACOS参与者丰富的生物样本和暴露，饮食，活动和健康结果的数据。通过将儿童评估延长至14岁，这项研究将包括从怀孕到青春期的肥胖发展关键时期。我们的研究结果将有助于阐明邻苯二甲酸酯对肥胖的纵向影响，探索表观遗传学和脂肪因子在肥胖和代谢综合征发展中的作用，并解决我们对肥胖理解的重要差距。它们还将为旨在改善儿童健康和预防儿童肥胖的政策提供信息。

项目成果

DNA methylation of imprinted genes in Mexican-American newborn children with prenatal phthalate exposure.

• DOI: 10.2217/epi-2017-0178
• 发表时间: 2018-06
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: G. Tindula;S. Murphy;Carole Grenier;Zhiqing Huang;K. Huen;Maria Escudero-Fung;A. Bradman;B. Eskenazi;C. Hoyo;N. Holland