Preconception phthalate exposure and offspring outcomes

孕前邻苯二甲酸盐暴露和后代结果

• 批准号: 10246409
• 负责人: MARISA S. BARTOLOMEI
• 金额: $ 44.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246409
• 关键词: ATAC-seq; Adipocytes; Adult; Adult Children; Animal Model; Animals; Awareness; Beta Cell; Biological; Biological Assay; Body fat; Bone Density; Brain; Cells; Chromatin; Complement; DNA Methylation; Data; Development; Diabetes Mellitus; Diet; Diethylhexyl Phthalate; Dose; Embryo; Endocrine; Endocrine Disruptors; Energy Metabolism; Environmental Exposure; Environmental Pollution; Epigenetic Process; Esters; Exposure to; Fetal Liver; Fetus; Food Processing; General Population; Genes; Hepatocyte; Human; Industrialization; Lactation; Lead; Life; Link; Liver; Measures; Membrane Potentials; Memory; Messenger RNA; Metabolic; Metabolic syndrome; MicroRNAs; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Muscle; Muscle Cells; Neurologic; Obesity; Oocytes; Organ; Outcome; Oxidative Phosphorylation; Phenotype; Physiological; Predisposition; Pregnancy; Production; Proteins; Respiration; Risk; Risk Assessment; Source; Tissues; Untranslated RNA; Weight; Weight Gain; Western Blotting; behavior change; behavioral phenotyping; bisulfite sequencing; blood glucose regulation; chromatin immunoprecipitation; critical period; dietary; epigenome; human model; insulin secretion; insulin sensitivity; light microscopy; metabolic phenotype; mitochondrial dysfunction; neurobehavioral; obesity development; obesogenic; offspring; phthalates; prenatal exposure; pyrosequencing; sex; transcriptome; transcriptome sequencing

Endocrine disruptors (EDs) are a group of molecules capable of altering normal endocrine function in animals and humans. We and others have demonstrated that in utero exposure to EDs causes obesity and abnormal glucose homeostasis in the offspring. Phthalates are an important group of EDs that are used in a diverse range of industrial applications leading to common exposure risk in humans. One major phthalate is di-(2-ethylhexyl)-phthalate (DEHP), a widely used compound for which dietary exposure (food processing, packaging) likely represents the main source of contamination for the general population. Both human and animal models show a link between phthalate exposure and the development of obesity and the metabolic syndrome. Similar to these studies, our preliminary data show that DEHP exposure through the diet in physiologically relevant doses prior to and during pregnancy and lactation alters DNA methylation in fetal liver, increases body weight in adult offspring in a sex-specific manner. It is becoming increasingly evident that the periconceptional stage also represents a window of susceptibility to environmental exposures on the offspring. While the mechanisms responsible for the transfer of metabolic memory from the oocyte to the offspring remain to be elucidated, 2 plausible possibilities are epigenetic dysregulation and abnormal mitochondria. Further, we and others have shown that epigenetic changes and abnormal mitochondrial function in key organs such as the liver, ß-cell and muscle have been linked to development of obesity and diabetes. Thus, we hypothesize that a preconception exposure to DEHP, similar to a gestational exposure, results in an abnormal metabolic phenotype in the offspring by altering either the epigenetic profile and or mitochondrial function in the oocyte. Thus we propose the following specific aims: Aim 1 will determine whether a preconception exposure to biologically relevant doses of DEHP results in a similar offspring phenotype as a gestational exposure. Aim 2 will determine the molecular and cellular mechanisms by which the two different exposure windows result in a similar or different metabolic phenotype in the offspring. We will profile the transcriptome by RNA-seq and the epigenome by ATACseq and bisulfite-seq in the oocyte and key tissues in the offspring. We will then determine the effects of DEHP on key aspects of mitochondrial function such as respiration, ATP, ROS, and morphology. The proof of the principle of preconception programming by environmental contaminants may change our awareness of critical assessment of the risk of such compounds.

内分泌干扰物是一组能够改变正常内分泌的分子 在动物和人类中发挥作用。我们和其他人已经证明，在子宫内暴露于 ED会导致后代肥胖和葡萄糖稳态异常。邻苯二甲酸酯是一种 在各种工业应用中使用的重要ED组， 人类常见的暴露风险。一种主要的邻苯二甲酸酯是邻苯二甲酸二（2-乙基己基）酯（DEHP）， 广泛使用的化合物，饮食接触（食品加工，包装）可能 是普通民众的主要污染源。人类和动物 模型显示邻苯二甲酸酯暴露与肥胖的发展之间存在联系， 代谢综合征与这些研究相似，我们的初步数据显示， 在妊娠和哺乳期之前和期间，通过饮食给予生理相关剂量 改变胎儿肝脏中的DNA甲基化，以性别特异性方式增加成年后代的体重， 方式越来越明显的是，近概念阶段也代表了一个 对环境暴露的敏感性窗口对后代。虽然机制 负责将代谢记忆从卵母细胞转移到后代的基因仍然是未知的。 阐明，2个合理的可能性是表观遗传失调和异常线粒体。 此外，我们和其他人已经表明，表观遗传变化和异常线粒体 肝脏、β细胞和肌肉等关键器官的功能与发育有关 肥胖和糖尿病。因此，我们假设接触DEHP的先入之见， 妊娠期暴露，通过改变 或者是卵母细胞中的表观遗传特征和/或线粒体功能。因此，我们建议， 以下具体目标：目标1将确定是否孕前接触生物学 相关剂量的DEHP导致与妊娠期暴露相似的后代表型。目的 2将确定两种不同暴露的分子和细胞机制， 窗口导致后代中相似或不同的代谢表型。我们将分析 在卵母细胞中通过RNA-seq检测转录组，通过ATACseq和亚硫酸氢盐-seq检测表观基因组， 后代的关键组织然后，我们将确定DEHP对以下关键方面的影响： 线粒体功能，如呼吸，ATP，ROS和形态。的证明 环境污染物的先入之见规划原则可能会改变我们的 对此类化合物的风险进行严格评估的意识。