Preconception phthalate exposure and offspring outcomes

孕前邻苯二甲酸盐暴露和后代结果

基本信息

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
项目类别：
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

项目摘要

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.

内分泌破坏者（EDS）是一组能够改变正常内分泌的分子在动物和人类中起作用。我们和其他人已经证明，在子宫里暴露 EDS导致后代肥胖和异常葡萄糖稳态。邻苯二甲酸盐是一个重要的ED组，这些ED用于潜水员的工业应用范围人类的常见风险。一种主要的邻苯二甲酸盐是二苯甲酸酯（2-乙基己基） - 邻苯二甲酸盐（DEHP），A 广泛使用的化合物可能会为此饮食暴露（食物加工，包装）代表了普通人群的主要污染根源。人类和动物模型显示邻苯二甲酸盐暴露与肥胖的发展与代谢综合征。与这些研究类似，我们的初步数据表明DEHP暴露通过饮食在怀孕和泌乳期间和期间以身体相关的剂量改变胎儿肝脏中的DNA甲基化，增加性别特异性的成人后代体重方式。越来越多的证据表明，周围的阶段也代表了对后代环境暴露的易感性窗口。而机制负责将代谢记忆从卵母细胞转移到后代的转移仍然是阐明的，2种合理的可能性是表观遗传失调和线粒体异常。此外，我们和其他人表明表观遗传变化和线粒体异常肝脏，β-细胞和肌肉等关键器官的功能与肥胖和糖尿病。这是，我们假设对DEHP的先入见面的暴露，类似于妊娠暴露，通过改变后代导致异常代谢表型卵母细胞中的表观遗传谱和 /或线粒体功能。我们提出了以下特定目的：AIM 1将确定是否在生物学上暴露于先入为主相关剂量的DEHP导致类似的后代表型与妊娠暴露。目的 2将确定两种不同暴露的分子和细胞机制 Windows在后代中导致类似或不同的代谢表型。我们将概括 RNA-Seq的转录组和卵母细胞中的Atacseq和Bisulfite-Seq的表观基因组和表观基因组。后代中的关键组织。然后，我们将确定DEHP对关键方面的影响线粒体功能，例如呼吸，ATP，ROS和形态。证明环境污染物的先选原则可能会改变我们的意识到对此类化合物风险的批判性评估。