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：
9759938
负责人：
MARISA S. BARTOLOMEI
金额：
$ 46.28万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759938
关键词：
ATAC-seq Adipocytes Adult Adult Children Animal Model Animals Awareness Behavioral 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 bisulfite sequencing blood glucose regulation chromatin immunoprecipitation critical period 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.

内分泌干扰物（ED）是一组能够改变正常内分泌的分子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。一组重要的 ED，用于各种工业应用，从而导致人类常见的一种主要邻苯二甲酸盐是邻苯二甲酸二(2-乙基己基)酯 (DEHP)，一种广泛使用的化合物，可能通过饮食接触（食品加工、包装）是人类和动物的主要污染源。模型显示邻苯二甲酸盐暴露与肥胖的发展之间存在联系与这些研究类似，我们的初步数据显示 DEHP 暴露。通过在怀孕和哺乳期之前和期间的生理相关剂量的饮食改变胎儿肝脏中的 DNA 甲基化，以性别特异性的方式增加成年后代的体重越来越明显的是，围孕阶段也代表了一个阶段。后代对环境暴露的易感性窗口。负责将代谢记忆从卵母细胞转移到后代的仍有待研究经阐明，两种可能的可能性是表观遗传失调和线粒体异常。此外，我们和其他人已经证明表观遗传变化和线粒体异常肝脏、ß 细胞和肌肉等关键器官的功能与因此，我们冒着孕前接触 DEHP 的风险，类似于这种情况。妊娠期暴露，通过改变后代的代谢表型异常卵母细胞中的表观遗传特征和/或线粒体功能因此我们提出。遵循特定目标：目标 1 将确定孕前是否接触过生物制剂相关剂量的 DEHP 会导致与妊娠期暴露相似的后代表型。 2 将确定两种不同暴露的分子和细胞机制窗口会导致后代出现相似或不同的代谢表型。卵母细胞中通过 RNA-seq 得到的转录组以及通过 ATACseq 和亚硫酸氢盐测序得到的表观基因组然后我们将确定 DEHP 对后代关键组织的影响。线粒体功能，如呼吸、ATP、ROS 和形态的证明。环境污染物的先入为主的编程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。