The influence of prenatal maternal exposures on fetal sterol metabolomics

产前母亲暴露对胎儿甾醇代谢组学的影响

• 批准号: 9222977
• 负责人: Nathaniel W. Snyder
• 金额: $ 15.65万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222977
• 关键词: Action Potentials; Address; Analytical Chemistry; Androgen Receptor; Androgens; Autistic Disorder; Bile Acids; Biological; Biological Assay; Biological Markers; Blood; Centers for Disease Control and Prevention (U.S.); Characteristics; Chemical Exposure; Chemicals; Child; Cholesterol; Classification; Data; Data Set; Defecation; Development; Developmental Biology; Developmental Delay Disorders; Endocrine disruption; Enrollment; Environment; Environmental Exposure; Event; Exposure to; Family; Feces; Future; Goals; Gonadal Steroid Hormones; Health; Human; Individual; Infant; Investigation; Least-Squares Analysis; Life; Light; Lipids; Maternal Exposure; Measures; Meconium; Membrane Lipids; Metabolic; Metabolism; Methods; Modeling; Mothers; Nature; Newborn Infant; Outcome; Phenols; Plasma; Population; Pregnancy; Production; Publishing; Research; Resolution; Resources; Risk; Sampling; Science; Stable Isotope Labeling; Statistical Methods; Sterols; Structure; Techniques; Time; Triclosan; Urine; Validation; Variant; Visit; Vitamin D Analog; Work; abstracting; analog; analytical method; autism spectrum disorder; base; biomarker discovery; cohort; disorder risk; fetal; improved; innovation; interest; male; member; metabolomics; neurodevelopment; neurosteroids; novel; persistent organic pollutants; polybrominated diphenyl ether; potential biomarker; prenatal; prenatal environmental exposure; prenatal exposure; prenatal influence; prospective; response; steroid hormone; steroid metabolism; triclocarban

Project abstract/summary Sterol metabolism includes the developmentally critical sex steroid hormones, bile acids, neurosteroids, and cholesterol metabolites of lipid membranes. Certain persistent organic pollutants, including polybrominated diphenyl ethers (PBDEs), as well as high volume production chemicals, including phenols such as triclosan (TCS), are thought to interfere with steroid metabolism and action. Meconium, the first bowel movements of a newborn, begins accumulation in approximately the 12th week of gestation, and contains high sterol content. Thus, meconium provides a window into the prenatal metabolic environment during neurodevelopmentally relevant periods. This proposal will quantify differences in sterol metabolites from meconium in children enrolled in a prospective cohort of early events in neurodevelopment by levels of maternal exposure to PBDEs and major phenols. To deal with the complexity of exposure quantification, we will use a novel variation on partial least squares (PLS) methods, incorporating assumptions of sparsity, non-negativity and biologically plausible structure. These additional modeling constraints will facilitate identification of the most likely biomarkers of exposure response within the already acquired dataset of sterol metabolites. To extend the relevance of the putatively identified sterols, the structures of the biomarkers will be partially or fully elucidated and targeted methods will be developed for future validation as potential biomarkers of exposure. We will conduct this research in three specific aims as follows; Aim 1: Identify unknown chromatographic features with differential abundance by maternal exposure to PBDEs and phenols. Aim 2: Elucidate structural characteristics of sterols identified as interesting in Aim 1. Aim 3: Examine the relationship of PBDE and phenol subtypes with sterols characterized in aim 2 using a Bayesian mixture model. This innovative work will generate testable hypotheses for future research in the field of prenatal neurodevelopment.

项目摘要/概要 固醇代谢包括发育关键性类固醇激素、胆汁酸、神经类固醇和 脂膜的胆固醇代谢物。某些持久性有机污染物， 二苯醚（PBDEs），以及大量生产的化学品，包括三氯生等酚类 (TCS)被认为会干扰类固醇的代谢和作用。胎粪，一个人的第一次排便 新生儿，大约在妊娠第12周开始积累，并含有高固醇含量。 因此，胎粪提供了一个窗口，了解产前代谢环境，在神经发育 相关时期。这项建议将量化儿童胎粪中甾醇代谢物的差异 根据母亲接触多溴联苯醚的水平，纳入神经发育早期事件的前瞻性队列 和主要酚类。为了处理曝光量化的复杂性，我们将使用一种新的变化， 偏最小二乘（PLS）方法，结合稀疏性，非负性和生物学假设 合理的结构这些额外的建模约束将有助于识别最有可能的 在已经获得的固醇代谢物数据集中，暴露反应的生物标志物。延长 相关性的pupestrian确定甾醇，生物标志物的结构将部分或全部阐明 并将开发有针对性的方法，作为潜在的暴露生物标志物，供今后验证。我们将 本研究有以下三个具体目标：目标1：识别未知的色谱特征， 母亲接触多溴联苯醚和酚类物质的丰度差异。目标2：阐明结构 目标1中确定为感兴趣的甾醇的特征。目的3：考察多溴联苯醚与苯酚的关系 使用贝叶斯混合模型，在aim 2中表征具有固醇的亚型。这项创新工作将 为未来产前神经发育领域的研究提供可验证的假设。