Developmental origins of child liver injury: Effects of prenatal environmental exposures

儿童肝损伤的发育起源：产前环境暴露的影响

• 批准号: 9922274
• 负责人: VAIA LIDA CHATZI
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922274
• 关键词: Adolescent; Adult; Age; Air Pollution; Alanine Transaminase; Animals; Apoptosis; Archives; Aspartate Transaminase; Biological; Biological Markers; Biological Monitoring; Biometry; Blood; Branched-Chain Amino Acids; Cadmium; Caliber; Chemical Exposure; Child; Childhood; Chlorinated Hydrocarbons; Chronic; Clinical; Clinical Research; Confidence Intervals; Country; Cytokeratin 18; Data; Development; Diagnosis; Diagnostic; Diethylhexyl Phthalate; Disease; Early Intervention; Endocrine Disruptors; Environmental Epidemiology; Environmental Exposure; Environmental Pollutants; Enzymes; Ethics; Etiology; Europe; European; Exposure to; Extrahepatic; Fatty Acids; Fatty Liver; Female; Fibrosis; Future; Gamma-glutamyl transferase; Glycerophospholipids; Goals; Gold; Health; Health Benefit; Hepatocyte; Hepatology; Hepatotoxicity; Human; Human Resources; Inflammation; Inflammatory; International; Investments; Life; Link; Liver; Liver diseases; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Metals; Methods; Morbidity - disease rate; Mothers; Mus; Nitrogen Dioxide; Obesity; Odds Ratio; Outcome; Particulate Matter; Pathway interactions; Physiology; Plasma; Plasticizers; Polychlorinated Biphenyls; Population Study; Pregnancy; Pregnancy Trimesters; Pregnant Women; Prevalence; Preventive Intervention; Public Health; Race; Research Institute; Risk; Sampling; Serum; Statistical Methods; Structure; Subgroup; Tissues; Work; adipokines; aged; ambient air pollution; bisphenol A; clinical biomarkers; clinically relevant; coarse particles; cost; cost efficient; cytokine; disorder prevention; fine particles; high risk; in utero; innovation; liver biopsy; liver injury; liver transplantation; male; mono-(2-ethylhexyl)phthalate; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; nutrition; oxidation; perfluorooctane sulfonate; perfluorooctanoic acid; persistent organic pollutants; phthalates; pollutant; polybrominated diphenyl ether; prenatal; prenatal environmental exposure; prenatal exposure; programs; residence; toxicant

ABSTRACT Emerging experimental evidence indicates that exposure to environmental pollutants causes liver injury and contributes to “toxicant-associated fatty liver disease”, specially if exposure occurs during critical stages of development. Animal studies show hetatotoxic effects even at low levels of exposure to many endocrine disrupting chemicals (EDCs), including persistent organic pollutants, plasticizers and certain metals. Moreover, chronic exposures to ambient fine particulate matter have been shown to induce liver steatosis, inflammation and fibrosis in mice, accompanied by elevated blood liver enzymes. Human studies have largely been cross- sectional, and no previous population study has examined associations of in utero exposure to air pollution and EDCs with subsequent pediatric liver injury. We propose a novel analytyical approach for investigating effects of in utero environmental exposures on child liver injury, leveraging the extraordinary existing resources of the “Human Early Life Exposome (HELIX)” project, which provides completely harmonized biomonitoring data on environmental exposures, geospatial data and omics biomarkers in 1200 pregnant mothers and their children followed longitudinally up to the age of 6-10 years in 6 European countries. We hypothesize that higher ambient air pollution and targeted EDC exposures during pregnancy are associated with subsequent child liver injury and associated dysregulation of metabolic and inflammatory pathways. We propose to measure in archived serum samples established clinical biomarkers of child liver injury. We will apply novel statistical methods to conduct integrated analyses of HELIX chemical exposures, endogenous metabolites, cytokines, adipokines, and established clinical liver injury biomarkers, with the goal of identifying latent variables representing distinct groups of children at risk for liver injury. Our specific aims are: 1: To evaluate the associations of pregnancy trimester-specific fine particle and other regulated air pollution exposures with biomarkers of child liver injury. 2: To evaluate the associations of prenatal exposure to targeted EDCs with biomarkers of child liver injury. 3: To assess associations of prenatal environmental exposures with biological distinct subgroups of children at risk for liver injury, using an innovative latent variable approach that integrates exposure profiles, clinical biomarkers, engogenous metabolites, cytokine and adipokine data. The proposal brings together international experts on environmental epidemiology, pediatric hepatology, omics, and biostatistics from different research institutes in the U.S. and Europe and will be the first study to link multiple prenatal environmental exposures with childhood liver injury outcomes. The study is cost efficient, leveraging a large European investment in HELIX, and has potential to advance our understanding of early life environmental contributions to child liver injury and to identify new targets for prevention and interventions starting early in life.

抽象的 新出现的实验证据表明，接触环境污染物会导致肝损伤和 会导致“与毒物相关的脂肪肝疾病”，特别是如果暴露发生在关键阶段 动物研究表明，即使在低水平接触许多内分泌物质的情况下也会产生肝毒性作用。 破坏性化学品 (EDC)，包括持久性有机污染物、增塑剂和某些金属。 长期暴露于环境细颗粒物已被证明会诱发肝脏脂肪变性、炎症 和小鼠纤维化，并伴有血液肝酶升高，人类研究很大程度上是交叉的。 区域性的，并且之前没有人口研究考察过子宫内暴露于空气污染和 我们提出了一种新的分析方法来研究 EDC 与随后的儿童肝损伤的影响。 子宫内环境暴露对儿童肝损伤的影响，利用现有的非凡资源 “人类早期生命暴露体（HELIX）”项目，提供完全统一的生物监测数据 1200 名孕妇及其孩子的环境暴露、地理空间数据和组学生物标志物 在 6 个欧洲国家纵向追踪至 6-10 岁。 环境空气污染和怀孕期间有针对性的 EDC 暴露与随后的 儿童肝损伤以及相关的代谢和炎症途径失调。 我们将应用新的方法来测量存档的血清样本中建立的儿童肝损伤的临床生物标志物。 对 HELIX 化学品暴露、内源代谢物进行综合分析的统计方法， 细胞因子、脂肪因子和已建立的临床肝损伤生物标志物，目的是识别潜在变量 代表有肝损伤风险的不同儿童群体。我们的具体目标是： 1：评估 妊娠三个月特有的细颗粒物和其他受管制的空气污染暴露与 儿童肝损伤的生物标志物2：评估产前接触靶向EDC与的关联。 儿童肝损伤的生物标志物3：评估产前环境暴露与生物的关联。 使用创新的潜变量方法，将有肝损伤风险的不同儿童亚组整合起来 暴露概况、临床生物标志物、内源性代谢物、细胞因子和脂肪因子数据。 汇集了环境流行病学、儿科肝病学、组学等领域的国际专家 来自美国和欧洲不同研究机构的生物统计学，这将是第一项将多个研究联系起来的研究 产前环境暴露与儿童肝损伤结果的关系该研究具有成本效益，利用了 欧洲对 HELIX 进行了大量投资，有潜力增进我们对早期生命环境的理解 对儿童肝损伤的贡献，并确定从生命早期开始预防和干预的新目标。

项目成果

Multi-omics signatures of the human early life exposome.

• DOI: 10.1038/s41467-022-34422-2
• 发表时间: 2022-11-21
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Maitre, Lea;Bustamante, Mariona;Hernandez-Ferrer, Carles;Thiel, Denise;Lau, Chung-Ho E.;Siskos, Alexandros;Vives-Usano, Marta;Ruiz-Arenas, Carlos;Pelegri-Siso, Dolors;Robinson, Oliver;Mason, Dan;Wright, John;Cadiou, Solene;Slama, Remy;Heude, Barbara;Casas, Maribel;Sunyer, Jordi;Papadopoulou, Eleni Z.;Gutzkow, Kristine B.;Andrusaityte, Sandra;Grazuleviciene, Regina;Vafeiadi, Marina;Chatzi, Leda;Sakhi, Amrit K.;Thomsen, Cathrine;Tamayo, Ibon;Nieuwenhuijsen, Mark;Urquiza, Jose;Borras, Eva;Sabido, Eduard;Quintela, Ines;Carracedo, Angel;Estivill, Xavier;Coen, Muireann;Gonzalez, Juan R.;Keun, Hector C.;Vrijheid, Martine
• 通讯作者: Vrijheid, Martine