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
基本信息
- 批准号:9922274
- 负责人:
- 金额:$ 19.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdolescentAdultAgeAir PollutionAlanine TransaminaseAnimalsApoptosisArchivesAspartate TransaminaseBiologicalBiological MarkersBiological MonitoringBiometryBloodBranched-Chain Amino AcidsCadmiumCaliberChemical ExposureChildChildhoodChlorinated HydrocarbonsChronicClinicalClinical ResearchConfidence IntervalsCountryCytokeratin 18DataDevelopmentDiagnosisDiagnosticDiethylhexyl PhthalateDiseaseEarly InterventionEndocrine DisruptorsEnvironmental EpidemiologyEnvironmental ExposureEnvironmental PollutantsEnzymesEthicsEtiologyEuropeEuropeanExposure toExtrahepaticFatty AcidsFatty LiverFemaleFibrosisFutureGamma-glutamyl transferaseGlycerophospholipidsGoalsGoldHealthHealth BenefitHepatocyteHepatologyHepatotoxicityHumanHuman ResourcesInflammationInflammatoryInternationalInvestmentsLifeLinkLiverLiver diseasesMeasuresMetabolicMetabolic DiseasesMetabolic PathwayMetabolismMetalsMethodsMorbidity - disease rateMothersMusNitrogen DioxideObesityOdds RatioOutcomeParticulate MatterPathway interactionsPhysiologyPlasmaPlasticizersPolychlorinated BiphenylsPopulation StudyPregnancyPregnancy TrimestersPregnant WomenPrevalencePreventive InterventionPublic HealthRaceResearch InstituteRiskSamplingSerumStatistical MethodsStructureSubgroupTissuesWorkadipokinesagedambient air pollutionbisphenol Aclinical biomarkersclinically relevantcoarse particlescostcost efficientcytokinedisorder preventionfine particleshigh riskin uteroinnovationliver biopsyliver injuryliver transplantationmalemono-(2-ethylhexyl)phthalatenon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnutritionoxidationperfluorooctane sulfonateperfluorooctanoic acidpersistent organic pollutantsphthalatespollutantpolybrominated diphenyl etherprenatalprenatal environmental exposureprenatal exposureprogramsresidencetoxicant
项目摘要
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.
摘要
新出现的实验证据表明,暴露在环境污染物中会导致肝脏损伤和
导致“毒物相关性脂肪性肝病”,特别是在暴露于
发展。动物研究表明,即使在低水平暴露于多种内分泌物质时,也会产生肝毒性作用
干扰化学品(EDCs),包括持久性有机污染物、增塑剂和某些金属。此外,
研究表明,长期暴露在环境中的细颗粒物会导致肝脏脂肪变性、炎症
和小鼠的纤维化,伴随着血液中肝酶的升高。人类研究在很大程度上是交叉的
以前没有一项人口研究考察了宫内暴露于空气污染和
EDC合并随后的儿科肝脏损伤。我们提出了一种新的分析方法来研究
宫内环境暴露对儿童肝脏损伤的影响,利用
“人类早期生命暴露(HELIX)”项目,该项目提供了完全统一的生物监测数据
1200名孕妇及其子女的环境暴露、地理空间数据和组学生物标志物
在6个欧洲国家对6-10岁的儿童进行纵向跟踪调查。我们假设更高的
怀孕期间环境空气污染和有针对性的EDC暴露与随后的
儿童肝脏损伤及相关的代谢和炎症途径失调。我们建议
在存档的血清样本中检测,建立了儿童肝损伤的临床生物标志物。我们将应用小说
统计方法对螺旋化学暴露、内源性代谢物、
细胞因子、脂肪因子和已建立的临床肝损伤生物标记物,目的是确定潜在变量
代表不同的儿童群体,有肝脏损伤的风险。我们的具体目标是:1:评估
孕期特定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:评估产前暴露于靶向EDCs的相关性
儿童肝损伤的生物标志物。3:评估产前环境暴露与生物学的关系
使用一种创新的潜变量方法,将有肝损伤风险的儿童分为不同的亚组
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。这项建议
汇集了环境流行病学、儿科肝病、组学和
来自美国和欧洲不同研究机构的生物统计数据,将是第一个将多个
产前环境暴露与儿童肝损伤结局的关系。这项研究具有成本效益,利用了
欧洲对螺旋的大量投资,并有可能促进我们对早期生命环境的理解
(C)加强对儿童肝脏损伤的贡献,并确定新的预防和干预目标,从生命早期开始。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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
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{{ truncateString('VAIA LIDA CHATZI', 18)}}的其他基金
Pediatric Autoimmune Consortium for Exposome Research (PACER)
儿科自身免疫暴露组研究联盟 (PACER)
- 批准号:
10871577 - 财政年份:2023
- 资助金额:
$ 19.19万 - 项目类别:
Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals
DDE 暴露对减肥手术后脂肪组织功能、体重减轻和代谢改善的影响:亲脂性化学物质研究的新范式
- 批准号:
10550120 - 财政年份:2020
- 资助金额:
$ 19.19万 - 项目类别:
Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals
DDE 暴露对减肥手术后脂肪组织功能、体重减轻和代谢改善的影响:亲脂性化学物质研究的新范式
- 批准号:
10305676 - 财政年份:2020
- 资助金额:
$ 19.19万 - 项目类别:
Hepatotoxic effects of perfluoroalkyl substances: a new epidemiological approach for studying environmental fatty liver disease
全氟烷基物质的肝毒性作用:研究环境脂肪肝疾病的新流行病学方法
- 批准号:
10155485 - 财政年份:2020
- 资助金额:
$ 19.19万 - 项目类别:
Hepatotoxic effects of perfluoroalkyl substances: a new epidemiological approach for studying environmental fatty liver disease
全氟烷基物质的肝毒性作用:研究环境脂肪肝疾病的新流行病学方法
- 批准号:
10391331 - 财政年份:2020
- 资助金额:
$ 19.19万 - 项目类别:
Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals
DDE 暴露对减肥手术后脂肪组织功能、体重减轻和代谢改善的影响:亲脂性化学物质研究的新范式
- 批准号:
10087930 - 财政年份:2020
- 资助金额:
$ 19.19万 - 项目类别:
Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals
DDE 暴露对减肥手术后脂肪组织功能、体重减轻和代谢改善的影响:亲脂性化学物质研究的新范式
- 批准号:
9884568 - 财政年份:2020
- 资助金额:
$ 19.19万 - 项目类别:
Environmental Chemical Exposures and Longitudinal Changes of Glucose Metabolism, Insulin Sensitivity and B Cell Function in Youth
青少年环境化学物质暴露与葡萄糖代谢、胰岛素敏感性和 B 细胞功能的纵向变化
- 批准号:
10401909 - 财政年份:2019
- 资助金额:
$ 19.19万 - 项目类别:
Environmental Chemical Exposures and Longitudinal Changes of Glucose Metabolism, Insulin Sensitivity and B Cell Function in Youth
青少年环境化学物质暴露与葡萄糖代谢、胰岛素敏感性和 B 细胞功能的纵向变化
- 批准号:
10626734 - 财政年份:2019
- 资助金额:
$ 19.19万 - 项目类别:
Environmental Chemical Exposures and Longitudinal Changes of Glucose Metabolism, Insulin Sensitivity and B Cell Function in Youth
青少年环境化学物质暴露与葡萄糖代谢、胰岛素敏感性和 B 细胞功能的纵向变化
- 批准号:
9815831 - 财政年份:2019
- 资助金额:
$ 19.19万 - 项目类别:
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