Perfluoroalkyl substances and non-alcoholic fatty liver disease in children: Leveraging magnetic resonance imaging to unravel potential mechanisms and exposure mixture effects

全氟烷基物质与儿童非酒精性脂肪肝：利用磁共振成像揭示潜在机制和暴露混合物效应

• 批准号: 10646759
• 负责人: Youssef Oulhote
• 金额: $ 47.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646759
• 关键词: Address; Adult; Affect; Age; Alanine Transaminase; Animals; Asia; Asian; Asian population; Biological Markers; Biological Monitoring; Child; Childhood; Childhood Injury; Clinical Markers; Country; Data; Detection; Elderly; Endocrine Disruptors; Environment; Environmental Exposure; Epidemic; Ethnic Population; Etiology; Experimental Models; Exposure to; Extrahepatic; Fatty Liver; Fatty acid glycerol esters; Fetus; Food Contamination; Genetic; Genetic Risk; Genomic approach; Glucose Intolerance; Growth; Hepatomegaly; Hepatotoxicity; Human; Imaging technology; Individual; Inflammation; Ingestion; Intervention; Life; Life Style; Link; Lipids; Liver; Liver Failure; Liver diseases; Longitudinal cohort; Low Birth Weight Infant; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetism; Measures; Metabolic; Metabolic Pathway; Metabolic syndrome; Methodological Studies; Mothers; Obesity; Outcome; Pathway interactions; Perinatal; Persons; Phenotype; Plasma; Poly-fluoroalkyl substances; Predisposition; Prevention strategy; Primary carcinoma of the liver cells; Prospective Studies; Protons; Reporting; Research; Resolution; Risk; Risk Factors; Serum; Singapore; Source; Technology; Testing; Tissues; Underrepresented Populations; aged; amino acid metabolism; bioaccumulation; cohort; comorbidity; consumer product; data repository; drinking water; early life exposure; environmental chemical; epidemiology study; exposed human population; follow-up; gene environment interaction; genetic risk factor; genome-wide; human tissue; in utero; insight; lipid metabolism; liver imaging; liver injury; liver transplantation; metabolic phenotype; metabolomics; non-alcoholic fatty liver disease; novel; obesity risk; pediatric non-alcoholic fatty liver disease; pollutant; polygenic risk score; population based; postnatal; prenatal; prenatal exposure; prospective; sex; spectroscopic imaging; study population; systematic review

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease globally. In the U.S., almost 30% of adults, and over 10% of children are estimated to have NAFLD facing increased risk for long-term complications, such as liver failure, hepatocellular carcinoma, extrahepatic comorbidities, and need for liver transplantation in later life. NAFLD is more prevalent in Asian countries, however Asians are underrepresented in previous NAFLD studies in the U.S. and elsewhere. Per- and polyfluoroalkyl substances (PFAS) are high-priority pollutants that bioaccumulate and persist in the environment and human tissues, such as the liver. Existing evidence from experimental models shows hepatotoxic effects caused by PFAS exposure, such as altered lipid metabolism, hepatic steatosis, and more advanced stages of NAFLD. There findings are in line with recent prospective epidemiology studies that have reported associations between prenatal PFAS exposures and multiple adverse metabolic outcomes. However, no previous study has utilized novel magnetic resolution imaging technologies that permit the quantification of fat and lipid content in the target liver tissue, and therefore can establish a causal link between PFAS and NAFLD. Moreover, human evidence is lacking to elucidate the potential interplay between PFAS exposures and well-established metabolic and genetic risk factors in NAFLD etiology. We hypothesize that prenatal exposure to PFAS promotes liver steatosis and injury in children (Aim 1) via alterations in lipid and amino acid metabolism (Aim 2), and that these effects are stronger in children who have higher genetic and/or metabolic susceptibility to NAFLD (Aim 3). To test these hypotheses, we will leverage the unique, existing, population-based mother-child cohort ‘Growing Up in Singapore Towards Healthy Outcomes (GUSTO)’ in Singapore with comprehensive assessments of pre- and perinatal PFAS exposures in maternal and cord serum, non-invasive proton magnetic resonance spectroscopy (MRS) measures of liver fat content and targeted metabolomics in 530 children aged 6-7.5 years, as well as extensive genome-wide, metabolic phenotype, lifestyle and relevant covariate data from longitudinal follow-up examinations. This is the first and most comprehensive study on PFAS exposures and pediatric NAFLD using state-of-the-art liver MRS imaging, metabolomics, environmental exposure mixture, and polygenic risk score approaches to determine the interplay of environmental, genetic, and metabolic risk factors in NAFLD. Findings will contribute to establish a causal link between PFAS exposures and pediatric NAFLD and inform early-life prevention and interventions strategies sorely needed to address the current NAFLD epidemic.

项目摘要 非酒精性脂肪性肝病（NAFLD）是全球最常见的肝病。在美国，几乎30%的 成人和超过10%的儿童估计患有NAFLD，面临长期并发症的风险增加， 如肝功能衰竭、肝细胞癌、肝外合并症，以及以后需要肝移植 生活NAFLD在亚洲国家更普遍，但在以前的NAFLD研究中，亚洲人的代表性不足 在美国和其他地方。全氟烷基和多氟烷基物质（PFAS）是高度优先的污染物， 在环境和人体组织（如肝脏）中生物累积并持久存在。现有证据显示， 实验模型显示了PFAS暴露引起的肝毒性作用，如脂质代谢改变， 肝脂肪变性和更晚期的NAFLD。这些发现符合最近的预期 流行病学研究报告了产前PFAS暴露与多种不良反应之间的关联， 代谢结果。然而，以前的研究没有利用新的磁分辨率成像技术， 允许量化目标肝脏组织中的脂肪和脂质含量，因此可以建立因果关系 PFAS和NAFLD之间的关系此外，缺乏人类证据来阐明 PFAS暴露与NAFLD病因中公认的代谢和遗传危险因素我们假设 产前暴露于PFAS通过改变脂质和氨基，促进儿童肝脏脂肪变性和损伤（目的1） 酸代谢（目标2），这些影响在遗传和/或代谢水平较高的儿童中更强。 NAFLD易感性（目标3）。为了验证这些假设，我们将利用独特的，现有的，基于人口的 母婴队列在新加坡开展的“在新加坡成长，迈向健康成果（GUSTO）”活动， 母体和脐带血清中产前和围产期PFAS暴露的综合评估， 530例肝脏脂肪含量和靶向代谢组学的质子磁共振波谱（MRS）测量 6-7.5岁儿童，以及广泛的全基因组、代谢表型、生活方式和相关协变量 纵向随访检查的数据。这是第一次也是最全面的研究PFAS暴露 和儿科NAFLD使用最先进的肝脏MRS成像，代谢组学，环境暴露混合物， 和多基因风险评分方法，以确定环境，遗传和代谢风险的相互作用 NAFLD的因素。研究结果将有助于建立PFAS暴露与儿童NAFLD之间的因果关系 并为解决当前NAFLD流行所急需的早期预防和干预策略提供信息。