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
• 负责人: VAIA LIDA CHATZI
• 金额: $ 64.11万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155485
• 关键词: Address; Adolescent; Adolescent obesity; Adult; Affect; Age; Alanine Transaminase; Animal Model; Archives; Attenuated; Biological; Biological Markers; Biometry; Blood; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Chemicals; Child; Childhood; Clinical; Cohort Effect; Cross-Sectional Studies; Data; Diagnosis; Disease; Dose; Environmental Epidemiology; Environmental Exposure; Environmental Pollutants; Epidemiology; Etiology; Exposure to; Fatty Liver; Fibrosis; Food Packaging; Funding; Gold; Health; Hepatic; Hepatocyte; Hepatology; Hepatomegaly; Hepatotoxicity; Histologic; Histopathology; Homeostasis; Human; Hypertrophy; Impairment; Individual; Inflammation; Inflammatory; Intervention; Investigation; Lead; Life; Link; Lipids; Liver; Liver diseases; Longitudinal prospective study; Measures; Metabolic; Metabolic Diseases; Modeling; Morbid Obesity; Natural experiment; Obesity; Operative Surgical Procedures; Outcome; Participant; Pathway interactions; Patients; Plasma; Poly-fluoroalkyl substances; Population; Population Study; Predisposition; Prevalence; Prevention; Product Packaging; Prospective Studies; Regulation; Research; Research Design; Research Personnel; Resolution; Risk; Rodent; Sampling; Screening procedure; Serum; Severities; Severity of illness; Subgroup; Teenagers; Testing; Textiles; Time; Tissue Sample; Tissues; Water; Youth; bariatric surgery; base; clinical phenotype; cohort; cost effective; data archive; disease diagnosis; disorder prevention; disorder risk; epidemiology study; experimental study; follow-up; hepatocyte injury; high risk; human study; innovation; lipid metabolism; liver biopsy; liver injury; metabolome; metabolomics; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obesity in children; response; sample archive; toxicant; treatment strategy

ABSTRACT The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has almost tripled over the past 20 years. NAFLD currently affects 8-12% of the general pediatric population in the U.S. and more that 30% of obese children. It is associated with an increased risk of developing advance stages of liver disease as well as cardiovascular and metabolic diseases. Mounting evidence suggests that early life environmental exposures contribute to the etiology of NAFLD. PFAS are persistent compounds widely used in water repellant textiles, nonstick coatings, and food packaging products, and have long half-lives (up to a decade) in humans. Almost all U.S. children and adolescents have detectable PFAS blood levels. Even low dose exposure to PFAS induces hepatotoxic effects in animal models. Despite abundant evidence from experimental studies, epidemiologic study is limited to a few cross-sectional studies in adults. We therefore propose a novel study design for investigating PFAS hepatotoxic effects in humans. We will leverage clinical and liver histopathological data from the Teen- Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study, which is the largest national multi-center longitudinal, prospective study on teenagers undergoing bariatric surgery, and offers a unique archive of liver tissue and blood samples. We hypothesize that higher PFAS concentrations will be associated with NAFLD and non-alcoholic steatohepatitis (NASH, more severe NAFLD) at the time of surgery; furthermore, the large metabolic changes occurring after the bariatric surgery “natural experiment” will magnify effects of PFAS exposures, resulting in attenuated improvement in liver injury after surgery. To test this hypothesis, we will use archived samples collected at the time of surgery to measure PFAS concentrations in plasma and liver and assess associations with liver histopathology at the time of surgery and with improvement in liver injury during follow up (Aims1&2). We will then identify pathways altered by PFAS exposure based on high resolution metabolomics profiles in liver tissue and plasma samples, using a hierarchical modeling approach (Aim 3). Finally, we will integrate results from the PFAS-omics analyses, using a novel latent variable modeling framework, to identify subgroups of adolescents who have less improvement in liver injury after bariatric surgery, based on their PFAS exposure and metabolomics profiles (Aim 4). The proposed research will be the first human study to examine the effects of PFAS exposure on NAFLD using the gold standard of liver biopsies for disease diagnosis and liver-specific and plasma metabolomic measures for examining biological mechanisms linking exposure to disease. A strong interdisciplinary team of investigators brings expertise in environmental epidemiology, pediatric hepatology, bariatric surgery, metabolomics, and biostatistics. The study, utilizing existing data and biosamples from a well-phenotyped clinical adolescent bariatric surgery cohort, is an innovative, cost-effective approach to advance our understanding of environmental contributions to pediatric liver disease that may identify new targets for prevention and intervention starting early in life.

抽象的 在过去的20年中，儿童非酒精性脂肪肝疾病（NAFLD）的患病率几乎增加了两倍。 NAFLD目前影响美国的8-12％的儿科人口，而30％的肥胖 孩子们。它与发展肝病的前期阶段的风险增加有关 心血管和代谢疾病。越来越多的证据表明，早期的环境暴露 有助于NAFLD的病因。 PFA是持续使用的化合物 不粘涂料和食品包装产品，在人类中有一半的年龄（长达十年）。几乎全部 美国的儿童和青少年发现了PFAS血液水平。甚至低剂量暴露于PFA的影响 动物模型中的肝毒性作用。尽管来自实验研究的大量证据，但流行病学研究 在成年人中仅限于一些横断面研究。因此，我们提出了一种用于研究的新型研究设计 PFA对人类的肝毒性作用。我们将利用青少年的临床和肝组织病理学数据 减肥手术纵向评估（TEEN-LABS）研究，这是最大的国家多中心 纵向，前瞻性研究对青少年接受减肥手术的研究，并提供独特的肝脏档案 组织和血液样本。我们假设较高的PFA浓度将与NAFLD和 手术时的非酒精性脂肪性肝炎（NASH，更严重的NAFLD）；此外，大 减肥手术“自然实验”后发生的代谢变化将放大PFA的影响 暴露，导致手术后肝损伤的改善。为了检验这一假设，我们将使用 在手术时收集的存档样品，以测量血浆和肝脏中的PFA浓度 评估手术时与肝组织病理学的关联，并在肝脏损伤中改善 跟进（AIMS1和2）。然后，我们将根据高分辨率确定PFAS暴露改变的途径 使用分层建模方法（AIM 3），肝组织和血浆样品中的代谢组学谱。 最后，我们将使用一种新型的潜在变量建模来整合PFAS-omics分析的结果 框架，确定减肥手术后肝损伤改善较小的青少年亚组 根据他们的PFAS暴露和代谢组学概况（AIM 4）。拟议的研究将是第一个人 研究使用肝活检的黄金标准来检查PFA暴露对NAFLD的影响 诊断和肝脏特异性和血浆代谢组学测量 暴露于疾病。一个强大的跨学科研究团队为环境带来了专业知识 流行病学，小儿肝病学，减肥手术，代谢组学和生物统计学。这项研究，利用 现有的数据和生物样本来自良好的临床青少年肢体外科同类，是一个 创新的，具有成本效益的方法来促进我们对环境对小儿肝脏的贡献的理解 可能从生命早期开始的疾病可以确定预防和干预的新目标。