Hepatotoxic effects of perfluoroalkyl substances: a new epidemiological approach for studying environmental fatty liver disease

摘要 在过去的20年里，儿童非酒精性脂肪肝（NAFLD）的患病率几乎增加了两倍。 NAFLD目前影响美国8-12%的普通儿科人群，超过30%的肥胖儿童。 孩子它与发展为肝脏疾病晚期的风险增加以及 心血管和代谢疾病。越来越多的证据表明，生命早期的环境暴露 导致NAFLD的病因。PFAS是广泛用于防水纺织品的持久性化合物， 不粘涂料和食品包装产品，在人体内的半衰期很长（长达十年）。几乎所有 美国儿童和青少年的血液中有可检测的PFAS水平。即使低剂量暴露于PFAS， 动物模型中的肝毒性作用。尽管有大量的实验研究证据， 仅限于成人的一些横断面研究。因此，我们提出了一种新的研究设计， PFAS对人体的肝毒性作用。我们将利用来自青少年的临床和肝脏组织病理学数据- 减肥手术纵向评估（Teen-LABS）研究，这是美国最大的多中心研究。 对接受减肥手术的青少年进行的纵向前瞻性研究，并提供了一个独特的肝脏档案。 组织和血液样本我们假设较高的PFAS浓度与NAFLD相关， 手术时非酒精性脂肪性肝炎（NASH，更严重的NAFLD）;此外， 减肥手术后发生的代谢变化“自然实验”将放大PFAS的效果 暴露，导致手术后肝损伤的减弱改善。为了验证这个假设，我们将使用 在手术时采集存档样本，以测量血浆和肝脏中的PFAS浓度， 评估与手术时肝组织病理学以及手术期间肝损伤改善的相关性。 后续行动（目标1和2）。然后，我们将根据高分辨率图像识别PFAS暴露改变的途径。 使用分层建模方法，在肝组织和血浆样品中进行代谢组学分析（目的3）。 最后，我们将整合PFAS组学分析的结果，使用一种新的潜变量模型 框架，以确定减肥手术后肝损伤改善较少的青少年亚组， 基于他们的PFAS暴露和代谢组学特征（目标4）。这项拟议中的研究将是第一个人类 一项研究，使用疾病肝活检金标准检查PFAS暴露对NAFLD的影响 诊断和肝脏特异性和血浆代谢组学测量，用于检查 接触疾病。强大的跨学科调查团队带来了环境方面的专业知识 流行病学、儿科肝病学、减肥手术、代谢组学和生物统计学。该研究利用 现有的数据和生物样本，从一个良好的表型临床青少年减肥手术队列，是一个 创新的，具有成本效益的方法，以促进我们对环境对儿科肝脏影响的理解 这种疾病可能会在生命早期发现预防和干预的新目标。

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.