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

项目总结 非酒精性脂肪性肝病(NAFLD)是全球最常见的肝病。在美国，近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。非酒精性脂肪肝在亚洲国家更为普遍，然而，在之前的非酒精性脂肪肝研究中，亚洲人的比例较低 在美国和其他地方。全氟和多氟烷基物质(PFAS)是高度优先的污染物， 在环境和人体组织中生物积累和持续存在，如肝脏。现有证据来自 实验模型显示，接触PFAS会引起肝脏毒性作用，如脂代谢改变， 肝脏脂肪变性，以及更晚期的NAFLD。这些发现与最近的预期是一致的 已报告产前接触全氟辛烷磺酸与多种不良反应之间关系的流行病学研究 代谢结果。然而，以前还没有研究利用新的磁分辨率成像技术来 允许量化目标肝组织中的脂肪和脂质含量，因此可以建立因果联系 在PFAS和NAFLD之间。此外，缺乏人类证据来阐明两者之间的潜在相互作用 非酒精性脂肪性肝病病因学中的全氟辛烷磺酸暴露和公认的代谢和遗传危险因素。我们假设 产前暴露于全氟辛烷磺酸可通过改变脂质和氨基酸促进儿童肝脏脂肪变性和损伤(目标1) 酸代谢(目标2)，这些影响在遗传和/或代谢率较高的儿童中更强 对非酒精性脂肪肝的易感性(目标3)。为了检验这些假设，我们将利用独特的、现有的、基于人口的 在新加坡成长的母子队列朝着健康的结果(兴趣)在新加坡 产前和围产期孕妇和脐带血中PFAS暴露的综合评估，非侵入性 530名人群肝脏脂肪含量的质子磁共振波谱测定及靶向代谢组学研究 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 来自纵向随访检查的数据。这是第一次也是最全面的关于全氟辛烷磺酸暴露的研究。 和儿童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、遗传和代谢风险之间的相互作用 非酒精性脂肪肝的影响因素。研究结果将有助于建立全氟辛烷磺酸暴露与儿童非酒精性脂肪肝之间的因果联系。 并告知应对当前NAFLD疫情迫切需要的早期预防和干预战略。

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.