Understanding mechanisms of liver carcinogenesis following developmental BPA exposure

了解发育性 BPA 暴露后肝癌发生的机制

基本信息

批准号：
10578624
负责人：
Caren Weinhouse
金额：
$ 52.16万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-20 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578624
关键词：
Acetylcysteine Adult Aflatoxin B1 Africa Agonist Alcohol abuse Antioxidants Binding Biological Availability Cancer Etiology Carcinogenesis Mechanism Carcinogens Cessation of life Characteristics Chemicals Chronic Conceptions Country DNA DNA Damage DNA Repair Disorder DNA Sequence Alteration Data Development Disease Dose Endocrine Endocrine Disruptors Endocrine disruption Enhancers Environment Environmental Pollutants Environmental Risk Factor Estrogen Receptor alpha Estrogen Receptors Estrogens Exposure to Far East Female Frequencies Gene Expression Genetic Transcription Half-Life Health Hepatitis B Hepatitis C Hepatocarcinogenesis Human In Vitro Incidence Infection Link Liver Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Mus Mutagenesis Mutagenicity Tests Mutation Pathway interactions Predisposition Primary carcinoma of the liver cells Prognosis Property Reactive Oxygen Species Reporting Research Research Design Risk Risk Factors Rodent Role Sex Differences Signal Transduction South America Survival Rate Testing Tissues Weaning Work antagonist bisphenol A cancer initiation carcinogenesis carcinogenicity disorder prevention driver mutation epidemiology study exome sequencing exposed human population genome-wide genotoxicity in vivo evaluation male mortality neonatal exposure nonalcoholic steatohepatitis novel oxidative DNA damage pollutant prevent protective effect response transcription factor

项目摘要

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and ranks third in cancer mortality. HCC has limited treatment options and carries a poor prognosis (17% 5-year survival rate), highlighting the importance of disease prevention. Known HCC risk factors include hepatitis B or C infection, alcohol abuse, or environmental contaminants like aflatoxin B1. These risk factors are most common in East Asia, South America, and Africa, which have proportionally higher HCC rates. However, HCC incidence and mortality in Western countries are increasing; liver cancer is poised to become the third leading cause of cancer-related death in the U.S. by 2030. New risk factors, including non-alcoholic steatohepatitis, account for less than a fifth of U.S. cases, suggesting the existence of unidentified environmental risk factors. We have found that developmental exposure to environmentally relevant doses of the chemical pollutant bisphenol A (BPA) is associated with HCC in both male and female C57BL/6J mice. Exposed mice show dose-responsive rates of HCC in response to BPA alone, with no known co-exposures. This finding implicates BPA as a complete carcinogen in the liver, responsible for both stages of carcinogenesis: initiation and promotion. In addition, the dose-responsive increase in HCC with increasing BPA dose is characteristic of genotoxic cancer initiation. Prior data show that BPA increases cellular reactive oxygen species (ROS) and that BPA induces a mutation spectrum consistent with ROS-induced oxidative DNA damage. BPA also disrupts endocrine signaling through estrogen receptor  (ER). ER signaling protects females against HCC, which is why males are more prone to this form of cancer. However, we found that this sex difference in HCC incidence was lost in BPA-exposed mice, suggesting that the endocrine disruptive effects of BPA eliminated the protection normally afforded females by intact ER function. In this proposal, we will test the central hypothesis that BPA acts as a complete carcinogen in the liver. Specifically, we hypothesize that developmental BPA initiates HCC via oxidatively induced DNA damage and promotes HCC via endocrine disruption. In Aim 1, we will test the causal role of oxidative mutagenesis in HCC initiation by experimentally increasing the rate of mutation accumulation (in DNA repair-deficient mice exposed to BPA) and rescuing damage (by co-exposing mice to an antioxidant). In Aim 2, we will test the causal role of ER signaling in HCC promotion by experimentally increasing signaling (by co-exposing mice to BPA and an ER agonist) and decreasing signaling (by co-exposing mice to BPA and an ER antagonist). The results of these studies will settle a long-standing debate about the carcinogenic potential of BPA, as well delineate the role of this ubiquitous environmental pollutant as a potential new environmental risk factor for HCC.

项目摘要肝细胞癌（HCC）是全球第五大癌症，在癌症死亡率中排名第三。 HCC的治疗选择有限，预后不良（5年5年生存率），强调了预防疾病的重要性。已知的HCC危险因素包括乙型肝炎或C感染，酗酒或黄曲霉毒素B1等环境污染物。这些危险因素在东亚，南美最常见，和非洲，其HCC率成比例更高。但是，西方的HCC发病率和死亡率国家正在增加；肝癌被中毒成为与癌症相关死亡的第三大主要原因美国到2030年。包括非酒精性脂肪性肝炎在内的新危险因素不到美国病例的五分之一，表明存在身份不明的环境风险因素。我们发现发育趋势对于环保剂量的化学污染物双酚A（BPA）都与HCC有关雄性和雌性C57BL/6J小鼠。暴露的小鼠仅对BPA响应HCC的剂量响应率，没有已知的共同曝光。这一发现将BPA视为肝脏中的完整致癌物，负责癌变的两个阶段：倡议和促进。另外，HCC的剂量响应性增加增加BPA剂量是遗传毒性癌症倡议的特征。先前的数据表明，BPA增加了细胞活性氧（ROS）和BPA诱导与ROS诱导的突变光谱氧化DNA损伤。 BPA还通过雌激素受体（ER）破坏内分泌信号传导。 er信号保护女性免受HCC的侵害，这就是为什么雄性更容易发生这种形式的癌症的原因。但是，我们发现在暴露于BPA的小鼠中，HCC发病率的这种性别差异已经丢失，表明内分泌破坏性 BPA的效果消除了通常通过完整的ERR功能提供的保护女性的保护。在这个建议中，我们将检验中心假设，即BPA在肝脏中充当完整的致癌物。具体来说，我们假设该发展性BPA通过氧化诱导的DNA损伤启动HCC，并通过内分泌促进HCC 破坏。在AIM 1中，我们将通过实验测试HCC倡议中氧化诱变的因果作用提高突变积累速率（在暴露于BPA的DNA修复缺陷小鼠中）并救援损坏（通过共暴露小鼠抗氧化剂）。在AIM 2中，我们将测试ER信号在HCC中的因果作用通过实验增加信号传导的促进（通过将小鼠共暴露于BPA和ER激动剂）和降低信号传导（通过将小鼠共发生至BPA和ER拮抗剂）。这些研究的结果将解决有关BPA的致癌潜力的长期辩论，并描述了这种无处不在的作用环境污染物是HCC的潜在新环境风险因素。