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

• 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
• 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

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.

项目概要 肝细胞癌（HCC）是全球第五大常见癌症，在癌症死亡率中排名第三。 HCC 的治疗选择有限且预后较差（5 年生存率为 17%），这凸显了 疾病预防的重要性。已知的 HCC 危险因素包括乙型或丙型肝炎感染、酗酒或 黄曲霉毒素 B1 等环境污染物。这些风险因素在东亚、南美洲、 和非洲，其 HCC 发病率比例较高。然而，西方国家的 HCC 发病率和死亡率 国家正在增加；肝癌有望成为癌症相关死亡的第三大原因 到 2030 年，美国新的危险因素，包括非酒精性脂肪性肝炎，占美国病例的比例不到五分之一， 表明存在未识别的环境风险因素。我们发现发育暴露 环境相关剂量的化学污染物双酚 A (BPA) 与肝癌相关 雄性和雌性 C57BL/6J 小鼠。暴露的小鼠仅对 BPA 表现出 HCC 的剂量反应率， 没有已知的共同暴露。这一发现表明 BPA 是肝脏中的一种完全致癌物，负责 癌发生的两个阶段：起始和促进。此外，HCC 的剂量反应性增加 增加 BPA 剂量是基因毒性癌症发生的特征。先前的数据表明 BPA 会增加细胞 活性氧 (ROS) 和 BPA 诱导的突变谱与 ROS 诱导的突变谱一致 DNA 氧化损伤。 BPA 还会通过雌激素受体 α (ERα) 扰乱内分泌信号。 ERα信号传导 保护女性免受肝癌的侵害，这就是为什么男性更容易患这种癌症的原因。然而我们发现 在暴露于 BPA 的小鼠中，这种 HCC 发病率的性别差异消失了，这表明内分泌干扰物 BPA 的影响消除了通常由完整的 ERα 功能为女性提供的保护。在这个提案中，我们 将检验 BPA 作为肝脏中的完全致癌物这一中心假设。具体来说，我们假设 发育中的 BPA 通过氧化诱导的 DNA 损伤引发 HCC，并通过内分泌促进 HCC 扰乱。在目标 1 中，我们将通过实验测试氧化突变在 HCC 发生中的因果作用 增加突变积累率（在暴露于 BPA 的 DNA 修复缺陷小鼠中）并拯救 损伤（通过将小鼠同时暴露于抗氧化剂）。在目标 2 中，我们将测试 ERα 信号传导在 HCC 中的因果作用 通过实验增加信号传导（通过将小鼠同时暴露于 BPA 和 ERα 激动剂）来促进 减少信号传导（通过将小鼠同时暴露于 BPA 和 ERα 拮抗剂）。这些研究的结果将 解决关于 BPA 致癌潜力的长期争论，并描述这种无处不在的物质的作用 环境污染物作为 HCC 潜在的新环境危险因素。