Understanding mechanisms of liver carcinogenesis following developmental BPA exposure

项目总结 肝细胞癌是世界上第五大常见癌症，在癌症死亡率中排名第三。 肝癌的治疗选择有限，预后很差(5年生存率为17%)，这突显了 疾病预防的重要性。已知的肝细胞癌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、 和非洲，这两个地区的肝癌发病率相对较高。然而，西部地区的肝癌发病率和死亡率 国家正在增加；肝癌有望成为世界上与癌症相关的第三大死亡原因 到2030年美国。新的风险因素，包括非酒精性脂肪性肝炎，占美国病例的不到五分之一， 这表明存在未知的环境风险因素。我们发现，发育中的暴露 对于环境相关剂量的化学污染物双酚A(BPA)在两种情况下都与肝癌有关 雄性和雌性C57BL/6J小鼠。暴露的小鼠显示出单独对BPA反应的肝癌的剂量响应率， 没有已知的联合曝光。这一发现表明，BPA是肝脏中的一种完全致癌物质，对 癌变的两个阶段：启动和促进。此外，肝细胞癌的剂量反应增加与 增加双酚A剂量是遗传毒性致癌的特征。先前的数据显示，双酚A增加了细胞 活性氧物种(ROS)和双酚A诱导的突变谱与ROS诱导的一致 氧化DNA损伤。双酚A还通过雌激素受体(ER)干扰内分泌信号。ER信令 保护女性免受肝癌的侵袭，这就是为什么男性更容易患上这种形式的癌症。然而，我们发现， 在暴露于双酚A的小鼠中，肝癌发病率的这种性别差异消失了，这表明内分泌干扰 双酚A的作用消除了正常情况下由完整的ER功能提供的保护。在这项提案中，我们 将检验核心假设，即BPA在肝脏中完全是致癌物。具体来说，我们假设 发育中的双酚A通过氧化诱导DNA损伤启动肝细胞癌，并通过内分泌促进肝细胞癌 颠覆。在目标1中，我们将通过实验测试氧化诱变在肝细胞癌启动中的因果作用。 提高突变累积率(在暴露于双酚A的DNA修复缺陷小鼠中)并挽救 损害(通过让小鼠同时接触抗氧化剂)。在目标2中，我们将测试ER信号在肝细胞癌中的因果作用 通过实验增加信号转导促进(通过双酚A和ER激动剂共同暴露小鼠)和 减少信号传递(通过让小鼠同时接触双酚A和ER-拮抗剂)。这些研究的结果将 解决关于双酚A致癌潜力的长期争论，以及描绘这种无处不在的 环境污染物是肝癌潜在的新的环境风险因素。

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.