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:
- 金额:$ 52.16万
- 依托单位:
- 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:
- 关键词:AcetylcysteineAdultAflatoxin B1AfricaAgonistAlcohol abuseAntioxidantsBindingBiological AvailabilityCancer EtiologyCarcinogenesis MechanismCarcinogensCessation of lifeCharacteristicsChemicalsChronicConceptionsCountryDNADNA DamageDNA Repair DisorderDNA Sequence AlterationDataDevelopmentDiseaseDoseEndocrineEndocrine DisruptorsEndocrine disruptionEnhancersEnvironmentEnvironmental PollutantsEnvironmental Risk FactorEstrogen Receptor alphaEstrogen ReceptorsEstrogensExposure toFar EastFemaleFrequenciesGene ExpressionGenetic TranscriptionHalf-LifeHealthHepatitis BHepatitis CHepatocarcinogenesisHumanIn VitroIncidenceInfectionLinkLiverMalignant NeoplasmsMalignant neoplasm of liverMeasuresMediatingMusMutagenesisMutagenicity TestsMutationPathway interactionsPredispositionPrimary carcinoma of the liver cellsPrognosisPropertyReactive Oxygen SpeciesReportingResearchResearch DesignRiskRisk FactorsRodentRoleSex DifferencesSignal TransductionSouth AmericaSurvival RateTestingTissuesWeaningWorkantagonistbisphenol Acancer initiationcarcinogenesiscarcinogenicitydisorder preventiondriver mutationepidemiology studyexome sequencingexposed human populationgenome-widegenotoxicityin vivo evaluationmalemortalityneonatal exposurenonalcoholic steatohepatitisnoveloxidative DNA damagepollutantpreventprotective effectresponsetranscription 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 等环境污染物在东亚、南美洲、
和非洲,其 HCC 发病率较高,但西方国家的 HCC 发病率和死亡率却较高。
肝癌将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 小鼠仅对 BPA 表现出 HCC 剂量反应率,
没有已知的共同暴露,这一发现表明 BPA 是一种完全致癌的肝脏致癌物。
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 会增加细胞的数量。
活性氧 (ROS) 和 BPA 诱导的突变谱与 ROS 诱导的突变谱一致
BPA 还会通过雌激素受体 α (ERα) 信号干扰内分泌信号。
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。
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 的影响消除了完整的 ERα 功能通常为女性提供的保护。
将检验 BPA 作为肝脏中的完全致癌物这一中心假设。
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
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
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
减少信号传递(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
环境污染物作为肝癌潜在的新环境危险因素。
项目成果
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Caren Weinhouse其他文献
Caren Weinhouse的其他文献
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{{ truncateString('Caren Weinhouse', 18)}}的其他基金
Understanding the causes of DNA methylation response to methylmercury: a novel approach to quantify genetic, environmental, and stochastic factors
了解 DNA 甲基化对甲基汞反应的原因:一种量化遗传、环境和随机因素的新方法
- 批准号:
10452549 - 财政年份:2020
- 资助金额:
$ 52.16万 - 项目类别:
Understanding the causes of DNA methylation response to methylmercury: a novel approach to quantify genetic, environmental, and stochastic factors
了解 DNA 甲基化对甲基汞反应的原因:一种量化遗传、环境和随机因素的新方法
- 批准号:
10238120 - 财政年份:2020
- 资助金额:
$ 52.16万 - 项目类别:
Understanding the causes of DNA methylation response to methylmercury: a novel approach to quantify genetic, environmental, and stochastic factors
了解 DNA 甲基化对甲基汞反应的原因:一种量化遗传、环境和随机因素的新方法
- 批准号:
10039951 - 财政年份:2020
- 资助金额:
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