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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.

项目总结