Formaldehyde Genotoxicity

甲醛的遗传毒性

基本信息

批准号：
8501467
负责人：
Anatoly Zhitkovich
金额：
$ 39.09万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-29 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501467
关键词：
Abbreviations Address Adult Alkylating Agents Amino Acids Animals Biological CD34 gene Carcinogens Cell physiology Cells Chemicals Chromosomal Breaks Chromosomal translocation Chromosome Breakage Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Sequence Rearrangement DNA lesion DNA-protein crosslink Dose Double Strand Break Repair Epidemiology Epigenetic Process Etiology Event Formaldehyde Gene Mutation Genes Genetic Genetic Markers Genomics Guidelines Histones Human Human Engineering Impairment Injury Lead Lesion Link Lipid Peroxidation Location Malignant Neoplasms Mammalian Cell Metabolic Metabolic Biotransformation Metabolism Modeling Molecular Mutation Myeloid Leukemia Nonhomologous DNA End Joining Nose Nucleotide Excision Repair Nucleotides Occupational Oxidative Stress Peptides Pharmaceutical Preparations Process Property Research Risk Risk Assessment Risk Factors Rodent Role Shuttle Vectors Site Source Stem cells System Tissues Toxic Environmental Substances Uncertainty Upper respiratory tract Wood material base cancer risk carcinogenesis carcinogenicity chromatin remodeling crosslink cytotoxic cytotoxicity demethylation design genotoxicity high risk homologous recombination human adult stem cell human tissue improved leukemia repaired toxicant

项目摘要

DESCRIPTION (provided by applicant): Formaldehyde (FA) is a ubiquitous environmental and occupational toxicant that is associated with an increasing number of human cancers. FA is also generated endogenously as a product of lipid peroxidation, drug biotransformation and several normal metabolic processes, such as histone demethylation during chromatin remodeling. Molecular mechanisms of FA carcinogenicity are poorly understood, in part reflecting its past association only with rare nasal cancers. A growing list of human cancers recently linked to FA exposure is difficult to explain by the cytotoxicity-based risk assessment models developed for nasal cancers in rodents. This application is designed to address major research gaps that hinder mechanistic understanding of FA-induced carcinogenic effects. Three specific aims are proposed to (1) determine main causes of FA mutagenicity in human cells, (2) identify genomic sites and genes that are prone to large rearrangements and (3) examine a role of epigenetic injury in the formation of large genetic changes by FA in human adult stem cells. A successful completion of these studies can lead to the identification of the mechanistically important biomarkers of genetic damage by FA and help resolve current uncertainties regarding its mode of carcinogenic action and ability to initiate leukemogenic events.

描述（由申请人提供）：甲醛 (FA) 是一种普遍存在的环境和职业毒物，与越来越多的人类癌症相关。 FA 也是脂质过氧化、药物生物转化和一些正常代谢过程（例如染色质重塑过程中组蛋白去甲基化）的产物内源性产生的。人们对 FA 致癌性的分子机制知之甚少，部分反映了它过去仅与罕见的鼻癌有关。最近，越来越多的人类癌症与 FA 暴露相关，很难用针对啮齿类动物鼻癌开发的基于细胞毒性的风险评估模型来解释。该应用旨在解决阻碍 FA 诱发致癌作用机制理解的主要研究空白。提出了三个具体目标：(1) 确定人类细胞中 FA 致突变性的主要原因，(2) 识别易于发生大规模重排的基因组位点和基因，以及 (3) 检查表观遗传损伤在大规模遗传变化形成中的作用在人类成体干细胞中通过 FA 进行检测。这些研究的成功完成可以识别 FA 造成的遗传损伤的机械上重要的生物标志物，并有助于解决目前关于其致癌作用模式和引发白血病事件能力的不确定性。