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Formaldehyde Genotoxicity

甲醛的遗传毒性

基本信息

批准号：
9040185
负责人：
Anatoly Zhitkovich
金额：
$ 39.92万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040185
关键词：
Address Adult Alkylating Agents 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 Nose 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 amino acid metabolism base cancer risk carcinogenesis carcinogenicity chromatin remodeling crosslink cytotoxic cytotoxicity demethylation design genotoxicity high risk 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有关。脂肪酸也作为脂质过氧化、药物生物转化和一些正常代谢过程（如染色质重塑过程中的组蛋白去甲基化）的产物内源性产生。FA致癌性的分子机制尚不清楚，部分反映了其过去仅与罕见的鼻癌有关。最近越来越多的人类癌症与FA暴露有关，这很难用针对啮齿动物鼻癌开发的基于细胞毒性的风险评估模型来解释。该应用程序旨在解决阻碍fa诱导的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)鉴定易发生大重排的基因组位点和基因，(3)研究表观遗传损伤在人类成体干细胞中FA形成大遗传变化中的作用。这些研究的成功完成可以确定FA遗传损伤的重要生物标志物，并有助于解决目前关于其致癌作用模式和启动白血病事件能力的不确定性。