Formaldehyde Genotoxicity

描述(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。FA也是内源性产生的，是脂质过氧化、药物生物转化和几个正常代谢过程的产物，如染色质重塑过程中的组蛋白去甲基化。FA致癌的分子机制目前知之甚少，部分原因是它过去只与罕见的鼻癌有关。最近越来越多的人类癌症与FA暴露有关，这很难用为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。这项应用旨在解决阻碍从机制上理解FA诱导的致癌效应的主要研究空白。提出了三个具体的目标：(1)确定FA在人类细胞中诱变的主要原因；(2)确定易于大重排的基因组位置和基因；(3)研究表观遗传损伤在FA在成人干细胞中形成大的遗传变化中的作用。这些研究的成功完成可以导致识别FA遗传损害的重要生物标志物，并有助于解决目前关于FA致癌作用模式和引发白血病事件的能力的不确定性。

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.