Formaldehyde Genotoxicity

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。FA也是内源性产生的，作为脂质过氧化、药物生物转化和几种正常代谢过程的产物，例如染色质重塑期间的组蛋白去甲基化。FA致癌性的分子机制知之甚少，部分反映了其过去仅与罕见的鼻癌相关。最近越来越多的人类癌症与FA暴露有关，这很难用啮齿动物鼻癌的细胞毒性风险评估模型来解释。该应用程序旨在解决阻碍FA诱导的致癌作用的机械理解的主要研究空白。提出了三个具体目标：（1）确定人细胞中FA致突变性的主要原因，（2）鉴定易于发生大重排的基因组位点和基因，以及（3）检查表观遗传损伤在人成体干细胞中FA形成大遗传变化中的作用。这些研究的成功完成，可以导致识别的遗传损伤的重要生物标志物的FA和帮助解决目前的不确定性，其致癌作用的模式和能力，启动白血病事件。 公共卫生相关性：甲醛是一种普遍存在的环境毒物，与其暴露相关的人类癌症越来越多。甲醛致癌特性的分子机制知之甚少，这使得很难充分评估人类风险。该提案的重点是确定在暴露于甲醛的人类细胞中引起突变和总染色体损伤的DNA损伤。完成拟议的研究可能会导致识别甲醛造成的遗传损伤的重要形式，并改善人类风险评估。

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. PUBLIC HEALTH RELEVANCE: Formaldehyde is a ubiquitous environmental toxicant with a growing list of human cancers associated with its exposure. The molecular mechanisms underlying carcinogenic properties of formaldehyde are poorly understood, which makes it difficult to adequately assess human risks. This proposal is focused on the determination of DNA lesions that cause mutations and gross chromosomal damage in formaldehyde-exposed human cells. The completion of the proposed studies could lead to the identification of the important forms of genetic damage by formaldehyde and improve human risk assessment.