Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.
Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.
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DOI：
10.1016/j.mrrev.2015.11.001
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Andersen ME
中科院分区：
文献类型：
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作者：
Klapacz J;Pottenger LH;Engelward BP;Heinen CD;Johnson GE;Clewell RA;Carmichael PL;Adeleye Y;Andersen ME
从风险评估的角度来看，DNA反应剂通常被认为在所有暴露水平下都有遗传毒性风险，因此对低剂量反应应用了线性外推。这里讨论的新方法，包括评估DNA损伤和DNA修复的更多样化和更灵敏的方法，有力地支持了可测量区域的存在，在这些区域中，随着剂量的增加，遗传毒性反应与对照相比微不足道。模型单功能烷基化试剂在体外和体内的数据集都可以确定遗传毒性效应的出发点(POD)。2013年毒理学学会会议上的一次会议提供了一次机会，以调查在了解DNA烷化剂的经验观察到的豆荚的生物学基础方面的进展情况。结合自那以后发表的文献，这篇综述讨论了内源性和外源性烷基化DNA损伤激活的细胞通路。细胞进化出了保守的过程，可以监测和抵消自发的稳定水平的DNA损伤。无处不在的DNA修复通路网络是清除DNA损伤和防止突变的第一道防线。本文讨论的其他由基因毒性应激激活的生物途径包括细胞周期网络的翻译后激活和细胞凋亡/细胞死亡的转录网络。各种DNA修复和DNA损伤反应通路的相互作用为观察到的遗传毒性化合物的豆荚行为提供了生物学基础。因此，在DNA加合物形成后，细胞通路的激活可以导致避免突变结果。对低剂量区域内作用的细胞机制的了解将有助于更好地描述暴露于与环境相关的浓度的DNA反应剂的风险。
From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.