Q Vuong Ngoc, Khilji Saadia, Williams Andrew, Adam Nadine, Flores Danicia, Fulton Kelly M, Baay Isabel, Twine Susan M, Meier Matthew J, Kumarathasan Premkumari, Wilkins Ruth C, Yauk Carole L, Chauhan Vinita
Radiation Protection Bureau, Health Canada, Ottawa, ON, Canada.
Environmental Health, Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
Int J Radiat Biol. 2025;101(3):240-253. doi: 10.1080/09553002.2024.2442694. Epub 2025 Jan 2.
Recent advancements in omics and benchmark dose (BMD) modeling have facilitated identifying the dose required for a predetermined change in a response (e.g. gene or protein change) that can be used to establish acceptable dose levels for hazardous exposures. Adverse Outcome Pathways (AOPs) describe the causal links between toxicants and adverse effects through key events (KEs). Integrating omics data within the AOP framework quantitatively links early molecular events to later phenotypic effects. In this study, we use omic-based BMD analyses in an in vitro blood model exposed to radiation to identify point of departure (POD) values across KEs to acute myeloid leukemia (www.aopwiki.org/aop/432).
Isolated white blood cells were cultured and X-irradiated (1 Gy/minute, 0-6 Gy). Transcriptomic and proteomic changes were assessed 24 h post-exposure. BMD modeling was applied and significantly perturbed genes/proteins and pathways were identified. Those pathways relevant to KEs outlined in AOP 432 were grouped and a POD was determined.
BMD modeling identified 1294 genes and 167 proteins with median BMD lower confident limit (BMD) values of 1.35 and 0.32 Gy, respectively. Pathway analysis identified biological processes related to DNA damage/repair, oxidative stress, cell cycle regulation, immune responses, and cancer development. These findings aligned with the KEs in AOP 432. The BMDL values of canonical pathways associated with these KEs were generally below 0.5 Gy with specific genes (e.g. GADD45A) displaying BMDLs <0.05 Gy.
This work provides insights into predictive radiation induced mechanisms and associated dose of activity that can be taken into consideration for low dose (< 0.1 Gy) risk analysis.
组学和基准剂量（BMD）建模的最新进展有助于确定响应（例如基因或蛋白质变化）发生预定变化所需的剂量，该剂量可用于确定有害暴露的可接受剂量水平。不良结局途径（AOP）描述了毒物与通过关键事件（KE）产生的不良反应之间的因果联系。将组学数据整合到AOP框架中，可将早期分子事件与后期表型效应进行定量关联。在本研究中，我们在体外血液模型中使用基于组学的BMD分析，该模型暴露于辐射下，以确定跨越关键事件到急性髓系白血病（www.aopwiki.org/aop/432）的起始点（POD）值。
分离的白细胞进行培养并进行X射线照射（1 Gy/分钟，0 - 6 Gy）。在照射后24小时评估转录组和蛋白质组的变化。应用BMD建模并识别出显著受干扰的基因/蛋白质和途径。将与AOP 432中概述的关键事件相关的那些途径进行分组并确定POD。
BMD建模确定了1294个基因和167种蛋白质，其BMD下限置信区间（BMD）的中位数分别为1.35和0.32 Gy。途径分析确定了与DNA损伤/修复、氧化应激、细胞周期调控、免疫反应和癌症发展相关的生物学过程。这些发现与AOP 432中的关键事件一致。与这些关键事件相关的经典途径的BMDL值通常低于0.5 Gy，特定基因（例如GADD45A）的BMDL < 0.05 Gy。
这项工作为预测辐射诱导机制和相关活性剂量提供了见解，可用于低剂量（< 0.1 Gy）风险分析。
