Consumer and Clinical Radiation Protection Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada.
Radiation Protection Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada.
Int J Radiat Biol. 2022;98(12):1845-1855. doi: 10.1080/09553002.2022.2110303. Epub 2022 Aug 23.
A vast amount of data regarding the effects of radiation stressors on transcriptional changes has been produced over the past few decades. These data have shown remarkable consistency across platforms and experimental design, enabling increased understanding of early molecular effects of radiation exposure. However, the value of transcriptomic data in the context of risk assessment is not clear and represents a gap that is worthy of further consideration. Recently, benchmark dose (BMD) modeling has shown promise in correlating a transcriptional point of departure (POD) to that derived using phenotypic outcomes relevant to human health risk assessment. Although frequently applied in chemical toxicity evaluation, our group has recently demonstrated application within the field of radiation research. This approach allows the possibility to quantitatively compare radiation-induced gene and pathway alterations across various datasets using BMD values and derive meaningful biological effects. However, before BMD modeling can confidently be used, an understanding of the impact of confounding variables on BMD outputs is needed.
To this end, BMD modeling was applied to a publicly available microarray dataset (Gene Expression Omnibus #GSE23515) that used peripheral blood ex-vivo gamma-irradiated at 0.82 Gy/min, at doses of 0, 0.1, 0.5 or 2 Gy, and assessed 6 hours post-exposure. The dataset comprised six female smokers (F-S), six female nonsmokers (F-NS), six male smokers (M-S), and six male nonsmokers (M-NS).
A combined total of 412 genes were fit to models and the BMD distribution was noted to be bi-modal across the four groups. A total of 74, 41, 62 and 62 genes were unique to the F-NS, M-NS, F-S and M-S groups. Sixty-two BMD modeled genes and nine pathways were common across all four groups. There were no differential sensitivity of BMD responses in the robust common genes and pathways.
For radiation-responsive genes and pathways common across the study groups, the BMD distribution of transcriptional activity was unaltered by sex and smoking status. Although further validation of the data is needed, these initial findings suggest BMD values for radiation relevant genes and pathways are robust and could be explored further in future studies.
在过去几十年中，已经产生了大量关于辐射应激对转录变化影响的数据。这些数据在平台和实验设计上表现出了显著的一致性，使人们对辐射暴露的早期分子效应有了更深入的了解。然而，转录组数据在风险评估中的价值尚不清楚，这是一个值得进一步考虑的差距。最近，基准剂量 (BMD) 建模已经显示出了将转录起始点 (POD) 与与人类健康风险评估相关的表型结果得出的 POD 相关联的潜力。虽然在化学毒性评估中经常应用，但我们的研究小组最近已经在辐射研究领域中进行了应用。这种方法允许使用 BMD 值定量比较不同数据集之间辐射诱导的基因和途径改变，并得出有意义的生物学效应。然而，在可以自信地使用 BMD 建模之前，需要了解混杂变量对 BMD 输出的影响。
为此，我们将 BMD 建模应用于一个公开的微阵列数据集（基因表达综合数据库 #GSE23515），该数据集使用外周血在 0.82Gy/min 的γ射线体外照射，剂量分别为 0、0.1、0.5 或 2Gy，并在暴露后 6 小时进行评估。该数据集包括 6 名女性吸烟者（F-S）、6 名女性不吸烟者（F-NS）、6 名男性吸烟者（M-S）和 6 名男性不吸烟者（M-NS）。
总共拟合了 412 个基因模型，并且发现在四个组中 BMD 分布呈双峰模式。F-NS、M-NS、F-S 和 M-S 组中分别有 74、41、62 和 62 个独特的基因。共有 62 个 BMD 建模基因和 9 条途径存在于所有四个组中。在稳健的共同基因和途径中，BMD 反应的敏感性没有差异。
对于跨研究组共同的辐射反应基因和途径，转录活性的 BMD 分布不受性别和吸烟状况的影响。尽管需要进一步验证数据，但这些初步发现表明，与辐射相关的基因和途径的 BMD 值是稳健的，可以在未来的研究中进一步探索。
