Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

Abstract

Ionizing radiation (IR) is a genuine genotoxic agent and a major modality in cancer treatment. IR disrupts DNA sequences and exerts mutagenic and/or cytotoxic properties that not only alter critical cellular functions but also impact tissues proximal and distal to the irradiated site. Unveiling the molecular events governing the diverse effects of IR at the cellular and organismal levels is relevant for both radiotherapy and radiation protection. Herein, we address changes in the expression of mammalian genes induced after the exposure of a wide range of tissues to various radiation types with distinct biophysical characteristics. First, we constructed a publicly available database, termed RadBioBase, which will be updated at regular intervals. RadBioBase includes comprehensive transcriptomes of mammalian cells across healthy and diseased tissues that respond to a range of radiation types and doses. Pertinent information was derived from a hybrid analysis based on stringent literature mining and transcriptomic studies. An integrative bioinformatics methodology, including functional enrichment analysis and machine learning techniques, was employed to unveil the characteristic biological pathways related to specific radiation types and their association with various diseases. We found that the effects of high linear energy transfer (LET) radiation on cell transcriptomes significantly differ from those caused by low LET and are consistent with immunomodulation, inflammation, oxidative stress responses and cell death. The transcriptome changes also depend on the dose since low doses up to 0.5 Gy are related with cytokine cascades, while higher doses with ROS metabolism. We additionally identified distinct gene signatures for different types of radiation. Overall, our data suggest that different radiation types and doses can trigger distinct trajectories of cell-intrinsic and cell-extrinsic pathways that hold promise to be manipulated toward improving radiotherapy efficiency and reducing systemic radiotoxicities.

The Role of TGF-β3 in Radiation Response

“…Low doses of ionizing radiation may induce specific effects that are not seen after higher doses, one of these being the HRS effect for doses below approximately 0.5 Gy. In a recent meta-analysis of 39 studies investigating gene expression after exposure to ionizing radiation, Sagkrioti et al found that while doses in the 0.6-2.0 Gy range generally induced genes related to ROS metabolism, doses below 0.5 Gy were associated with the expression of genes related to cytokine and inflammatory response pathways [141].…”

Effects of acute low-moderate dose ionizing radiation to human brain organoids

“…Comparing these results to existing literature, the downregulation of DNA damage repair genes by 48 hours provide further evidence that low-moderate dose proton irradiation can inhibit DNA damage repair [ 95 ]. A recent study found identified radiation type- and dose-specific transcriptional responses across healthy and diseased mammalian tissues reported that low doses up to 0.5 Gy are related with cytokine cascades, while higher doses with ROS metabolism [ 96 ]. This study reported significantly enriched GO pathways associated with 0.6–2 Gy doses of IR that were also significantly enriched in our study: negative regulation of mitotic cell cycle (GO:0045930), negative regulation of cell cycle process (GO:0010948), mitotic cell cycle phase transition (GO:0044772), organelle fission (GO:0048385) [ 96 ].…”

“…A recent study found identified radiation type- and dose-specific transcriptional responses across healthy and diseased mammalian tissues reported that low doses up to 0.5 Gy are related with cytokine cascades, while higher doses with ROS metabolism [ 96 ]. This study reported significantly enriched GO pathways associated with 0.6–2 Gy doses of IR that were also significantly enriched in our study: negative regulation of mitotic cell cycle (GO:0045930), negative regulation of cell cycle process (GO:0010948), mitotic cell cycle phase transition (GO:0044772), organelle fission (GO:0048385) [ 96 ]. In addition, their study reported that transcriptional responses such as immunomodulation, inflammation, oxidative stress responses, and cell death were different from those caused by lower doses or less energetic radiation [ 96 ].…”

Role of TLR4 signaling pathway in the mitigation of damaged lung by low‐dose gamma irradiation

“…Additionally, it has mutagenic and/or cytotoxic effects that affect tissues both near and far from the irradiated area. These effects affect vital biological processes 5,6 . In numerous tissues and organs of rodents, N ‐nitrosodiethylamine (NDEA) is a strong carcinogen and promoter of lipid peroxidation (LPO) and/or pro‐oxidant changes 7 .…”

“…These effects affect vital biological processes. 5,6 In numerous tissues and organs of rodents, N-nitrosodiethylamine (NDEA) is a strong carcinogen and promoter of lipid peroxidation (LPO) and/or pro-oxidant changes. 7 The interaction between NDEA and other LPO generators, such as gamma radiation, is of relevance since LPO may be induced in rats administered NDEA, 8 In a short-term radiation carcinogenesis model, the NDEA can raise the danger of gamma ray-induced damage.…”