Chronic Low Dose-rate Exposure Research Articles

Dose rate dependent reduction in chromatin accessibility at transcriptional start sites long time after exposure to gamma radiation

ABSTRACT Ionizing radiation (IR) impact cellular and molecular processes that require chromatin remodelling relevant for cellular integrity. However, the cellular implications of ionizing radiation (IR) delivered per time unit (dose rate) are still debated. This study investigates whether the dose rate is relevant for inflicting changes to the epigenome, represented by chromatin accessibility, or whether it is the total dose that is decisive. CBA/CaOlaHsd mice were whole-body exposed to either chronic low dose rate (2.5 mGy/h for 54 d) or the higher dose rates (10 mGy/h for 14 d and 100 mGy/h for 30 h) of gamma radiation (60Co, total dose: 3 Gy). Chromatin accessibility was analysed in liver tissue samples using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-Seq), both one day after and over three months post-radiation (>100 d). The results show that the dose rate contributes to radiation-induced epigenomic changes in the liver at both sampling timepoints. Interestingly, chronic low dose rate exposure to a high total dose (3 Gy) did not inflict long-term changes to the epigenome. In contrast to the acute high dose rate given to the same total dose, reduced accessibility at transcriptional start sites (TSS) was identified in genes relevant for the DNA damage response and transcriptional activity. Our findings link dose rate to essential biological mechanisms that could be relevant for understanding long-term changes after ionizing radiation exposure. However, future studies are needed to comprehend the biological consequence of these findings.

MRNA Expression of GATA3, FOXP3, TBX21, STAT3, NFKB1, and MAPK8 Transcription Factors in Humans and Their Cooperative Interactions Long-Term after Exposure to Chronic Radiation

The results of mRNA expression of the GATA3, FOXP3, TBX21, STAT3, NFKB1, and MAPK8 transcription factors in peripheral blood cells of 264 residents of the Techa riverside villages of the Chelyabinsk and Kurgan regions, who were affected by chronic low dose-rate exposure in the 1950s, are shown. The range of individual doses to the red bone marrow due to external gamma exposure and 90Sr was 77.8–3507.1 mGy, and the mean dose was 706.3±46.3 mGy. It has been found that changes in the transcriptional response of the cell occur at the molecular level in the long term after chronic exposure. A modified expression of the immunoregulatory genes NFKB1 and MAPK8 in the peripheral blood cells of exposed people was found. A comparative analysis of the interaction of the studied mRNAs demonstrated the presence of a link between the MAPK8 and NFKB1 genes in the group of chronically exposed individuals. The results obtained may indicate the involvement of these transcription factors in the impairment of the immune response in the exposed population.

Perturbed transcriptional profiles after chronic low dose rate radiation in mice.

Adverse health outcomes of ionizing radiation given chronically at low dose rates are highly debated, a controversy also relevant for other stressors. Increased knowledge is needed for a more comprehensive understanding of the damaging potential of ionizing radiation from all dose rates and doses. There is a lack of relevant low dose rate data that is partly ascribed to the rarity of exposure facilities allowing chronic low dose rate exposures. Using the FIGARO facility, we assessed early (one day post-radiation) and late (recovery time of 100-200 days) hepatic genome-wide transcriptional profiles in male mice of two strains (CBA/CaOlaHsd and C57BL/6NHsd) exposed chronically to a low dose rate (2.5 mGy/h; 1200h, LDR), a mid-dose rate (10 mGy/h; 300h, MDR) and acutely to a high dose rate (100 mGy/h; 30h, HDR) of gamma irradiation, given to an equivalent total dose of 3 Gy. Dose-rate and strain-specific transcriptional responses were identified. Differently modulated transcriptional responses across all dose rate exposure groups were evident by the representation of functional biological pathways. Evidence of changed epigenetic regulation (global DNA methylation) was not detected. A period of recovery markedly reduced the number of differentially expressed genes. Using enrichment analysis to identify the functional significance of the modulated genes, perturbed signaling pathways associated with both cancer and non-cancer effects were observed, such as lipid metabolism and inflammation. These pathways were seen after chronic low dose rate and were not restricted to the acute high dose rate exposure. The transcriptional response induced by chronic low dose rate ionizing radiation suggests contribution to conditions such as cardiovascular diseases. We contribute with novel genome wide transcriptional data highlighting dose-rate-specific radiation responses and emphasize the importance of considering both dose rate, duration of exposure, and variability in susceptibility when assessing risks from ionizing radiation.

Predicting the Effects of Low Dose-Rate Ionizing Radiation on Redox Potential in Plant Cells.

During exposure of cells to acute high dose-rate ionizing radiation (IR), oxidants from the radiolysis of water can overwhelm antioxidant systems. Protecting flora from the effects of IR released from a nuclear industry of increasing global significance and managing the growth of plants during space flight both necessitate estimating the effects of chronic low dose-rate exposure to IR. In contrast to effects at acute high-dose rates, under chronic low dose-rate exposure it is subtle, progressive, long-term effects on antioxidant systems that it is important to estimate. Here, we outline a method that combines biochemical measurement and mathematical modeling to predict the effects of chronic low dose-rate IR on redox potential in plant cells over time.

The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation

The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.