Abstract
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.
Highlights
We identified statistically significant changed hepatic transcriptional profiles, in both CBA and B6, for both the low (2.5 mGy/h), medium (10 mGy/h), and high (100 mGy/h) dose rate exposure groups one day post-radiation, when radiation was given to a similar total dose of 3 Gy
The fact that ionizing radiation is a potent inducer of reactive oxygen species (ROS), we investigated how our significant differential expressed genes (DEGs) overlapped with the Biological Process Gene Ontology (GO) Term “Response to oxidative stress” (GO:0006979) consisting of 408 genes (Mouse Genome Informatics, www.informatics.jax.org, date:11.2.2021)
Our study shows that hepatic transcriptional profiles are modulated dose-rate-specific in response to whole-body exposure to an equal total dose gamma irradiation, given at low, medium, and high dose rates, chronic to acute
Summary
Animals and housingSpecific Pathogen Free CBA/CaOlaHsd and C57BL/6NHsd male mice (called CBA and B6 throughout the article), purchased from Envigo (Horst, The Netherlands), were used (3–8 weeks old at arrival). The mice were acclimatized for a minimum of four days after delivery and randomly housed in groups of five. Mice from each line were mixed in the cages (2–3 per mouse strain). They were housed in individually ventilated disposable PET plastic cages (IVC racks) (Innovive, San Diego, USA) under controlled temperature and light conditions (21 ±2 ̊C, 45±15% relative humidity, 50 air changes h-1 and 12h light phase) with ad libitum access to tap water in PET bottles and SDS RM1 feed (Special Diet Services, Essex, UK). Due to space limitations in the radiation field, the mid dose rate (MDR) groups were housed in disposable PET cages like the other groups but using transport lids outside the IVC rack during the radiation exposure. No mice died or showed clinical signs due to the exposure
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