Perturbed transcriptional profiles after chronic low dose rate radiation in mice

Hildegunn Dahl; Dag M Eide; Torstein Tengs; Nur Duale; Jorke H Kamstra; Deborah H Oughton; Ann-Karin Olsen

doi:10.1371/journal.pone.0256667

Perturbed transcriptional profiles after chronic low dose rate radiation in mice

PLoS One. 2021 Aug 24;16(8):e0256667. doi: 10.1371/journal.pone.0256667. eCollection 2021.

Authors

Hildegunn Dahl^{1

2}, Dag M Eide^{1

2}, Torstein Tengs^{1

2}, Nur Duale^{1

2}, Jorke H Kamstra^{2

3}, Deborah H Oughton², Ann-Karin Olsen^{1

2}

Affiliations

¹ Department of Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
² Centre for Environmental Radiation (CERAD), Norwegian University of Life Sciences (NMBU), Ås, Norway.
³ Faculty of Veterinary Medicine, Department of Population Health Sciences, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA Methylation / radiation effects
Gamma Rays*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Oxidative Stress / radiation effects
Radiation Dosage
Radiation, Ionizing*
Transcription, Genetic / drug effects*

Grants and funding

DO received fundings from the Research Council of Norway through its Centres of Excellence funding scheme, project number 223268/F50 CERAD. AKO received fundings from CERAD. AKO had a role in study design, decision to publish, and preparation of the manuscript. DO had a role in the preparation of the manuscript. https://www.forskningsradet.no/en/. https://www.nmbu.no/en/services/centers/cerad The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.