Adaptive responses to low doses of radiation or chemicals: their cellular and molecular mechanisms

Abstract

This article reviews the current knowledge on the mechanisms of adaptive response to low doses of ionizing radiation or chemical exposure. A better knowledge of these mechanisms is needed to improve our understanding of health risks at low levels of environmental or occupational exposure and their involvement in cancer or non-cancer diseases. This response is orchestrated through a multifaceted cellular program involving the concerted action of diverse stress response pathways. These evolutionary highly conserved defense mechanisms determine the cellular response to chemical and physical aggression. They include DNA damage repair (p53, ATM, PARP pathways), antioxidant response (Nrf2 pathway), immune/inflammatory response (NF-κB pathway), cell survival/death pathway (apoptosis), endoplasmic response to stress (UPR response), and other cytoprotective processes including autophagy, cell cycle regulation, and the unfolded protein response. The coordinated action of these processes induced by low-dose radiation or chemicals produces biological effects that are currently estimated with the linear non-threshold model. These effects are controversial. They are difficult to detect because of their low magnitude, the scarcity of events in humans, and the difficulty of corroborating associations over the long term. Improving our understanding of these biological consequences should help humans and their environment by enabling better risk estimates, the revision of radiation protection standards, and possible therapeutic advances.

Keywords: Adaptive response; Defense mechanism; Epigenetic regulation; Low-dose; Signaling pathway; Stress response.

Fig. 1

Cellular processes of stress response pathways (adapted from [185])

Fig. 2

Crosstalk of signaling pathways between intracellular molecules involved in the adaptive response. The figure highlights the different pathways and main factors involved in autophagy, apoptosis, inflammation, antioxidant, DNA damage, UPR and detoxification response. AhR aryl hydrocarbon receptor, Akt protein kinase B, AP1 activator protein 1, ARE antioxidant response element, ATF activating transcription factor, ATM ataxia-telangiectasia mutated, Atg autophagy-related, Bax Bcl-2–associated X, Bcl2 B-cell lymphoma 2, CHOP C/EBP homologous protein, ER endoplasmic reticulum, GPx glutathione peroxidase, IRE1 inositol requiring enzyme 1, ERSE ER stress-response element, IL interleukin, JNK c-Jun N-terminal kinases, MAPK mitogen-activated protein kinase, mTOR mechanistic target of rapamycin, LC3B light chain 3β, NF-κB nuclear factor-kappa B, NRE NF-κB response element, Nrf2 nuclear factor erythroid 2 (NFE2)-related factor 2, PERK protein kinase RNA-like ER kinase, PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase, ROS reactive oxygen species, SOD superoxide dismutase, TLR toll-like receptors, TNF tumor necrosis factor, TRE 12-O-tetradecanoylphorbol-13-acetate (TPA) response element, UPR unfolded protein response, UPRE unfolded protein response element, XBP-1S X-box binding protein 1, XIAP X-linked inhibitor of apoptosis protein, XRE xenobiotic response element

Fig. 3

Schematic representation of the hierarchical cell stress model in response to chemical or physical stress (adapted from [16, 80]). AhR aryl hydrocarbon receptor, ATM ataxia-telangiectasia mutated, ATF activating transcription factor, Bax Bcl-2–associated X, Bcl2 B-cell lymphoma 2, MAPK mitogen-activated protein kinases, NF-κB nuclear factor-kappa B, Nrf-2 nuclear factor erythroid 2 (NFE2)-related factor 2