Radiation-Stimulated Epigenetic Reprogramming of Adaptive-Response Genes in the Lung: An Evolutionary Gift for Mounting Adaptive Protection against Lung Cancer

Abstract

ᮀ Humans are continuously exposed to low-level ionizing radiation from natural sources. However, harsher radiation environments persisted during our planet's early years and mammals survived via an evolutionary gift -a system of radiation-induced natural protective measures (adaptive protection). This system includes antioxidants, DNA repair, apoptosis of severely damaged cells, epigenetically regulated apoptosis (epiapoptosis) pathways that selectively remove precancerous and other aberrant cells, and immunity against cancer. We propose a novel model in which the protective system is regulated at least in part via radiation-stress-stimulated epigenetic reprogramming (epireprogramming) of adaptive-response genes. High-dose radiation can promote epigenetically silencing of adaptive-response genes (episilencing), for example via promoter-associated DNA and/or histone methylation and/or histone deacetylation. Evidence is provided for low linear-energy-transfer (LET) radiation-activated natural protection (ANP) against high-LET alpha-radiation-induced lung cancer in plutonium-239 exposed rats and radon-progeny-exposed humans. Using a revised hormetic relative risk model for cancer induction that accounts for both epigenetic activation (epiactivation) and episilencing of genes, we demonstrate that, on average, >80% of alpha-radiation-induced rat lung cancers were prevented by chronic, low-rate gamma-ray ANP. Interestingly, lifetime exposure to residential radon at the Environmental Protection Agency's action level of 4 pCi L -1 appears to be associated with on average a > 60% reduction in lung cancer cases, rather than an increase. We have used underlined italics to indicate newly introduced terminology.

Radiation-hormesis phenotypes, the related mechanisms and implications for disease prevention and therapy

“…Components of the presumed epiregulated system of natural protection can be activated by gamma-ray doses as low as 0.5 mGy above natural background as was demonstrated by Ogura et al (2009) for suppression of spontaneous mutations and the activation likely involves rapid epireprogramming of the genome (Scott et al 2009). This allows for rapidly mounting DNA damage repair, antioxidant production, protective cytokine (e.g., low-level TGF-β1) releases, etc.…”

“…These findings support the view that exposure to low radiation doses (mild stresses) increase protective antioxidants which may contribute to hormetic phenotypes. Stochastic low-dose-radiation thresholds are likely involved as well as intercellular signaling, which may be epigenetically regulated (i.e., epiregulated; Scott et al 2009). …”

“…Because there is on average less than 1 electron track (from ionizations) per cell at the indicated absorbed dose, this is likely a protective bystander effect that relates to epigenetic activation (epiactivation) of adaptiveresponse genes (Scott et al 2009). Thus, the initial basis for use of the LNT risk model has been invalidated.…”

“…Hormetic dose responses for stochastic radiation effects generally have a U or J shape, reflective of low-dose stimulation and high-dose inhibition (Luckey 1980;Ducoff 2002;Baldwin 1999, 2003) and the related stimulatory and inhibitory stochastic thresholds (Scott 2004(Scott , 2005Scott et al 2009). …”

Hormesis, Adaptive Epigenetic Reorganization, and Implications for Human Health and Longevity

“…Large-scale changes in gene expression were repeatedly found in a number of hormetic interventions including irradiation, both heat and cold shocks, repeated mild heat stress, dietary restriction, hypergravity (for review see Vaiserman, 2008), and antioxidant supplementation (Brack et al, 1997). Scott et al (2009) suggested that the hormetic effect may be attributed to induction of the adaptiveresponse genes due to a long-lasting epigenetic memory: once threatening damage of the nuclear DNA occurs, it is quickly recognized with subsequent, rapid up-regulation of the adaptive-response genes.…”