Bio-positive effects of ionizing radiation on pollen: The role of ROS.

The concept of 'hormesis' is defined as a dose-response relationship whereby low doses of various toxic substances or physical stressors trigger bio-positive effects in diverse biological systems, whereas high doses cause inhibition of cellular performance (e.g. growth, viability). The two-sided phenomenon of specific low-dose stimulation and high-dose inhibition imposed by a 'hormetic-factor' has been well documented in toxicology and pharmacology. Multitudinous factors have been identified that correspondingly cause hormetic effects in diverse taxa of animals, fungi, and plants. This study particularly aims to elucidate the molecular basis for stimulatory implications of ionizing radiation (IR) on plant male gametophytes (pollen). Beyond that, this analysis impacts general research on cell growth, plant breeding, radiation protection, and, in a wider sense, medical treatment. For this purpose, IR-related data were surveyed and discussed in connection with the present knowledge about pollen physiology. It is concluded that IR-induced reactive oxygen species (ROS) have a key role here. Moreover, it is hypothesized that IR-exposure shifts the ratio between diverse types of ROS in the cell. The interrelation between ROS, intracellular Ca2+-gradient, NADPH oxidases, ROS-scavengers, actin dynamics, and cell wall properties are most probably involved in IR-hormesis of pollen germination and tube growth. Modulation of gene expression, phytohormone signalling, and cellular antioxidant capacity are also implicated in IR-hormesis.

Low-dose ionizing radiation generates a hormetic response to modify lipid metabolism in Chlorella sorokiniana.

Algal biomass is a viable source of chemicals and metabolites for various energy, nutritional, medicinal and agricultural uses. While stresses have commonly been used to induce metabolite accumulation in microalgae in attempts to enhance high-value product yields, this is often very detrimental to growth. Therefore, understanding how to modify metabolism without deleterious consequences is highly beneficial. We demonstrate that low-doses (1-5 Gy) of ionizing radiation in the X-ray range induces a non-toxic, hormetic response in microalgae to promote metabolic activation. We identify specific radiation exposure parameters that give reproducible metabolic responses in Chlorella sorokiniana caused by transcriptional changes. This includes up-regulation of >30 lipid metabolism genes, such as genes encoding an acetyl-CoA carboxylase subunit, phosphatidic acid phosphatase, lysophosphatidic acid acyltransferase, and diacylglycerol acyltransferase. The outcome is an increased lipid yield in stationary phase cultures by 25% in just 24 hours, without any negative effects on cell viability or biomass.

Hormesis effects of gamma radiation on growth of quinoa (Chenopodium quinoa).

PURPOSE: Quinoa is an annual plant that grows well in high altitude regions with high radiation and ultraviolet intensity. It has known that high-dose radiation damages living organisms, but low-dose radiation also has a beneficial effect. Therefore, the purpose of this study is to investigate the hormesis effect of gamma-ray on quinoa by growth analysis and hyperspectral imaging. MATERIALS AND METHODS: Quinoa seeds were irradiated at 50, 100, and 200 Gy emitted by 60CO. Subsequently, the seeds were germinated and transplanted into pots, then conducted growth analysis and physiological evaluation every week, and hyperspectral imaging. Photosynthetic ability was measured at 35 days after transplanting (DAT), and the plants for each dose were divided into aerial and underground parts for biomass evaluation at 91 DAT. Various vegetation indices were estimated from 14 to 35 DAT by hyperspectral analysis, and the specific bands were extracted based on the PLS model using plant height, SPAD value, and chlorophyll fluorescence parameters. RESULTS: We found that plant height and biomass were increased in quinoa plants treated with a low dose (50 Gy) as compared to control. Chlorophyll content and chlorophyll fluorescence were not different between doses at the early growth stage, but as growth progressed, the plant irradiated at 200 Gy began to be lower. The photosynthetic ability of the quinoa plant treated at 50 Gy was greater than other plants at 35 DAT. The vegetation indices related to the pigment status also were higher in the plants treated by irradiation at 50 Gy than the plants grown in other doses treatment units at the beginning of the growth. Using the PLS model we collected sensitive band wavelengths from hyperspectral image analysis. Among the collected bands, eight bands closely related to plant height, nine bands to chlorophyll content, and ten bands to chlorophyll fluorescence were identified. CONCLUSION: Our results showed that the growth and physiological parameters of quinoa treated by low dose gamma irradiation to seeds were greater than that of control as well as the plant with higher doses. These findings confirm that the positive changes in the characteristics of quinoa with low dose radiation indicated that hormesis occurs at 50 Gy radiation.

Enzymatic Responses to Low-Intensity Radiation of Tritium.

The present study considers a possible role of enzymatic reactions in the adaptive response of cells to the beta-emitting radionuclide tritium under conditions of low-dose exposures. Effects of tritiated water (HTO) on the reactions of bacterial luciferase and NAD(P)H:FMN-oxidoreductase, as well as a coupled system of these two reactions, were studied at radioactivity concentrations ≤ 200 MBq/L. Additionally, one of the simplest enzymatic reactions, photobiochemical proton transfer in Coelenteramide-containing Fluorescent Protein (CLM-FP), was also investigated. We found that HTO increased the activity of NAD(P)H:FMN-oxidoreductase at the initial stage of its reaction (by up to 230%); however, a rise of luciferase activity was moderate (<20%). The CLM-FP samples did not show any increase in the rate of the photobiochemical proton transfer under the exposure to HTO. The responses of the enzyme systems were compared to the 'hormetic' response of luminous marine bacterial cells studied earlier. We conclude that (1) the oxidoreductase reaction contributes significantly to the activation of the coupled enzyme system and bacterial cells by tritium, and (2) an increase in the organization level of biological systems promotes the hormesis phenomenon.

El ocaso del modelo lineal sin umbral / The downfall of the linear non-threshold model

El modelo lineal sin umbral (MLSU) es una función dosis-respuesta teórica obtenida de extrapolar los efectos tardíos debidos a la exposición a altas dosis de radiación ionizante al rango de las bajas dosis, pero existen grandes incertidumbres respecto a su validez. La aceptación del MLSU como modelo probabilístico preponderante ha sobrevivido hasta nuestros días y constituye la piedra angular que sostiene las políticas actuales de protección radiológica. En las últimas décadas, los avances en biología molecular y evolutiva, en la inmunología del cáncer, así como los resultados obtenidos de los estudios epidemiológicos y en modelos animales, han puesto en entredicho la fiabilidad del MLSU en favor de otras alternativas, como la teoría hormética. A la vista de las evidencias, se hace necesario un debate entre las sociedades científicas implicadas y los organismos reguladores que aborde una redefinición de las bases de la protección radiológica, cuya importancia sería capital en el ámbito médico

The linear non-threshold model (LNTM) is a theoretical dose-response function as a result of extrapolating the late effects of high-dose exposure to ionizing radiation to the low-dose range, but there is great uncertainty about its validity. The acceptance of LNTM as the dominant probabilistic model have survived to the present day and it is actually the cornerstone of current radiation protection policies. In the last decades, advances in molecular and evolutive biology, cancer immunology, and many epidemiological and animal studies have cast serious doubts about the reliability of the NLTM, as well as suggesting alternative models, like the hormetic theory. Considering the given evidences, a discussion between the involved scientific societies and the regulatory commissions is promtly required in order to to reach a redefiniton of theradiation protection basis, as it would be specially crucial in the medical field

Linear No-threshold (LNT) vs. Hormesis: Paradigms, Assumptions, and Mathematical Conventions that Bias the Conclusions in Favor of LNT and Against hormesis.

The linear no-threshold assumption misunderstands the complex multiphasic biological response to ionizing radiation, focusing solely on the initial physical radiogenic damage. This misunderstanding is enabled (masked and amplified) by a number of mathematical approaches that bias results in favor of linear no-threshold and away from alternatives, like hormesis, that take biological response into account. Here we explore a number of these mathematical approaches in some detail, including the use of frequentist rather than Bayesian statistical rules and methods. We argue that a Bayesian approach cuts through an epidemiological stalemate, in part because it enables a better understanding of the concept of plausibility, which in turn properly rests on empirical evidence of actual physical and biological mechanisms. Misuse of the concept of plausibility has sometimes been used to justify the mathematically simple and convenient linearity-without-a-threshold assumption, in particular with the everywhere-positive slope that is central to linear no-threshold and its variants. Linear no-threshold's dominance in the area of dose regulation further rests on a misapplication of the precautionary principle, which only holds when a putative caution has positive effects that outweigh the negative unintended consequences. In this case the negative consequences far outweigh the presumed hazards.

The linear no-threshold model is less realistic than threshold or hormesis-based models: An evolutionary perspective.

The linear no-threshold (LNT) risk model is the current human health risk assessment paradigm. This model states that adverse stochastic biological responses to high levels of a stressor can be used to estimate the response to low or moderate levels of that stressor. In recent years the validity of the LNT risk model has increasingly been questioned because of the recurring observation that an organism's response to high stressor doses differs from that to low doses. This raises important questions about the biological and evolutionary validity of the LNT model. In this review we reiterate that the LNT model as applied to stochastic biological effects of low and moderate stressor levels has less biological validity than threshold or, particularly, hormetic models. In so doing, we rely heavily on literature from disciplines like ecophysiology or evolutionary ecology showing how exposure to moderate amounts of stress can have severe impacts on phenotype and organism reproductive fitness. We present a mathematical model that illustrates and explores the hypothetical conditions that make a particular kind of hormesis (conditioning hormesis) ecologically and evolutionarily plausible.

Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway.

Low-dose ionizing radiation (LDIR) induces hormesis, exerts an adoptive effect on normal mammalian cells and stimulates cell proliferation; however, this effect is absent in cancer cells. Little is known on the molecular mechanisms underlying this differential response between normal and cancer cells. In the present study, it was demonstrated that the human prostate cancer cell line PC-3 and the normal prostate cell line RWPE-1 exhibited differential biological responses to LDIR. Through cell cycle analyses, it was demonstrated that LDIR inhibited cell growth and arrested the cell cycle at the S and G2/M phases in PC-3 cells, but not in RWPE-1 cells. Using western blotting, it was demonstrated that LDIR at 75 mGy induced the expression of ataxia-telangiectasia mutated (ATM) protein in PC-3 as well as RWPE-1 cells. However, the ATM̸p21 pathway was activated in PC-3, but not in RWPE-1 cells. Although the expression of p53 was not affected by 75 mGy LDIR in RWPE-1 cells, the ATM̸p21 pathway was activated when RWPE-1 cells lost p53 function. In addition, when using ATM inhibitors, the ATM̸p21 pathway was inactivated in both cell lines, and the LDIR-induced cell proliferation inhibition was also abolished. These findings suggested that the ATM/p21 pathway directly participated in the LDIR-induced cell proliferation inhibition in p53null type prostate tumor cells, whereas this mechanism was absent in normal prostate cells. Thus, p53 may affect cell stability following LDIR, and plays a crucial role in regulating the ATM/p21 pathway activated by LDIR.

Radiation Hormesis: The Link to Nanomolar Hydrogen Peroxide.

Hydrogen peroxide (H2O2) is a stable product of water radiolysis, occurring at nanomolar concentration upon low-dose ionizing radiation (LDIR) (<100 mGy). In view of the recent recognition of H2O2 as a central redox signaling molecule that, likewise, is maintained in the nanomolar range in cells, we propose a role for H2O2 in radiation hormesis. LDIR is capable of utilizing known molecular redox master switches such as Nrf2/Keap1 or NF-κB/IκB to effect adaptive resistance. This leads to the hypothesis that, as a normal component of the exposome, LDIR mediates hormetic effects by H2O2 signaling. Antioxid. Redox Signal. 27, 596-598.

Lessons to be learned from a contentious challenge to mainstream radiobiological science (the linear no-threshold theory of genetic mutations).

There are both statistically valid and invalid reasons why scientists with differing default hypotheses can disagree in high-profile situations. Examples can be found in recent correspondence in this journal, which may offer lessons for resolving challenges to mainstream science, particularly when adherents of a minority view attempt to elevate the status of outlier studies and/or claim that self-interest explains the acceptance of the dominant theory. Edward J. Calabrese and I have been debating the historical origins of the linear no-threshold theory (LNT) of carcinogenesis and its use in the regulation of ionizing radiation. Professor Calabrese, a supporter of hormesis, has charged a committee of scientists with misconduct in their preparation of a 1956 report on the genetic effects of atomic radiation. Specifically he argues that the report mischaracterized the LNT research record and suppressed calculations of some committee members. After reviewing the available scientific literature, I found that the contemporaneous evidence overwhelmingly favored a (genetics) LNT and that no calculations were suppressed. Calabrese's claims about the scientific record do not hold up primarily because of lack of attention to statistical analysis. Ironically, outlier studies were more likely to favor supra-linearity, not sub-linearity. Finally, the claim of investigator bias, which underlies Calabrese's accusations about key studies, is based on misreading of text. Attention to ethics charges, early on, may help seed a counter narrative explaining the community's adoption of a default hypothesis and may help focus attention on valid evidence and any real weaknesses in the dominant paradigm.

Hormetic Response to Low-Dose Radiation: Focus on the Immune System and Its Clinical Implications.

The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and dependent on radiation dose/quality and immune cell type. High-dose radiation usually results in immune suppression. On the contrary, low-dose radiation (LDR) modulates a variety of immune responses that have exhibited the properties of immune hormesis. Although the underlying molecular mechanism is not fully understood yet, LDR has been used clinically for the treatment of autoimmune diseases and malignant tumors. These advancements in preclinical and clinical studies suggest that LDR-mediated immune modulation is a well-orchestrated phenomenon with clinical potential. We summarize recent developments in the understanding of LDR-mediated immune modulation, with an emphasis on its potential clinical applications.

The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 1. The Russell-Muller debate.

This paper assesses the discovery of the dose-rate effect in radiation genetics and how it challenged fundamental tenets of the linear non-threshold (LNT) dose response model, including the assumptions that all mutational damage is cumulative and irreversible and that the dose-response is linear at low doses. Newly uncovered historical information also describes how a key 1964 report by the International Commission for Radiological Protection (ICRP) addressed the effects of dose rate in the assessment of genetic risk. This unique story involves assessments by two leading radiation geneticists, Hermann J. Muller and William L. Russell, who independently argued that the report's Genetic Summary Section on dose rate was incorrect while simultaneously offering vastly different views as to what the report's summary should have contained. This paper reveals occurrences of scientific disagreements, how conflicts were resolved, which view(s) prevailed and why. During this process the Nobel Laureate, Muller, provided incorrect information to the ICRP in what appears to have been an attempt to manipulate the decision-making process and to prevent the dose-rate concept from being adopted into risk assessment practices.

The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 2. How a mistake led BEIR I to adopt LNT.

This paper reveals that nearly 25 years after the National Academy of Sciences (NAS), Biological Effects of Ionizing Radiation (BEIR) I Committee (1972) used Russell's dose-rate data to support the adoption of the linear-no-threshold (LNT) dose response model for genetic and cancer risk assessment, Russell acknowledged a significant under-reporting of the mutation rate of the historical control group. This error, which was unknown to BEIR I, had profound implications, leading it to incorrectly adopt the LNT model, which was a decision that profoundly changed the course of risk assessment for radiation and chemicals to the present.

Mobile phone signal exposure triggers a hormesis-like effect in Atm+/+ and Atm-/- mouse embryonic fibroblasts.

Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm+/+) or deficient (Atm-/-) ATM. In Atm+/+ MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm-/- MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF.

Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics.

It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.

Molecular mechanisms of low dose ionizing radiation-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability.

PURPOSES: To review research progress on the molecular mechanisms of low dose ionizing radiation (LDIR)-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability in order to provide clues for therapeutic approaches to enhance biopositive effects (defined as radiation-induced beneficial effects to the organism), and control bionegative effects (defined as radiation-induced harmful effects to the organism) and related human diseases. CONCLUSIONS: Experimental studies have indicated that Ataxia telangiectasia-mutated (ATM), extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK), phospho-c-Jun NH(2)-terminal kinase (JNK) and protein 53 (P53)-related signal transduction pathways may be involved in LDIR-induced hormesis; MAPK, P53 may be important for adaptive response; ATM, cyclooxygenase-2 (COX-2), ERK, JNK, reactive oxygen species (ROS), P53 for radioresistance; COX-2, ERK, MAPK, ROS, tumor necrosis factor receptor alpha (TNFα) for LDIR-induced bystander effect; whereas ATM, ERK, MAPK, P53, ROS, TNFα-related signal transduction pathways are involved in LDIR-induced genomic instability. These results suggest that different manifestations of LDIR-induced cellular responses may have different signal transduction pathways. On the other hand, LDIR-induced different responses may also share the same signal transduction pathways. For instance, P53 has been involved in LDIR-induced hormesis, adaptive response, radioresistance and genomic instability. Current data therefore suggest that caution should be taken when designing therapeutic approaches using LDIR to induce beneficial effects in humans.

Low-dose radiation induces antitumor effects and erythrocyte system hormesis.

OBJECTIVE: Low dose radiation may stimulate the growth and development of animals, increase life span, enhance fertility, and downgrade the incidence of tumor occurrence.The aim of this study was to investigate the antitumor effect and hormesis in an erythrocyte system induced by low-dose radiation. METHODS: Kunming strain male mice were subcutaneously implanted with S180 sarcoma cells in the right inguen as an experimental in situ animal model. Six hours before implantation, the mice were given 75mGy whole body X-ray radiation. Tumor growth was observed 5 days later, and the tumor volume was calculated every other day. Fifteen days later, all mice were killed to measure the tumor weight, and to observe necrotic areas and tumor-infiltration-lymphoreticular cells (TILs). At the same time, erythrocyte immune function and the level of 2,3-diphosphoglyceric acid (2,3- DPG) were determined. Immunohistochemical staining was used to detect the expression of EPO and VEGFR of tumor tissues. RESULTS: The mice pre-exposed to low dose radiation had a lower tumor formation rate than those without low dose radiation (P < 0.05). The tumor growth slowed down significantly in mice pre-exposed to low dose radiation; the average tumor weight in mice pre-exposed to low dose radiation was lighter too (P < 0.05). The tumor necrosis areas were larger and TILs were more in the radiation group than those of the group without radiation. The erythrocyte immune function, the level of 2,3-DPG in the low dose radiation group were higher than those of the group without radiation (P < 0.05). After irradiation the expression of EPO of tumor tissues in LDR group decreased with time. LDR-24h, LDR-48h and LDR-72h groups were all statistically significantly different from sham-irradiation group. The expression of VEGFR also decreased, and LDR-24h group was the lowest (P < 0.05). CONCLUSION: Low dose radiation could markedly increase the anti-tumor ability of the organism and improve the erythrocyte immune function and the ability of carrying O2. Low-dose total body irradiation, within a certain period of time, can decrease the expression of hypoxia factor EPO and VEGFR, which may improve the situation of tumor hypoxia and radiosensitivity of tumor itself.

Issues in low dose radiation biology: the controversy continues. A perspective.

Both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. Much of this is unavoidable, e.g., natural background radiation, but as the use of radiation increases, so does the potential health risk and the public's concerns. This perspective reflects the authors' view of current issues in low dose radiation biology research, highlights some of the controversies therein, and suggests areas of future research to address both issues in low dose radiation research and the controversies. This is a critical time for the radiation sciences and the implications of future research will have a significant impact on radiation protection, medicine, national security, research and industry. The views expressed here are the authors' own and do not represent any institution, organization or funding body.

GSM 900 MHz microwave radiation affects embryo development of Japanese quails.

A wide range of non thermal biological effects of microwave radiation (MW) was revealed during the last decades. A number of reports showed evident hazardous effects of MW on embryo development in chicken. In this study, we aimed at elucidating the effects of MW emitted by a commercial model of GSM 900 MHz cell phone on embryo development in quails (Coturnix coturnix japonica) during both short and prolonged exposure. For that, fresh fertilized eggs were irradiated during the first 38 h or 14 days of incubation by a cell phone in "connecting" mode activated continuously through a computer system. Maximum intensity of incident radiation on the egg's surface was 0.2 µW/cm2.The irradiation led to a significant (p<0.001) increase in numbers of differentiated somites in 38-hour exposed embryos and to a significant (p<0.05) increase in total survival of embryos from exposed eggs after 14 days exposure. We hypothesized that observed facilitating effect was due to enhancement of metabolism in exposed embryos provoked via peroxidation mechanisms. Indeed, a level of thiobarbituric acid (TBA) reactive substances was significantly (p<0.05-0.001) higher in brains and livers of hatchlings from exposed embryos. Thus, observed effects of radiation from commercial GSM 900 MHz cell phone on developing quail embryos signify a possibility for non-thermal impact of MW on embryogenesis. We suggest that the facilitating effect of low doses of irradiation on embryo development can be explained by a hormesis effect induced by reactive oxygen species (ROS). Future studies need to be done to clarify this assumption.