mild stress; fecundity; reproduction; longevity; aging; health
Geocap Study; childhood leukemia; radiation; nuclear power plant; cancer; low dose
Humans and their predecessors evolved in environments where they were challenged intermittently with: 1) food scarcity; 2) the need for aerobic fitness to catch/kill prey and avoid or repel attackers; and 3) exposure to biological toxins present in foodstuffs. Accordingly, cells and organ systems acquired and retained molecular signaling and metabolic pathways through which the environmental challenges enhanced the functionality and resilience of the cells and organisms. Within the past 60 years there has been a precipitous diminution of such challenges in modern societies because of the development of technologies that provide a continuous supply of energy-dense processed foods and that largely eliminate the need for physical exertion. As a consequence of the modern ‘couch potato’ lifestyle, signaling pathways that mediate beneficial effects of environmental challenges on health and disease resistance are disengaged, thereby rendering people vulnerable to obesity, diabetes, cardiovascular disease, cancers and neurodegenerative disorders. Reversal of the epidemic of diseases caused by unchallenging lifestyles will require a society-wide effort to re-introduce intermittent fasting, exercise and consumption of plants containing hormetic phytochemicals into daily and weekly routines.
brain function; exercise; hormesis; intermittent fasting
Thousands of articles have been published on the topic of ischemic conditioning. Nevertheless, relatively little attention has been given to assessment of conditioning’s dose-response characteristics. Specifically, the consequences of multiple conditioning episodes, what we will term “hyperconditioning”, have seldom been examined. We propose that hyperconditioning warrants investigation because it; (1) may be of clinical importance, (2) could provide insight into conditioning mechanisms, and (3) might result in development of novel models of human disease. The prevalence of angina pectoris and intermittent claudication is sufficiently high and the potential for daily ischemia-reperfusion episodes sufficiently large that hyperconditioning is a clinically relevant phenomenon. In basic science, attenuation of conditioning-mediated infarct size reduction found in some studies after hyperconditioning offers a possible means to facilitate further discernment of cardioprotective signaling pathways. Moreover, hyperconditioning’s impact extends beyond cytoprotection to tissue structural elements. Several studies demonstrate that hyperconditioning produces collagen injury (primarily fiber breakage). Such structural impairment could have adverse clinical consequences; however, in laboratory studies, selective collagen damage could provide the basis for models of cardiac rupture and dilated cardiomyopathy. Accordingly, we propose that hyperconditioning represents the dark, but potentially illuminating, side of ischemic conditioning - a paradigm that merits attention and prospective evaluation.
angina pectoris; collagen; hyperconditioning; infarct size; intermittent claudication; ischemic conditioning
Pre-conditioning by ischemia, hyperthermia, hypothermia, hyperbaric oxygen (and numerous other modalities) is a rapidly growing area of investigation that is used in pathological conditions where tissue damage may be expected. The damage caused by surgery, heart attack, or stroke can be mitigated by pre-treating the local or distant tissue with low levels of a stress-inducing stimulus, that can induce a protective response against subsequent major damage. Low-level laser (light) therapy (LLLT) has been used for nearly 50 years to enhance tissue healing and to relieve pain, inflammation and swelling. The photons are absorbed in cytochrome(c) oxidase (unit four in the mitochondrial respiratory chain), and this enzyme activation increases electron transport, respiration, oxygen consumption and ATP production. A complex signaling cascade is initiated leading to activation of transcription factors and up- and down-regulation of numerous genes. Recently it has become apparent that LLLT can also be effective if delivered to normal cells or tissue before the actual insult or trauma, in a pre-conditioning mode. Muscles are protected, nerves feel less pain, and LLLT can protect against a subsequent heart attack. These examples point the way to wider use of LLLT as a pre-conditioning modality to prevent pain and increase healing after surgical/medical procedures and possibly to increase athletic performance.
Pre-conditioning; Remote Ischemic Pre-conditioning; LLLT; Photobiomodulation; Mitochondria; Reactive Oxygen Species
Present communication reports the effects of environmentally available, low doses of tetra chloro di benzo-p-dioxin (2,3,7,8 TCDD) to lysosomal enzymes in mice liver. The study tests the hypothesis, in vivo exposure of low dose TCDD provokes dose and duration dependent toxic effects to key lysosomal enzymes and thereby causes cellular apoptotic changes. Three groups of female Swiss albino mice were subjected to two doses of TCDD (0.004 mg/kg bw/d, 0.04 mg/kg bw/d) for 2, 4 and 6 days of exposure durations. The results indicated significant exposure duration dependent effects of TCDD in mice liver cells. The results suggested that TCDD possibly induced an increase in intracellular ions or ROS which in turn altered different physiological activities by affecting different metabolic pathway of the liver cells. The altered functions of key lysosomal enzymes by TCDD may also evoke the process of cellular apoptosis.
Dioxin; TCDD; lysosomal enzymes; dose and duration; liver; mice
There is growing evidence that the radiation effects at low doses are not adequately described by a simple linear extrapolation from high doses, due, among others, to bystander effects. Though several studies have been published on this topic, the explanation of the mechanisms describing the bystander effects remains unclear. This study aims at understanding how the bystander signals are or can be propagated in the cell culture, namely if the number of irradiated cells influences the bystander response. An A549 cell line was exposed to several doses of α-particles, being the bystander response quantified in two non-irradiated areas. The radius of irradiated areas differs by a factor of 2, and the non-irradiated areas were optimally designed to have the same number of cells. Our results show evidence for bystander effects occurring in cells far away from the irradiated ones, meaning that bystander signals can easily spread throughout the cell culture. Additionally, our study highlights that the damage caused by radiation on the surrounding of irradiated areas could be different according to the number of irradiated cells, i.e., for the same dose value; the overall cellular damage could be different.
Low dose; spatial distribution; bystander effects; A549 cells; alpha-radiation
Dandelion (Taraxacum officinale Wigg.) seed reproduction indices such as the total number of seeds, the number of normally developed seeds and underdeveloped seeds per anthodium, and seed weight are suggested to assess the level of environmental pollution (bioindication). However, the non-monotonic dose-response dependences (hormesis and paradoxical effects) of these indices are insufficiently explored upon exposure to pollution. We studied the dependence of some T. officinale seed reproduction indices on intensity of motor traffic pollution in wide range of values over 2 years of observation. In 2010, the increase in traffic intensity induced a monotonic increase in the total seed number and the number of normally developed seeds. Besides, motor traffic pollution decreased the number of undeveloped seeds and seed weight in comparison with the control. In 2011, for all studied T. officinale indices except seed weight, complicated non-monotonic dependences on traffic intensity were found that could be attributed to paradoxical effects. It is hypothesised that the significant differences in the studied dependencies in 2010–2011 were caused by changes in weather conditions because traffic intensity did not differ significantly between the two observation years.
Taraxacum officinale Wigg; dose–response dependences; seed reproduction indices; motor traffic pollution; plant paradoxical effects
Endogenous mechanisms of protection against ischemia can be demonstrated in brain and other organs. The induction of such protection is via a response to sub lethal stress which induces “preconditioning”. The preconditioned organ is then “tolerant” to injury from subsequent severe stress of the same or different etiology. Protection is substantial (70% reduction) but delayed in onset and is transient. Gene expression is unique between brains preconditioned, injured (stroke) or made tolerant. Thus, preconditioning reprograms the response to lethal ischemic stress (stroke), reprogrammed from an injury induction response to a neuroprotective processes. Postconditioning refers to attenuation of injurious processes occurring during reperfusion of ischemic brain. Transient mechanical interruption of reperfusion induces post-conditioning which can attenuate reperfusion injury. Post-conditioning protects ischemic brain by decreasing reperfusion induced oxygen free radical formation. The free radicals produce injury via mitochondrial damage which can be repaired experimentally. Post-conditioning produces neuroprotection as potent as experimental preconditioning. The recognition of broad based gene silencing (suppression of thousands of genes) as the phenotype of the preconditioned, ischemic tolerant brain, may explain failure of all single target drugs for stroke. As risks of reperfusion injury accompany treatment for acute stroke, endogenous neuroprotective and repair mechanisms offer translational stroke therapy.
Preconditioning; post-conditioning; ischemia; stroke
Mothersill and many others during the last hundred years have shown that cells and now whole animals may communicate with each other by electromagnetic waves called biophotons. This would explain the source of the bystander phenomena. These ultra-weak photons are coherent, appear to originate and concentrate in DNA of the cell nucleus and rapidly carry large amounts of data to each cell and to the trillions of other cells in the human body. The implications of such a possibility can be wonderfully important.
biphotons; bystander; light; cell
We investigate the biological effects of radiation using adult Drosophila melanogaster as a model organism, focusing on gene expression and lifespan analysis to determine the effect of different radiation doses. Our results support a threshold effect in response to radiation: no effect on lifespan and no permanent effect on gene expression is seen at incident radiation levels below 100 J/kg. We also find that it is more appropriate to compare radiation effects in flies using the absorbed energy rather than incident radiation levels.
low dose radiation; gene expression; Drosophila melanogaster; threshold effect
We reviewed the beneficial or harmful effects of low-dose ionizing radiation on several diseases based on a search of the literature. The attenuation of autoimmune manifestations in animal disease models irradiated with low-dose γ-rays was previously reported by several research groups, whereas the exacerbation of allergic manifestations was described by others. Based on a detailed examination of the literature, we divided animal disease models into two groups: one group consisting of collagen-induced arthritis (CIA), experimental encephalomyelitis (EAE), and systemic lupus erythematosus, the pathologies of which were attenuated by low-dose irradiation, and another group consisting of atopic dermatitis, asthma, and Hashimoto’s thyroiditis, the pathologies of which were exacerbated by low-dose irradiation. The same biological indicators, such as cytokine levels and T-cell subpopulations, were examined in these studies. Low-dose irradiation reduced inter-feron (IFN)-gamma (γ) and interleukin (IL)-6 levels and increased IL-5 levels and the percentage of CD4+CD25+Foxp3+Treg cells in almost all immunological disease cases examined. Variations in these biological indicators were attributed to the attenuation or exacerbation of the disease’s manifestation. We concluded that autoimmune diseases caused by autoantibodies were attenuated by low-dose irradiation, whereas diseases caused by antibodies against external antigens, such as atopic dermatitis, were exacerbated.
low-dose irradiation; immune response; autoimmune disease; allergic diseases; cytokines; T-cell subpopulation
Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/− mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01–2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/−) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/− between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/−. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.
Trp53; cell cycle arrest; apoptosis; DNA damage; ionizing radiation
There is widespread concern among the general public regarding the ever increasing use of mobile phones. The concern is mainly because the antenna which transmits nonionizing radiofrequency fields is held close to the head during use and thus might cause brain cancer. By far, the largest epidemiological study was conducted by the INTER-PHONE study group and the results were published in 2011. The author’s conclusions were (i) no increased risk of meningioma and glioma in mobile phone users and (ii) there were suggestions of an increased risk for glioma at the highest exposure levels but, bias and error prevented a causal interpretation. We have carefully examined all of the odd ratios presented in the INTERPHONE study publication: our results showed 24.3% decreased and 0.7% increased risk for meningioma and 22.1% decreased and 6.6% increased risk for glioma. Hence, we hypothesize that the overwhelming evidence for the decreased risk for both diseases may be due to the induction of ‘adaptive response’ which is well-documented in scientific literature
Mobile Phones; Radiofrequency fields; Brain Cancer; Adaptive Response
The relationship between the dose of an effector and the biological response frequently is not described by a linear function and, moreover, in some cases the dose-response relationship may change from positive/adverse to adverse/positive with increasing dose. This complicated relationship is called “hormesis”. This paper provides a short analysis of the concept along with a description of used approaches to characterize hormetic relationships. The whole hormetic curve can be divided into three zones: I – a lag-zone where no changes are observed with increasing dose; II – a zone where beneficial/adverse effects are observed, and III – a zone where the effects are opposite to those seen in zone II. Some approaches are proposed to analyze the molecular components involved in the development of the hormetic character of dose-response relationships with the use of specific genetic lines or inhibitors of regulatory pathways. The discussion is then extended to suggest a new parameter (half-width of the hormetic curve at zone II) for quantitative characterization of the hormetic curve. The problems limiting progress in the development of the hormesis concept such as low reproducibility and predictability may be solved, at least partly, by deciphering the molecular mechanisms underlying the hormetic dose-effect relationship.
hormesis; reactive oxygen species; mechanisms; components
While contradictory reports are available on the yield of dicentric chromosomes (DC) in blood samples stored at different temperature and stimulated to enter into cell cycle, various times gap followed by exposure, limited information is available on the micronucleus (MN) assay. As scoring the micronuclei frequency from the blood lymphocytes of exposed individuals is an alternative to the gold standard DC assay for triage applications, we examined radiation induced MN yield in delayed mitogenic stimulation after irradiation of in vitro. Peripheral blood lymphocytes (PBL) were exposed to low LET (60Co) radiation dose (0.1 to 5Gy) and incubated at 37°C for 2, 6 and 24 hours. The MN frequency obtained in blood samples stimulated 2 hours post-irradiation showed a dose dependent increase and used to construct the dose-response curve. Further, the results also showed that blood samples stimulated twenty four hours of post-irradiation, a significant reduction (p<0.05) in MN frequencies were obtained when compared to that of blood samples stimulated two hours and six hours after post-irradiation (0.5, 1, 3 and 5Gy). The observed result suggests that the prolonged PBL storage without mitogenic stimulation could lead to interphase cell death and a delayed blood sampling could results in underestimation of dose in biological dosimetry.
Micronuclei; Mitogenic stimulation; Peripheral blood lymphocytes; NDI; 60Co
Imidacloprid-induced hormesis in the form of stimulated reproduction has previously been reported in green peach aphid, Myzus persicae. Changes in gene expression accompanying this hormetic response have not been previously investigated. In this study, expression of stress response (Hsp60), dispersal (OSD, TOL and ANT), and developmental (FPPS I) genes were examined for two generations during imidacloprid-induced reproductive stimulation in M. persicae. Global DNA methylation was also measured to test the hypothesis that changes in gene expression are heritable. At hormetic concentrations, down-regulation of Hsp60 was followed by up-regulation of this gene in the subsequent generation. Likewise, expression of dispersal-related genes and FPPS I varied with concentration, life stage, and generation. These results indicate that reproductive hormesis in M. persicae is accompanied by a complex transgenerational pattern of up- and down-regulation of genes that likely reflects trade-offs in gene expression and related physiological processes during the phenotypic dose-response. Moreover, DNA methylation in second generation M. persicae occurred at higher doses than in first-generation aphids, suggesting that heritable adaptability to low doses of the stressor might have occurred.
Hormesis; Myzus persicae; fecundity; gene expression; global DNA methylation
Seeking a remedy for the radiation fear in Japan, the author re-examined an article on radiation hormesis. It describes the background for this fear and evidence in the first UNSCEAR report of a reduction in leukemia of the Hiroshima survivors in the low dose zone. The data are plotted and dose-response models are drawn. While UNSCEAR suggested the extra leukemia incidence is proportional to radiation dose, the data are consistent with a hormetic J-shape and a threshold at about 100 rem (1 Sv). UNSCEAR data on lifespan reduction of mammals exposed continuously to gamma rays indicate a 2 gray/year threshold. This contradicts the conceptual basis for radiation protection and risk determination established in 1956–58. In this paper, beneficial effects and thresholds for harmful effects are discussed, and the biological mechanism is explained. The key point: the rate of DNA damage (double-strand breaks) caused by background radiation is 1000 times less than the endogenous (spontaneous) rate. It is the effect of radiation on an organism’s very powerful adaptive protection systems that determines the dose-response characteristic. Low radiation up-regulates the protection systems, while high radiation impairs these systems. The remedy for radiation fear is to expose and discard the politicized science.
A few reports of increased numbers of leukaemia cases (clusters) in children living in the vicinity of nuclear power plants (NPP) and other nuclear installations have triggered a heated debate over the possible causes of the disease. In this review the most important cases of childhood leukaemia clusters around NPPs are described and analyzed with special emphasis on the relationship between the environmental exposure to ionizing radiation and the risk of leukaemia. Since, as indicated, a lifetime residency in the proximity of an NPP does not pose any specific health risk to people and the emitted ionizing radiation is too small to cause cancer, a number of hypotheses have been proposed to explain the childhood leukaemia clusters. The most likely explanation for the clusters is ‘population mixing’, i.e., the influx of outside workers to rural regions where nuclear installations are being set up and where local people are not immune to pathogens brought along with the incomers.
childhood leukaemia; nuclear installations; ionizing radiation exposure
The reported incidence of thyroid cancer in children and adolescents in Soviet Union before the Chernobyl accident was lower than in other developed countries. This is not clearly recognizable from the literature because comparisons of the high incidence figures 4 years after the accident and later have been made with those from the first years after the accident, when the registered incidence had already started to increase. Considering the low pre-accident registered incidence, there was an accumulated pool of undiagnosed thyroid tumors before the accident. The percentage of more advanced cancers, larger in size and less differentiated, was higher after the accident, when the pool of neglected cancers was diagnosed due to the screening and improved diagnostics. Some of these advanced tumors found by screening were interpreted as aggressive radiogenic cancers. The same tendency might be true also for other cancers, e.g. renal cell carcinoma. Furthermore, the screening-effect, false-positivity and registration of non-exposed patients as Chernobyl victims has obviously contributed to the registered incidence increase of malignancy.
thyroid cancer; ionizing radiation; Chernobyl
Referring to the Golden Ratio (i.e. expressed in the Fibonacci sequence) in nature and art, we conclude that toxicology knows its own Golden Ration, namely linearity. The latter seems imposed on pharmaco-toxicological processes that in fact show far more complexity than simple linearity could hope to elucidate. Understanding physiological and pharmaco-toxicological processes as primarily linear is challenged in this contribution based on very straightforward principles and examples.
Golden Ratio; LNT; adaption; reification fallacy
Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.
ED001-study data on increased liver and stomach tumor risks in >40,000 trout fed dibenzo[a,l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide the greatest low-dose dose-response resolution of any experimentally induced tumor data set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic carcinogens increase tumor risk in linear no-threshold proportion to dose at low doses, ED001 tumor data curiously exhibit substantial low-dose nonlinearity. To explore the role that nongenotoxic mechanisms may have played to yield such nonlinearity, the liver and stomach tumor data sets were each fit by two models that each assume a genotoxic and a nongenotoxic pathway to increased tumor risk: the stochastic 2-stage (MVK) cancer model, and a model implementing the more recent dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis. MVK and DAH fits to the data sets were each excellent, but unexpectedly each MVK fit implies that DBP acts to increase tumor risk by entirely non-mutagenic mechanisms. Given that DBP is such a potent mutagen, the MVK-model fits obtained appear to be biologically implausible, whereas the DAH-model fits reflect that model’s assumption that chemical-induced tumorigenesis typically is driven by elevated repair-cell populations rather than mutations per se.
bioassay; cancer; low-dose linearity; biologically based models; tumorigenesis; mutagen
Whole-body exposure to large radiation doses can cause severe loss of hematopoietic tissue cells and threaten life if the lost cells are not replaced in a timely manner through natural repopulation (a homeostatic mechanism). Repopulation to the baseline level N0 is called reconstitution and a reconstitution deficit (repopulation shortfall) can occur in a dose-related and organ-specific manner. Scott et al. (2013) previously introduced a deterministic version of a threshold exponential (TE) model of tissue-reconstitution deficit at a given follow-up time that was applied to bone marrow and spleen cellularity (number of constituent cells) data obtained 6 weeks after whole-body gamma-ray exposure of female C.B-17 mice. In this paper a more realistic, stochastic version of the TE model is provided that allows radiation response to vary between different individuals. The Stochastic TE model is applied to post gamma-ray-exposure cellularity data previously reported and also to more limited X-ray cellularity data for whole-body irradiated female C.B-17 mice. Results indicate that the population average threshold for a tissue reconstitution deficit appears to be similar for bone marrow and spleen and for 320-kV-spectrum X-rays and Cs-137 gamma rays. This means that 320-kV spectrum X-rays could successfully be used in conducting such studies.
X rays; gamma rays; bone marrow; spleen; reconstitution