According to the definition delivred by the WHO, a biomarker, independently from its role that may be indicative of exposure, response or effect, is inevitably linked to a clinical outcome or to a disease. The presence of a continuum from early biological events to therapy, and prognosis is the unifying mechanism that justifies this conclusion. Traditionally, the technical and inter-individual variability of the assays, together with the long duration between early pathogenetic events and the disease, prevented clinical applications to these biomarkers. These limitations became less important with the emerging of personalized preventive medicine because of the focus on disease prediction and prevention, and the recommended use of all data concerning measurable patient's features. Several papers have been published on the best validation procedures for translating biomarkers to real life. The history of cholesterol concentration is extensively discussed as a reliable example of a biomarker that - after a long and controversial validation process - is currently used in clinical practice. The frequency of micronucleated cells is a reliable biomarker for the pathogenesis of cancer and other non-communicable diseases, and the link with clinical outcomes is substantiated by epidemiological evidence and strong mechanistic basis. Available literature concerning the use of the micronucleus assay in clinical studies is discussed, and a suitable three-levels road-map driving this biomarker towards clinical practice is presented. Under the perspective of personalized medicine, the use of the micronucleus assays can play a decisive role in addressing preventive and therapeutic strategies of chronic diseases. In many cases the MN assay is either currently used in clinical practice or classified as adequate to consider translation into practice. The roadmap to clinical validation of the micronucleus assay finds inspiration from the history of biomarkers such as cholesterol, which clearly showed that the evidence from prospective studies or RCTs is critical to achieve the required level of trust from the healthcare profession. (307 words).
In this review we bring together evidence that (i) RNA viruses are a cause of chromosomal instability and micronuclei (MN), (ii) those individuals with high levels of lymphocyte MN have a weakened immune response and are more susceptible to RNA virus infection and (iii) both RNA virus infection and MN formation can induce inflammatory cytokine production. Based on these observations we propose a hypothesis that those who harbor elevated frequencies of MN within their cells are more prone to RNA virus infection and are more likely, through combined effects of leakage of self-DNA from MN and RNA from viruses, to escalate pro-inflammatory cytokine production via the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) and the Senescence Associated Secretory Phenotype (SASP) mechanisms to an extent that is unresolvable and therefore confers high risk of causing tissue damage by an excessive and overtly toxic immune response. The corollaries from this hypothesis are (i) those with abnormally high MN frequency are more prone to infection by RNA viruses; (ii) the extent of cytokine production and pro-inflammatory response to infection by RNA viruses is enhanced and possibly exceeds threshold levels that may be unresolvable in those with elevated MN levels in affected organs; (iii) reduction of MN frequency by improving nutrition and life-style factors increases resistance to RNA virus infection and moderates inflammatory cytokine production to a level that is immunologically efficacious and survivable.
An increased intake of Zinc (Zn) may reduce the risk of degenerative diseases but may prove to be toxic if taken in excess. This study aimed to investigate whether zinc carnosine supplement can improve Zn status, genome stability events, and Zn transporter gene expression in an elderly (65-85 years) South Australian cohort with low plasma Zn levels.
Micronucleus assay has been used as a biomarker of DNA damage, chromosomal instability, cancer risk and accelerated aging. In this review, a meta-analysis was performed to assess the association between micronuclei (MNi) and diseases with increased advanced glycation end products (AGEs) and HbA1c. The review identified eight studies with 632 subjects with disease and 547 controls. The Mean Ratio (MRi) for AGE levels (MRi = 2.92, 95 %CI: 2.06-4.13, P < 0.00001) and HbA1c levels (MRi = 1.32, 95 %CI: 1.12-1.56, P = 0.001) were significantly higher in the disease group compared to healthy controls. The meta-analysis indicated that the overall estimates of MRi for MNi was 1.83 (95 %CI: 1.38-2.42, p < 0.0001) in subjects with disease compared to controls. Significant increases in MRi for MNi were also observed in the following sub-groups: subjects with disease for elevated AGEs (MRi = 1.62, 95 %CI: 1.12-2.35, P = 0.01), elevated HbA1c (MRi = 2.13, 95 %CI: 1.33-3.39, P = 0.002), lymphocytes MNi (MRi = 1.74, 95 %CI: 1.29-2.33, P = 0.0003), exfoliated buccal cells MNi (MRi = 2.86, 95 %CI: 1.19-6.87, P = 0.02), type 2 diabetes mellitus (T2DM) (MRi = 1.99, 95 %CI: 1.17-3.39, P = 0.01), chronic renal disease (MRi = 1.68, 95 %CI: 1.18-2.38, P = 0.004) and other disease groups (MRi = 2.52, 95 %CI: 1.28-4.96, P = 0.008). The results of this review suggest that MNi could be used as a biomarker of DNA damage and chromosomal instability in degenerative disease where increased AGEs and HbA1c are implicated. The lack of heterogeneity for MN frequency when considered either for all studies or subgroup strengthened the MRi of the meta-analysis. However, the lack of significant association between MRi for MNi and MRi for AGEs or HbA1c indicates that the case-control studies investigated may be confounded by other variables. Thus, larger studies with long term AGE exposure is warranted to further understand the role of MN formation in the initiation and progression of diseases caused by excessive glycation.
Folate and methionine are critical for one-carbon metabolism impacting DNA synthesis, repair, and methylation processes, as well as polyamine synthesis. These micronutrients have been implicated in colorectal cancer risk. There are, however, inconsistencies within the literature, with some studies showing restriction to have tumour-inhibitory effects, whereas others suggest excess to have adverse outcomes. We conducted a review of the published data to examine the accumulated evidence for involvement of dietary folate and/or methionine restriction or excess in intestinal tumour development in the Apc(Min/+) mouse model, which is genetically prone to develop such cancers. Thirteen publications were selected for evaluation based on the following inclusion criteria: (i) use of Apc(Min/+) mouse model; (ii) interventions using dietary folate and/or methionine; and (iii) primary outcome measures focused on intestinal tumour development. We found that nutritional modulation of folate and methionine was shown to have different effects on intestinal cancer in the Apc(Min/+) mouse, depending on the dosage, duration and timing of intervention, and interaction of the Apc(Min/+) genotype with other genetic factors affecting folate and DNA methylation metabolism. Although some studies showed that folate deficiency before tumorigenesis tended to increase risk of tumour formation, there are inconsistencies regarding whether excess folate post-weaning or after tumour initiation increases intestinal tumour burden. Altogether, the pooled data do not appear to indicate a difference in effect on intestinal tumour incidence between post-weaning diets that are folate deficient or folate adequate. The Apc(Min/+) mouse is a useful model for assessment of the impact of dietary folate on intestinal tumour development, but further research is required to understand the reasons for these inconsistencies amongst studies based on likely mechanisms, including modulation of nucleotide synthesis, DNA methylation, and chromosomal instability, which may affect the rate of cellular division and its control.
The incidence of cancer globally is increasing, partly due to lifestyle factors. Despite a better understanding of cancer biology and advancement in cancer management and therapies, current strategies in cancer treatment remain costly and cause socioeconomic burden especially in Asian countries. Hence, instead of putting more efforts in searches for new cancer cures, attention has now shifted to understanding how to mitigate cancer risk by modulating lifestyle factors. It has been established that carcinogenesis is multifactorial, and the important detrimental role of oxidative stress, chronic inflammation, and genomic instability is evident. To date, there is no study linking dietary pattern and genomic stability in cancer risk in the Asian food landscape. Thus, this present review article discusses recent literature on dietary pattern and genomic stability and its relationship with cancer risk in Asia.
Red blood cell (RBC) fatty acids status is used as a biomarker of dietary intake of fats however, there is still a paucity of evidence regarding individual fatty acids and modulation of endogenous advanced glycation end-product (AGE) levels. Due to membrane PUFA being a well-known target for peroxidation, we hypothesized that cellular PUFAs are positively associated with circulatory N ε-carboxymethyllysine (CML) that is also influenced by glyoxal (GO) levels in healthy cohorts. To test this, we investigated the association between RBC fatty acids and circulatory AGEs biomarkers in healthy individuals. The results showed a negative association between saturated fatty acids (SFA) and CML and stepwise multivariate regression analysis indicated stearic acid was negatively associated with CML levels (β = -0.200, p=0.008) after adjusting for age, BMI, and gender. In addition, stearic acid: palmitic acid ratio was also negatively correlated with plasma concentrations of CML (rp= -0.191, p = 0.012) and glucose (rp= -0.288, p = 0.0001). Polyunsaturated fatty acids (PUFA) showed a positive association with CML levels particularly, docosapentaenoic acid, γ-Linolenic acid, arachidonic acid, and docosadienoic acid. However, these associations were not evident after the multiple regression analysis adjusted for age, BMI, and gender. A strong negative correlation (rp= -0.98, p< 0.0001) between total PUFA and total SFA was observed. Furthermore, the SFA:PUFA ratio was inversely correlated with CML (rp= -0.227, p< 0.003). Overall, this study indicates that different fats and their combinations may influence the formation of AGEs and that carefully controlled interventions are required to further test this hypothesis.
As human life expectancy increases substantially and aging is the primary risk factor for most chronic diseases, there is an urgent need for advancing the development of post-genomic era biomarkers that can be used for disease prediction and early detection (DPED). Mosaic loss of Y chromosome (LOY) is the state of nullisomy Y in sub-groups of somatic cells acquired from different post-zygotic development stages and onwards throughout the lifespan. Multiple large-cohort based epidemiology studies have found that LOY in blood cells is a significant risk factor for future mortality and various diseases in males. Many features intrinsic to LOY analysis may be leveraged to enhance its use as a non-invasive, sensitive, reliable, high throughput-biomarker for DPED. Here, we review the emerging literatures in LOY studies and highlight ten strengths for using LOY as a novel biomarker for genomics-driven DPED diagnostics. Meanwhile, the current limitations in this area are also discussed. We conclude by identifying some important knowledge gaps regarding the consequences of malsegregation of the Y chromosome and propose further steps that are required before clinical implementation of LOY. Taken together, we think that LOY has substantial potential as a biomarker for DPED, despite some hurdles that still need to be addressed before its integration into healthcare becomes acceptable.
Significant alterations in sleep duration and/or quality of sleep become more pronounced as people get older. Poor sleep in elderly people is associated with adverse health outcomes and cellular aging. We examined the relationship between telomere length (TL) and sleep duration, Health Promotion Index (HPI), and tested whether the presence of Apolipoprotein-E4 (ApoE-ε4) allele affects both sleep and TL. The present study was carried out in 174 healthy participants (21% male; mean age 53.79 years) from South Australia. Lymphocyte TL was measured by real-time quantitative PCR (qPCR) and ApoE genotype was determined by TaqMan assay. HPI was calculated from a questionnaire regarding 8 lifestyle habits, including sleeping hours. Multivariate regression analysis was used to establish these associations adjusted for specified confounders. TL was found to be inversely associated with age (r = -0.199; p = .008) and body mass index (r = -0.121; p = .11), and was significantly shorter in participants who slept for less than 7 hours (p = .001) relative to those sleeping ≥7 hours. TL was positively correlated with HPI (r = 0.195; p = .009). ApoE-ε4 allele carriers who slept for less than 7 hours had shortest TL (p = .01) compared to noncarriers. Plasma soluble receptor for advanced glycation end product (sRAGE) level was significantly (p = .001) lower in individuals who sleep less than 7 hours and ApoE-ε4 carriers. Our results suggest that inadequate sleep duration or poor HPI is associated with shorter TL in cognitively normal people and that carriage of APOE-ε4 genotype may influence the extent of these effects.
Micronutrient malnutrition is thought to play an important role in the cause of cognitive impairment and physical frailty. The purpose of this scoping review was to map current evidence on the association between micronutrient deficiency in blood and mild cognitive impairment, frailty, and cognitive frailty among older adults. The scoping review was conducted based on the 2005 methodological framework by Arksey and O'Malley. The search strategy for potential literature on micronutrient concentration in blood and cognitive frailty was retrieved based on the keywords using electronic databases (PubMed, Cochrane Library, Google Scholar, Ovid, and Science Direct) from January 2010 to December 2021. Gray literature was also included in the searches. A total of 4310 articles were retrieved and 43 articles were incorporated in the review. Findings revealed a trend of significant association between low levels of B vitamins (folate and vitamin B12), vitamin D, vitamin A, vitamin E, omega 3 fatty acid, and albumin, and high homocysteine levels in blood with an increased risk of mild cognitive impairment among older adults. The results also indicated that low vitamin D levels, albumin, and antioxidants (lutein and zeaxanthin) in blood were significantly associated with frailty among older adults, while β-cryptoxanthin and zeaxanthin in blood were inversely associated with the risk of cognitive frailty. Vitamin D and antioxidants seemed to be targeted nutrients for the prevention of cognitive frailty. In conclusion, a wide range of micronutrient deficiency was associated with either mild cognitive impairment or frailty; however, little evidence exists on the dual impairment, i.e., cognitive frailty. This scoping review can serve as preliminary evidence for the association between micronutrient deficiency in blood and mild cognitive impairment, frailty, and cognitive frailty among older adults and prove the relevancy of the topic for future systematic reviews.
Micronucleus (MN) assay has been widely used as a biomarker of DNA damage, chromosomal instability, cancer risk and accelerated aging in many epidemiological studies. In this narrative review and meta-analysis we assessed the association between lymphocyte micronuclei (MNi) and cancers of the skin, blood, digestive tract, and prostate. The review identified nineteen studies with 717 disease subjects and 782 controls. Significant increases in MRi for MNi were observed in the following groups: subjects with blood cancer (MRi = 3.98; 95 % CI: 1.98-7.99; p = 0.000) and colorectal cancer (excluding IBD) (MRi = 2.69; 95 % CI: 1.82-3.98, p
Advanced glycation end products (AGEs) are formed via non-enzymatic reactions between amino groups of proteins and the carbonyl groups of reducing sugars. Previous studies have shown that highly glycated albumin prepared using a glucose-bovine serum albumin (Glu-BSA) model system incubated at 60°C for 6 weeks induces genotoxicity in WIL2-NS cells at 9 days of exposure measured by the cytokinesis-block micronucleus cytome (CBMNcyt) assay. However, this AGE model system is not physiologically relevant as normal body temperature is 37°C and the degree of glycation may exceed the extent of albumin modification in vivo. We hypothesised that the incubation temperature and purification method used in these studies may cause changes to the chemical profile of the glycated albumin and may influence the extent of genotoxicity observed at 3, 6 and 9 days of exposure. We prepared AGEs generated using Glu-BSA model systems incubated at 60°C or 37°C purified using trichloroacetic acid (TCA) precipitation or ultrafiltration (UF) and compared their chemical profile (glycation, oxidation, and aggregation) and genotoxicity in WIL2-NS cells using the CBMNcyt assay after 3, 6 and 9 days of exposure. The number of micronuclei (MNi) was significantly higher for cells treated with Glu-BSA incubated at 60°C and purified via TCA (12 ± 1 MNi/1000 binucleated cells) compared to Glu-BSA incubated at 37°C and purified using UF (6 ± 1 MNi/1000 binucleated cells) after 9 days (P < 0.0001). The increase in genotoxicity observed could be explained by a higher level of protein glycation, oxidation, and aggregation of the Glu-BSA model system incubated at 60°C relative to 37°C. This study highlighted that the incubation temperature, purification method and cell exposure time are important variables to consider when generating AGEs in vitro and will enable future studies to better reflect in vivo situations of albumin glycation.
Type 2 diabetes is associated with elevated levels of DNA damage, in particular micronuclei (MNi) which are formed by acentric chromosome fragments caused by double-stranded DNA breaks (DSBs), or whole chromosomes which fail to segregate during mitosis. We investigated if methylglyoxal (MGO), a reactive dicarbonyl known to be elevated in type 2 diabetes is capable of increasing chromosomal instability and DNA damage as measured by the cytokinesis block micronucleus cytome (CBMNcyt) assay in B-lymphoblastoid WIL2-NS cells and primary peripheral blood lymphocytes (PBL). We also investigated the level of various dicarbonyl stress biomarkers, including extracellular and intracellular MGO, protein and MGO modifications of DNA. WIL2-NS cells exposed to either MGO or a glyoxalase 1 inhibitor showed increases in MNi and nuclear buds, which were associated with an increase in intracellular MGO. DNA damage in the form of MNi and nucleoplasmic bridges were observed in primary PBL exposed to 10 µM MGO, suggesting low concentrations of MGO may be genotoxic. Furthermore, we showed, using fluorescent in situ hybridisation, that the majority of MNi caused by MGO in WIL2-NS cells were caused by whole chromosome loss events, rather than DSBs. Our data suggest that MGO, a reactive metabolite elevated in type 2 diabetes and other pathologies, can affect genomic integrity by impairing chromosome segregation during mitosis.
Individual dietary patterns may be influenced by diet-related behaviours, which may eventually play a significant role in contributing to colorectal cancer risk. As nearly half of colorectal cancer cases can be prevented through diet and lifestyle modification, in this study, we aimed to present an overview of the literature on diet-related behaviour and its effect on colorectal cancer risk among adults. Articles published from 2011 until July 2021 were selected. Out of the 1,198 articles retrieved, 25 were analyzed. There were 16 case-control studies, and nine of them were cohort studies. As a finding, the instruments used in this review were food frequency questionnaires (n = 23), followed by a semi-structured interview (n = 1), and diet records (n = 1). We demonstrated that unhealthy diet-related behaviours are linked to an increased risk of colorectal cancer in adults and those food frequency questionnaires or food records are common instruments used to collect diet-related behaviours. This article imparts the research trends and directions of colorectal cancer risk factors and shows that diet-related behaviour varies and changes over time.
Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.
Dietary pattern (DP) and its relationship with disease biomarkers have received recognition in nutritional epidemiology investigations. However, DP relationships with adipokines (i.e., adiponectin and leptin) among breast cancer survivors remain unclear. Therefore, we assessed relationships between DP and high-molecular weight (HMW) adiponectin and leptin concentration among breast cancer survivors. This cross-sectional study involved 128 breast cancer survivors who attended the oncology outpatient clinic at two main government hospitals in the East Coast of Peninsular Malaysia. The serum concentration of HMW adiponectin and leptin were measured using enzyme-linked immunosorbent assay (ELISA) kits. A reduced rank regression method was used to analyze DP. Relationships between DP with HMW adiponectin and leptin were examined using regression models. The findings show that with every 1-unit increase in the 'energy-dense, high-SFA, low-fiber' DP z-score, there was a reduction by 0.41 μg/mL in HMW adiponectin which was independent of age, BMI, education level, occupation status, cancer stage, and duration since diagnosis. A similar relationship with leptin concentration was not observed. In conclusion, the 'energy-dense, high-saturated fat and low-fiber' DP, which is characterized by high intake levels of sugar-sweetened drinks and fat-based spreads but low intake of fruits and vegetables, is an unhealthy dietary pattern and unfavorable for HMW adiponectin concentration, but not for leptin. These findings could serve as a basis in developing specific preventive strategies that are tailored to the growing population of breast cancer survivors.
Consumption of very hot beverages and foods increases the incidence of oral and esophageal cancer but the mechanisms are not known and the critical temperature is not well defined. We realized a study with exfoliated cells from the oral cavity of individuals (n = 73) that live in an area in Iran which has the highest incidence of EC worldwide. Consumption of beverages at very high temperatures is a characteristic feature of this population. We analyzed biomarkers which are (i) indicative for genetic instability (micronuclei that are formed as a consequence of chromosomal damage, nuclear buds which are a consequence of gene amplifications and binucleated cells which reflect mitotic disturbances), (ii) markers that reflect cytotoxic effects (condensed chromatin, karyorrhectic, karyolitic and pyknotic cells), (iii) furthermore, we determined the number of basal cells which is indicative for the regenerative capacity of the buccal mucosa. The impact of the drinking temperature on the frequencies of these parameters was monitored with thermometers. We found no evidence for induction of genetic damage but an increase of the cytotoxic effects with the temperature was evident. This effect was paralleled by an increase of the cell division rate of the mucosa which was observed when the temperature exceeded 60 °C. Our findings indicate that cancer in the upper digestive tract in drinkers of very hot beverages is not caused by damage of the genetic material but by an increase of the cell division rate as a consequence of cytotoxic effects which take place at temperatures over 60 °C. It is known from earlier experiments with rodents that increased cell divisions lead to tumor promotion in the esophagus. Our findings provide a mechanistic explanation and indicate that increased cancer risks can be expected when the drinking temperature of beverages exceeds 60 °C.
The purpose of the "Micronuclei and Disease" special issue (SI) is to: (i) Determine the level of evidence for association of micronuclei (MN), a biomarker of numerical and structural chromosomal aberrations, with risk of specific diseases in humans; (ii) Define plausible mechanisms that explain association of MN with each disease; (iii) Identify knowledge gaps and research needed to translate MN assays into clinical practice. The "MN and Disease" SI includes 14 papers. The first is a review of mechanisms of MN formation and their consequences in humans. 11 papers are systematic reviews and/or meta-analyses of the association of MN with reproduction, child health, inflammation, auto-immune disease, glycation, metabolic diseases, chronic kidney disease, cardiovascular disease, eleven common cancers, ageing and frailty. The penultimate paper focuses on effect of interventions on MN frequency in the elderly. A road map for translation of MN data into clinical practice is the topic of the final paper. The majority of reviewed studies were case-control studies in which the ratio of mean MN frequency in disease cases relative to controls, i.e. the mean ratio (MR), was calculated. The mean of these MR values, estimated by meta-analyses, for lymphocyte and buccal cell MN in non-cancer diseases were 2.3 and 3.6 respectively, and for cancers they were 1.7 and 2.6 respectively. The highest MR values were observed in studies of cancer cases in which MN were measured in the same tissue as the tumour (MR = 4.9-10.8). This special issue is an important milestone in the evidence supporting MN as a reliable genomic biomarker of developmental and degenerative disease risk. These advances, together with results from prospective cohort studies, are helping to identify diseases in which MN assays can be practically employed in the clinical setting to better identify high risk patients and to prioritise them for preventive therapy.
Background: Exposure to genotoxic stress such as radiation is an important public health issue affecting a large population. The necessity of analyzing cytogenetic effects of such exposure is related to the need to estimate the associated risk. Cytogenetic biological dosimetry is based on the relationship between the absorbed dose and the frequency of scored chromosomal aberrations. The influence of confounding factors on radiation response is a topical issue. The role of ethnicity is unclear. Here, we compared the dose-response curves obtained after irradiation of circulating lymphocytes from healthy donors of African and European ancestry. Materials and Methods: Blood samples from six Africans living in Africa, five Africans living in Europe, and five Caucasians living in Europe were exposed to various doses (0-4 Gy) of X-rays at a dose-rate of 0.1 Gy/min using an X-RAD320 irradiator. A validated cohort composed of 14 healthy Africans living in three African countries was included and blood samples were irradiated using the same protocols. Blood lymphocytes were cultured for 48 h and chromosomal aberrations scored during the first mitosis by telomere and centromere staining. The distribution of dicentric chromosomes was determined and the Kruskal-Wallis test was used to compare the dose-response curves of the two populations. Results: No spontaneous dicentric chromosomes were detected in African donors, thus establishing a very low background of unstable chromosomal aberrations relative to the European population. There was a significant difference in the dose response curves between native African and European donors. At 4 Gy, African donors showed a significantly lower frequency of dicentric chromosomes (p = 8.65 10-17), centric rings (p = 4.0310-14), and resulting double-strand-breaks (DSB) (p = 1.32 10-18) than European donors. In addition, a significant difference was found between African donors living in Europe and Africans living in Africa. Conclusion: This is the first study to demonstrate the important role of ethnic and environmental factors that may epigenetically influence the response to irradiation. It will be necessary to establish country-of-origen-specific dose response curves to practice precise and adequate biological dosimetry. This work opens new perspective for the comparison of treatments based on genotoxic agents, such as irradiation.