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      Global transcriptome profile reveals abundance of DNA damage response and repair genes in individuals from high level natural radiation areas of Kerala coast

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          Abstract

          The high level natural radiation areas (HLNRA) of Kerala coast in south west India is unique for its wide variation in the background radiation dose (<1.0mGy to 45mGy/year) and vast population size. Several biological studies conducted in this area did not reveal any adverse effects of chronic low dose and low dose rate radiation on human population. In the present study, global transcriptome analysis was carried out in peripheral blood mono-nuclear cells of 36 individuals belonging to different background dose groups [NLNRA, (Group I, ≤1.50 mGy/year) and three groups of HLNRA; Group II, 1.51–5.0 mGy/year), Group III, 5.01-15mGy/year and Group IV, >15.0 mGy/year] to find out differentially expressed genes and their biological significance in response to chronic low dose radiation exposure. Our results revealed a dose dependent increase in the number of differentially expressed genes with respect to different background dose levels. Gene ontology analysis revealed majority of these differentially expressed genes are involved in DNA damage response (DDR) signaling, DNA repair, cell cycle arrest, apoptosis, histone/chromatin modification and immune response. In the present study, 64 background dose responsive genes have been identified as possible chronic low dose radiation signatures. Validation of 30 differentially expressed genes was carried out using fluorescent based universal probe library. Abundance of DDR and DNA repair genes along with pathways such as MAPK, p53 and JNK in higher background dose groups (> 5.0mGy/year) indicated a possible threshold dose for DDR signaling and are plausible reason of observing in vivo radio-adaptive response and non-carcinogenesis in HLNRA population. To our knowledge, this is the first study on molecular effect of chronic low dose radiation exposure on human population from high background radiation areas at transcriptome level using high throughput approach. These findings have tremendous implications in understanding low dose radiation biology especially, the effect of low dose radiation exposure in humans.

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          Most cited references70

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          Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.

          DNA double-strand breaks (DSBs) are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease. However, no information on the induction and processing of DSBs after physiologically relevant radiation doses is available. Many of the methods used to measure DSB repair inadvertently introduce this form of damage as part of the methodology, and hence are limited in their sensitivity. Here we present evidence that foci of gamma-H2AX (a phosphorylated histone), detected by immunofluorescence, are quantitatively the same as DSBs and are capable of quantifying the repair of individual DSBs. This finding allows the investigation of DSB repair after radiation doses as low as 1 mGy, an improvement by several orders of magnitude over current methods. Surprisingly, DSBs induced in cultures of nondividing primary human fibroblasts by very low radiation doses (approximately 1 mGy) remain unrepaired for many days, in strong contrast to efficient DSB repair that is observed at higher doses. However, the level of DSBs in irradiated cultures decreases to that of unirradiated cell cultures if the cells are allowed to proliferate after irradiation, and we present evidence that this effect may be caused by an elimination of the cells carrying unrepaired DSBs. The results presented are in contrast to current models of risk assessment that assume that cellular responses are equally efficient at low and high doses, and provide the opportunity to employ gamma-H2AX foci formation as a direct biomarker for human exposure to low quantities of ionizing radiation.
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            Evidence for beneficial low level radiation effects and radiation hormesis.

            Low doses in the mGy range cause a dual effect on cellular DNA. One is a relatively low probability of DNA damage per energy deposition event and increases in proportion to the dose. At background exposures this damage to DNA is orders of magnitude lower than that from endogenous sources, such as reactive oxygen species. The other effect at comparable doses is adaptive protection against DNA damage from many, mainly endogenous, sources, depending on cell type, species and metabolism. Adaptive protection causes DNA damage prevention and repair and immune stimulation. It develops with a delay of hours, may last for days to months, decreases steadily at doses above about 100 mGy to 200 mGy and is not observed any more after acute exposures of more than about 500 mGy. Radiation-induced apoptosis and terminal cell differentiation also occur at higher doses and add to protection by reducing genomic instability and the number of mutated cells in tissues. At low doses reduction of damage from endogenous sources by adaptive protection maybe equal to or outweigh radiogenic damage induction. Thus, the linear-no-threshold (LNT) hypothesis for cancer risk is scientifically unfounded and appears to be invalid in favour of a threshold or hormesis. This is consistent with data both from animal studies and human epidemiological observations on low-dose induced cancer. The LNT hypothesis should be abandoned and be replaced by a hypothesis that is scientifically justified and causes less unreasonable fear and unnecessary expenditure.
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              The linear no-threshold relationship is inconsistent with radiation biologic and experimental data.

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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draft
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 November 2017
                2017
                : 12
                : 11
                Affiliations
                [1 ] Low Level Radiation Research Section, Radiation Biology and Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India
                [2 ] Homi Bhabha National Institute, Anushakti Nagar, Mumbai, India
                Texas Tech University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-22092
                10.1371/journal.pone.0187274
                5697823
                29161272
                9987474a-c8f8-4d10-9edd-21f3558d8971
                © 2017 Jain, Das

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 10, Tables: 5, Pages: 28
                Product
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Biology and life sciences
                Genetics
                DNA
                DNA repair
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA repair
                Biology and life sciences
                Genetics
                DNA
                DNA damage
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA damage
                Biology and Life Sciences
                Immunology
                Immune Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcriptional Control
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                MAPK signaling cascades
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Custom metadata
                The database has been submitted to GEO repository under the accession number GSE95279.

                Uncategorized
                Uncategorized

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