Purpose: Ionizing radiation (IR) is a ubiquitous environmental stressor with genotoxic and epigenotoxic capabilities. Terrestrial IR, predominantly a low-linear energy transfer (LET) radiation, is ...being widely utilized in medicine, as well as in multiple industrial applications. Additionally, an interest in understanding the effects of high-LET irradiation is emerging due to the potential of exposure during space missions and the growing utilization of high-LET radiation in medicine.
Conclusions: In this review, we summarize the current knowledge of the effects of IR on DNA methylation, a key epigenetic mechanism regulating the expression of genetic information. We discuss global, repetitive elements and gene-specific DNA methylation in light of exposure to high and low doses of high- or low-LET IR, fractionated IR exposure, and bystander effects. Finally, we describe the mechanisms of IR-induced alterations to DNA methylation and discuss ways in which that understanding can be applied clinically, including utilization of DNA methylation as a predictor of response to radiotherapy and in the manipulation of DNA methylation patterns for tumor radiosensitization.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The goal of this study was to investigate Cannabidiol (CBD) hepatotoxicity in 8-week-old male B6C3F
mice. Animals were gavaged with either 0, 246, 738, or 2460 mg/kg of CBD (acute toxicity, 24 h) or ...with daily doses of 0, 61.5, 184.5, or 615 mg/kg for 10 days (sub-acute toxicity). These doses were the allometrically scaled mouse equivalent doses (MED) of the maximum recommended human maintenance dose of CBD in EPIDIOLEX
(20 mg/kg). In the acute study, significant increases in liver-to-body weight (LBW) ratios, plasma ALT, AST, and total bilirubin were observed for the 2460 mg/kg dose. In the sub-acute study, 75% of mice gavaged with 615 mg/kg developed a moribund condition between days three and four. As in the acute phase, 615 mg/kg CBD increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression arrays revealed that CBD differentially regulated more than 50 genes, many of which were linked to oxidative stress responses, lipid metabolism pathways and drug metabolizing enzymes. In conclusion, CBD exhibited clear signs of hepatotoxicity, possibly of a cholestatic nature. The involvement of numerous pathways associated with lipid and xenobiotic metabolism raises serious concerns about potential drug interactions as well as the safety of CBD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
LINE-1 (L1) is the most abundant mammalian transposable element that comprises nearly 20% of the genome, and nearly half of the mammalian genome has stemmed from L1-mediated mobilization. Expression ...and retrotransposition of L1 are suppressed by complex mechanisms, where the key role belongs to DNA methylation. Alterations in L1 methylation may lead to aberrant expression of L1 and have been described in numerous diseases. Accumulating evidence clearly indicates that loss of global DNA methylation observed in cancer development and progression is tightly associated with hypomethylation of L1 elements. Significant progress achieved in the last several years suggests that such parameters as L1 methylation status can be potentially utilized as clinical biomarkers for determination of the disease stage and in predicting the disease-free survival in cancer patients. In this paper, we summarize the current knowledge on L1 methylation, with specific emphasis given to success and challenges on the way of introduction of L1 into clinical practice.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons are the major repetitive elements in mammalian genomes. LINE-1s are well-accepted as driving forces of evolution and critical regulators ...of the expression of genetic information. Alterations in LINE-1 DNA methylation may lead to its aberrant activity and are reported in virtually all human cancers and in experimental carcinogenesis. In this study, we investigated the endogenous DNA methylation status of the 5' untranslated region (UTR) of LINE-1 elements in the bone marrow hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and mononuclear cells (MNCs) in radioresistant C57BL/6J and radiosensitive CBA/J mice and in response to ionizing radiation (IR). We demonstrated that basal levels of DNA methylation within the 5'-UTRs of LINE-1 elements did not differ significantly between the two mouse strains and were negatively correlated with the evolutionary age of LINE-1 elements. Meanwhile, the expression of LINE-1 elements was higher in CBA/J mice. At two months after irradiation to 0.1 or 1 Gy of
Cs (dose rate 1.21 Gy/min), significant decreases in LINE-1 DNA methylation in HSCs were observed in prone to radiation-induced carcinogenesis CBA/J, but not C57BL/6J mice. At the same time, no residual DNA damage, increased ROS, or changes in the cell cycle were detected in HSCs of CBA/J mice. These results suggest that epigenetic alterations may potentially serve as driving forces of radiation-induced carcinogenesis; however, future studies are needed to demonstrate the direct link between the LINE-1 DNA hypomethylation and radiation carcinogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ionizing radiation is an important treatment modality, but it is also a well-known genotoxic agent capable of damaging cells and tissues. Therefore radiation treatment can cause numerous side effects ...in exposed tissues and organs. Radiotherapy is a part of the front-line treatment regime for brain cancer patients, but can cause severe functional and morphological changes in exposed brain tissues. However, the mechanisms of radiation-induced effects in the brain are not well understood and are under-investigated. Recent data has implicated short RNAs, especially microRNAs, as important in radiation responses, yet nothing is known about radiation-induced changes in the brain microRNAome.
We analyzed the effects of X-ray irradiation on microRNA expression in the hippocampus, frontal cortex, and cerebellum of male and female mice. Here, we report tissue-, time-, and sex-specific brain radiation responses, as well as show evidence of an interplay between microRNAs and their targets. Specifically, we show that changes in the expression of the miR-29 family may be linked, at least in part, to altered expression of de novo methyltransferase DNMT3a and changed global DNA methylation levels. Further, these sex-specific epigenetic changes may be correlated to the prevalence of radiation-induced cancers in males.
We identified several microRNAs that can potentially serve as biomarkers of brain radiation exposure. In summary, our study may provide an important roadmap for further analysis of microRNA expression in different brain regions of male and female mice and for detailed dissection of radiation-induced brain responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Astronauts in space are subject to continuous exposure to ionizing radiation. There is concern about the acute and late-occurring adverse health effects that astronauts could incur following a ...protracted exposure to the space radiation environment. Therefore, it is vital to consider the current tools and models used to describe and study the organic consequences of ionizing radiation exposure. It is equally important to see where these models could be improved. Historically, radiobiological models focused on how radiation damages nuclear deoxyribonucleic acid (DNA) and the role DNA repair mechanisms play in resulting biological effects, building on the hypotheses of Crowther and Lea from the 1940s and 1960s, and they neglected other subcellular targets outside of nuclear DNA. The development of these models and the current state of knowledge about radiation effects impacting astronauts in orbit, as well as how the radiation environment and cellular microenvironment are incorporated into these radiobiological models, aid our understanding of the influence space travel may have on astronaut health. It is vital to consider the current tools and models used to describe the organic consequences of ionizing radiation exposure and identify where they can be further improved.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Exposure of animal body parts to ionizing radiation (IR) can lead to molecular changes in distant shielded "bystander" tissues and organs. Nevertheless, tissue specificity of bystander responses ...within the same organism has not been examined in detail. Studies on in vivo bystander effect conducted so far analyzed changes induced by single-dose exposure. The potential of fractionated irradiation to induce bystander effects in vivo has never been studied. We analyzed changes in global DNA methylation and microRNAome in skin and spleen of animals subjected to single-dose (acute or fractionated) whole-body or cranial exposure to 0.5 Gy of X-rays. We found that IR-induced DNA methylation changes in bystander spleen and skin were distinct. Acute radiation exposure resulted in a significant loss of global DNA methylation in the exposed and bystander spleen 6 hr, 96 hr, and 14 days after irradiation. Fractionated irradiation led to hypomethylation in bystander spleen 6 hr after whole-body exposure, and 6 hr, 96 hr, and 14 days after cranial irradiation. Contrarily, changes in the skin of the same animals were seen only 6 hr after acute whole-body and head exposure. DNA hypomethylation observed in spleen was paralleled by a reduction of methyl-binding protein MeCP2 expression. Irradiation also induced tissue-specific microRNAome alterations in skin and spleen. For the first time, we have shown that IR-induced epigenetic bystander effects that occur in the same organism are triggered by both acute and fractionated exposure and are very distinct in different bystander organs. Future studies are clearly needed to address organismal and carcinogenic repercussions of those changes. Environ. Mol. Mutagen., 2009.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human ...malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene–environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor‐specific (“fingerprints”) that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
It is well accepted that irradiated cells may "forward" genome instability to nonirradiated neighboring cells, giving rise to the "bystander effect" phenomenon. Although bystander effects were well ...studied by using cell cultures, data for somatic bystander effects in vivo are relatively scarce.
We set out to analyze the existence and molecular nature of bystander effects in a radiation target-organ spleen by using a mouse model. The animal's head was exposed to X-rays while the remainder of the body was completely protected by a medical-grade shield. Using immunohistochemistry, we addressed levels of DNA damage, cellular proliferation, apoptosis, and p53 protein in the spleen of control animals and completely exposed and head-exposed/body bystander animals.
We found that localized head radiation exposure led to the induction of bystander effects in the lead-shielded distant spleen tissue. Namely, cranial irradiation led to increased levels of DNA damage and p53 expression and also altered levels of cellular proliferation and apoptosis in bystander spleen tissue. The observed bystander changes were not caused by radiation scattering and were observed in two different mouse strains; C57BL/6 and BALB/c.
Our study proves that bystander effects occur in the distant somatic organs on localized exposures. Additional studies are required to characterize the nature of an enigmatic bystander signal and analyze the long-term persistence of these effects and possible contribution of radiation-induced bystander effects to secondary radiation carcinogenesis.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in ...gametes of male mice exposed to particulate air pollution in an industrial/urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPA-filtered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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