Spectrum of TP53 Sequence Variants on Chronically Exposed Humans

This paper presents the results of the analysis of mutations such as G:CT:A, G:CA:T and G:CC:G in the TP53 gene in peripheral blood cells in women affected by chronic radiation exposure with breast cancer (24 persons) and without breast cancer (17 persons). 17 different variants representing single nucleotide substitutions were registered. The differences in the frequencies of carriers of the detected variants between the comparison and the main group were not statistically significant. All detected variants were present in the IARC TP53 database and had no clinical significance as “pathogenic.” Despite the absence of statistically significant differences, the question of the effect of chronic low dose rate exposure on the frequency of mutations in the TP53 gene remains open and requires further research involving a greater amount of data.

The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.

The atomic bombings of Hiroshima and Nagasaki in 1945 created a unique environment of acute, high-dose ionizing radiation, contrasting sharply with the chronic low-dose rate exposure in the Chernobyl and Fukushima Exclusion Zones. This stands in stark contrast to the chronic, low-dose rate contamination that defines the Chernobyl and Fukushima Exclusion Zones. While the long-term ecological effects of the latter are well-documented, a systematic synthesis of the floral response to the atomic bombings is lacking. This review integrates historical data with modern radio-ecological principles to analyze plant survival and succession. We document the remarkable recovery of vegetation, from the resprouting of survivor trees, the hibakujumoku, such as Ginkgo biloba trees, to the role of soil seed banks. We propose that this recovery was driven by constitutive resilience, relying on pre-existing traits such as robust DNA repair, antioxidant capacity, and protective morphology, rather than the multi-generational genetic adaptation observed in chronic exposure zones. By framing these events against the backdrop of Chernobyl and Fukushima, this review demonstrates how the nature of the radiological insult dictates fundamentally different ecological and evolutionary outcomes. The flora of Hiroshima and Nagasaki thus serves as a critical case study of extreme instantaneous stress tolerance. We conclude by proposing a future research agenda that employs advanced genomic tools on these living archives to uncover the mechanistic basis of their survival, thereby integrating a pivotal historical case into a holistic understanding of plant persistence in radically altered environments.

The understanding of the exposure effects on the human health could be improved by analyzing the influence of the chronic low dose rate exposure on the senescence of the immune system cells. It will also help to develop the measures aimed at the mitigation of the adverse effects. The objective of the study is to investigate the influence of the chronic low dose rate exposure on the senescence of the immune system cells using the cytogenetic markers. In the course of the research the authors evaluated the cellular senescence markers — genome instability and telomere depletion — in T-lymphocytes of the individuals exposed in the Southern Urals (exposure doses were 0.001 Gy — 4.7 Gy, the age of examined people was 40–89 years). The data analysis has demonstrated that the effect of chronic exposure on the T-cell senescence was indirect. Unstable chromosome aberrations occurred statistically significantly more frequently in exposed people aged 40–59 years (p = 0.012). Frequency of lymphocytes with micronuclei in exposed individuals differed in men and women (p = 0.001). Statistically significant decrease in the telomere length was revealed (for the chromosome arms 1q, 3p, 3q, 20p, 20q, 13q, 15p, 22q (p < 0.05); 19p, 21q (p < 0.01)).

Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys

Purpose Nuclear medicine is the fastest growing segment in imaging due to an increase in demand for procedures, development of advanced scanners and new radioactive tracers. Technologists are exposed to radiation throughout the workday. Key protection approaches are time, distance, and shielding; these can be difficult to achieve since patients are usually the main source of radiation and close contact is required. Technologists in general nuclear medicine receive annual effective doses of approximately 0.1 mSv. Doses in positron emission tomography (PET) imaging can be close to 6 mSv. Without appropriate radiation protection measures, finger doses from handling PET radiopharmaceuticals can exceed the annual dose limit of 500 mSv. Estimates of health risks from low dose-rate exposures are extrapolated from risk coefficients calculated from Japanese atomic bomb survivors. Effects of chronic exposure are obtained from nuclear workers and radiotherapy patients. This review aims to consolidate existing research in biomarkers of low dose radiation exposure to determine whether they may form a part in occupational health monitoring. Conclusions The link between chronic low-dose exposure in nuclear medicine technologists and health risks using radiation-related biomarkers as a proxy remains relatively unexplored. Further work is needed to identify and characterize biomarkers in technologists.

The present investigation dealt with harmful effects of hexavalent chromium (Cr [VI]) on liver of Swiss albino mice. This variant exhibited cytotoxicity, mutagenicity, and carcinogenicity. Our study focused on elucidating the hepatotoxic effects of chronic low-dose exposure to Cr (VI) (2, 5, and 10ppm) administered via drinking water for 4 and 8months. The observed elevation in SGPT, ALP, and SGOT and increased oxidative stress markers unequivocally confirmed the severe disruption of liver homeostasis at these low treatment doses. Noteworthy alterations in histoarchitecture, body weight, and water intake provided further evidences of the harmful effects of Cr (VI). Production of reactive oxygen species (ROS) during metabolism led to DNA damages. Immunohistochemistry and qRT-PCR analyses revealed that chronic low-dose exposure of Cr (VI) induced apoptosis in liver tissue. Our study exhibited alterations in the expression pattern of DNA repair genes (Rad51, Mutyh, Mlh1, and Ogg1), coupled with promoter hypermethylation of Mutyh and Rad51, leading to transcriptional inhibition. Our findings underscored the potential of low-dose Cr (VI) exposure on hepatotoxicity by the intricate interplay between apoptosis induction and epigenetic alterations of DNA repair genes.

Phoxim is a pesticide extensively applied in mulberry fields, and residues may persist on leaves even after the recommended pre-harvest interval. However, the potential risks of these residues to Bombyx mori L. (Lepidoptera: Bombycidae) have long been overlooked. The results demonstrated that chronic low-dose exposure from the second to fifth instars significantly impaired silkworm development and silk production. Specifically, larvae in the 0.316 μg/mL treatment group (1/2 LC50) exhibited a significant reduction in body weight, while the cocoon shell ratio was significantly decreased in both the 0.079 μg/mL (1/8 LC50) and 1/2 LC50 groups. Cocoon deformities were observed in the 0.032 μg/mL (1/20 LC50), 1/8 LC50, and 1/2 LC50 groups. Histopathological analysis revealed silk gland damage in the treatment groups, with severity increasing with higher phoxim concentrations. Biochemical analyses indicated elevated malondialdehyde (MDA) levels accompanied by increased superoxide dismutase (SOD) and peroxidase (POD) activities. Notably, phoxim exposure selectively reduced juvenile hormone (JH) titers without affecting ecdysone titers. JH-regulated genes including the receptors Met1 and Met2, and transcription factors Kr-h1 and Dimm were downregulated, accompanied by suppressed expression of the fibroin synthesis gene Fib-H. These results collectively indicate that chronic low-concentration phoxim exposure disrupts endocrine regulation, damages silk gland integrity, and ultimately reduces silk production in silkworm.

It is well established that radiation effects on wild organisms from nuclear power plant accidents primarily depend on the dose received at the accident; however, impacts of prolonged low-dose exposure remain poorly understood. In this study, oxidative DNA damage in Pinus densiflora, assessed via 8-OHdG levels, was compared between inside (0.87–7.74 μSv/h) and outside (0.094–0.16 μSv/h) the difficult-to-return zone 10 years after the Fukushima accident. Leaf 8-OHdG levels varied among the sites but were unrelated to the absorbed dose. In buds, 8-OHdG levels were very low. An irradiation experiment on 2-year seedlings using Cs-137 at three dose rates (44.8, 461, 1738 mGy/h) also found no association between dose rate and 8-OHdG levels; only sampling points correlated with 8-OHdG levels. In contrast, both dose rate and 8-OHdG levels negatively affected seedling survival after the irradiation experiment. Even without irradiation, samples with >0.04% 8-OHdG did not survive. These results suggest 8-OHdG status indicates seedling health and that environmental stress induces oxidative stress via photosynthesis disruption. Additionally, microsatellite mutation rate in megagametophytes was assessed in 1136 seeds using nine markers, detecting only one mutation in contaminated areas, not statistically significant. This mutation rate was too low for sufficient statistical power. In this study, no evidence was found that low-dose chronic exposure affects oxidative DNA damage or mutation rate in P. densiflora. To understand the impact of low-dose chronic radiation exposure on wild plants, further studies incorporating environmental stress and using endpoints other than mutations, such as genome methylation levels and/or responses to oxidative stress, are necessary.

This study presents further research into the spectrum of variants in genes responsible for the development of phenylketonuria (PKU) and hyperphenylalaninemia (HPA) in patients in Russia. After a study of 25 frequent variants, 293 patients (327 chromosomes without detected variants) from among 1265 probands still had no confirmed diagnosis. A study involving methods of next generation sequencing (NGS) of PAH, PTS, GCH1, PCBD1, QDPR, SPR and DNAJC12 genes to search for point mutations and multiplex ligation-dependent probe amplification (MLPA) methods to search for gross deletions were conducted for these patients. Among 327 chromosomes without identified variants, variants in the PAH gene were found on 260 chromosomes, and variants in the PTS gene were found on 10 chromosomes. On 10 chromosomes gross deletions by the MLPA method were detected. 104 rare variants of the РАН gene, including 10 variants not previously described, and 6 variants of the PTS gene were revealed. The NGS method revealed additional РАН gene variants on 10.3% of chromosomes and PTS gene variants on 0.4%. Gross deletions of the РАН gene were revealed in 0.5% of chromosomes. Thus, the most complete understanding of the spectrum of variants leading to the development of the PKU and HPA in Russia with the use of all methods available today has been obtained. Such a detailed study of the spectrum of rare variants on the genetic material from Russia was undertaken for the first time.

Low concentrations of chemicals are widespread in the environment, but exploration of the effects of their chronic exposures on animal life span in the wild is limited. Field investigations showed that fish populations of lake skygazer (Culter dabryi) with chronic low-dose chlorpyrifos loads had shortened telomeres and truncated age structures. Laboratory experiments confirmed that chronic low-dose chlorpyrifos exposure induced telomere degradation and reduced survival in a dose- and physiological age-dependent manner, whereas acute high-dose exposure did not. Together, these studies provide evidence that chronic low-level chlorpyrifos exposure reduces life span and population viability in a wild fish by accelerating physiological aging. Given the pervasive presence of low pesticide concentrations in the environment and the conserved mechanisms of aging across vertebrates, these findings raise concerns that even low doses of pesticides may pose long-term risks to longevity.

Chronic low-dose exposure of nonylphenol alters energy homeostasis in the reproductive system of female rats

The results of mRNA expression of the GATA3, FOXP3, TBX21, STAT3, NFKB1, and MAPK8 transcription factors in peripheral blood cells of 264 residents of the Techa riverside villages of the Chelyabinsk and Kurgan regions, who were affected by chronic low dose-rate exposure in the 1950s, are shown. The range of individual doses to the red bone marrow due to external gamma exposure and 90Sr was 77.8–3507.1 mGy, and the mean dose was 706.3±46.3 mGy. It has been found that changes in the transcriptional response of the cell occur at the molecular level in the long term after chronic exposure. A modified expression of the immunoregulatory genes NFKB1 and MAPK8 in the peripheral blood cells of exposed people was found. A comparative analysis of the interaction of the studied mRNAs demonstrated the presence of a link between the MAPK8 and NFKB1 genes in the group of chronically exposed individuals. The results obtained may indicate the involvement of these transcription factors in the impairment of the immune response in the exposed population.

The recently discovered high-level natural background radiation area (HBRA) of Mamuju in Indonesia provides a unique opportunity to study the biological effects of chronic low-dose radiation exposure on a human population. The mean total effective dose in the HBRA was approximately 69.6 mSv y-1 (range: 47.1 to 115.2 mSv y-1), based on a re-evaluation of the individual radiation exposure dose; therefore, proteomic analyses of serum components and oxidative modification profiling of residents living in the HBRA were reconducted using liquid chromatography-tandem mass spectrometry. The analysis of the oxidative modification sequences of human serum albumin revealed significant moderate correlations between the radiation dose and the modification of 12 sequences, especially the 111th methionine, 162nd tyrosine, 356th tyrosine, and 470th methionine residues. In addition, a dose-dependent variation in 15 proteins of the serum components was detected in the serum of residents exposed to chronic low-dose radiation. These findings suggest that the alterations in the expression of specific proteins and the oxidative modification responses of serum albumin found in exposed humans may be important indicators for considering the effects of chronic low-dose radiation exposure on living organisms, implying their potential utility as biomarkers of radiation dose estimation.

Sequence variants in genes involved in the immune system have previously been linked to neutropenia as well as infections in cancer patients. Sequence variants in genes coding for TLR4, MBL, and IL-1Ra were investigated in relation to clinical utility of identifying severe episodes of febrile neutropenia (FN) in a cohort of children undergoing treatment for acute lymphoblastic leukemia. The study included 122 children, where data on FN and microbiological findings were retrospectively collected from medical records. Sequence variants in genes coding for MBL, TLR4, and IL-1Ra were identified by pyrosequencing, TaqMan SNP genotyping assay, and gel electrophoresis. A total of 380 episodes of FN were identified and in 139 episodes, there was a microbiological defined infection. Age and treatment intensity were all associated with the risk of developing FN. No sequence variant was associated to increased numbers of FN episodes. Two sequence variants in the TLR4 gene increased the risk of viral infection, whilst sequence variants in the IL-1Ra gene were associated to a decreased risk of bacterial blood-stream infection (BSI). The investigated sequence variants did not associate with increased risk for FN or to severe infections, as to why the clinical utility as a risk-stratification tool is low. Most episodes of FN were classified as fever with unknown origin, emphasizing the need for improved microbial detection methods.