The ICRP, MELODI, and ALLIANCE workshop on effects of ionizing radiation exposure in offspring and next generations: a summary of discussions.

PURPOSE: Task Group 121 - Effects of ionizing radiation exposure in offspring and next generations - is a task group under the Committee 1 of the International Commission on Radiological Protection (ICRP), approved by the Main Commission on 18th November 2021. The main goals of Task Group 121 are to (1) review and update the scientific literature of relevance to radiation-related effects in the offspring of parent(s) exposed to ionizing radiation in both human and non-human biota; (2) to assess preconceptional and intrauterine effects of radiation exposure and related morbidity and mortality; and, (3) to provide advice about the level of evidence and how to consider these preconceptional and postconceptional effects in the system of radiological protection for humans and non-human biota. METHODS: The Task Group is reviewing relevant literature since Publication 90 'Biological effects after prenatal irradiation (embryo and fetus)' (2003) and will include radiation-related effects on future generations in humans, animals, and plants. This review will be conducted to account for the health effects on offspring and subsequent generations in the current system of radiological protection. Radiation detriment calculation will also be reviewed. Finally, preliminary recommendations will be made to update the integration of health effects in offspring and next generations in the system of radiological protection. RESULTS: A Workshop, jointly organized by ICRP Task Group 121 and European Radiation Protection Research Platforms MELODI and ALLIANCE was held in Budapest, Hungary, from 31st May to 2nd June 2022. Participants discussed four important topics: (1) hereditary and epigenetic effects due to exposure of the germ cell line (preconceptional exposure), (2) effects arising from exposure of the embryo and fetus (intrauterine exposure), (3) transgenerational effects on biota, and (4) its potential impact on the system of radiological protection. CONCLUSIONS: Based on the discussions and presentations during the breakout sessions, newer publications, and gaps on the current scientific literature were identified. For instance, there are some ongoing systematic reviews and radiation epidemiology reviews of intrauterine effects. There are newer methods of Monte Carlo simulation for fetal dosimetry, and advances in radiation genetics, epigenetics, and radiobiology studies. While the current impact of hereditary effects on the global detriment was reported as small, the questions surrounding the effects of radiation exposure on offspring and the next generation are crucial, recurring, and with a major focus on exposed populations. This article summarizes the workshop discussions, presentations, and conclusions of each topic and introduces the special issue of the International Journal of Radiation Biology resulting from the discussions of the meeting.

Ionizing radiation exposure effects across multiple generations: evidence and lessons from non-human biota.

A Task Group (TG121) of the International Commission on Radiological Protection (ICRP) Committee 1 was launched in 2021 to study the effects of ionizing radiation in offspring and next generations. In this report, we summarize the evidence of multi- and trans-generational effects in non-human biota species that was discussed at the ICRP workshop entitled "Effects of Ionizing Radiation Exposure in Offspring and Next Generations" in June 2022. Epigenetic changes, including changes in DNA methylation, have been observed in trans- and multi-generational irradiation studies in both plants and animals. There were also reports of changes in offspring survival and reproduction. The reported evidence for altered reproduction is an area of potential concern, due to possible effects at the population or ecosystem level. Different considerations are also discussed regarding non-human biota data, such as transferability of data between different species or extending knowledge to humans, differences in species radiosensitivity, the presence of adaptive responses, and dose reconstruction for exposures that occur across multiple generations. Overall, there is a diverse range of available data of the effects in non-human biota, and it will require careful consideration when incorporating this evidence into the system of radiological protection of humans and of the environment.

Absence of Depressive and Anxious Behavior with Genetic Dysregulation in Adult C57Bl/6J Mice after Prenatal Exposure to Ionizing Radiation.

The exposure of ionizing radiation during early gestation often leads to deleterious and even lethal effects; however, few extensive studies have been conducted on late gestational exposures. This research examined the behavior al effects of C57Bl/6J mouse offspring exposed to low dose ionizing gamma irradiation during the equivalent third trimester. Pregnant dams were randomly assigned to sham or exposed groups to either low dose or sublethal dose radiation (50, 300, or 1000 mGy) at gestational day 15. Adult offspring underwent a behavioral and genetic analysis after being raised under normal murine housing conditions. Our results indicate very little change in the behavioral tasks measuring general anxiety, social anxiety, and stress-management in animals exposed prenatally across the low dose radiation conditions. Quantitative real-time polymerase chain reactions were conducted on the cerebral cortex, hippocampus, and cerebellum of each animal; results indicate some dysregulation in markers of DNA damage, synaptic activity, reactive oxygen species (ROS) regulation, and methylation pathways in the offspring. Together, our results provide evidence in the C57Bl/6J strain, that exposure to sublethal dose radiation (<1000 mGy) during the last period of gestation leads to no observable changes in behaviour when assessed as adults, although some changes in gene expression were observed for specific brain regions. These results indicate that the level of oxidative stress occurring during late gestation for this mouse strain is not sufficient for a change in the assessed behavioral phenotype, but results in some modest dysregulation of the genetic profile of the brain.

Lasting Effects of Low to Non-Lethal Radiation Exposure during Late Gestation on Offspring's Cardiac Metabolism and Oxidative Stress.

Ionizing radiation (IR) is known to cause fetal programming, but the physiological effects of low-dose IR are not fully understood. This study examined the effect of low (50 mGy) to non-lethal (300 and 1000 mGy) radiation exposure during late gestation on cardiac metabolism and oxidative stress in adult offspring. Pregnant C57BL/6J mice were exposed to 50, 300, or 1000 mGy of gamma radiation or Sham irradiation on gestational day 15. Sixteen weeks after birth, 18F-Fluorodeoxyglucose (FDG) uptake was examined in the offspring using Positron Emission Tomography imaging. Western blot was used to determine changes in oxidative stress, antioxidants, and insulin signaling related proteins. Male and female offspring from irradiated dams had lower body weights when compared to the Sham. 1000 mGy female offspring demonstrated a significant increase in 18F-FDG uptake, glycogen content, and oxidative stress. 300 and 1000 mGy female mice exhibited increased superoxide dismutase activity, decreased glutathione peroxidase activity, and decreased reduced/oxidized glutathione ratio. We conclude that non-lethal radiation during late gestation can alter glucose uptake and increase oxidative stress in female offspring. These data provide evidence that low doses of IR during the third trimester are not harmful but higher, non-lethal doses can alter cardiac metabolism later in life and sex may have a role in fetal programming.

Cardiovascular and growth outcomes of C57Bl/6J mice offspring exposed to maternal stress and ionizing radiation during pregnancy.

Purpose: Developmental programming involves an adverse intrauterine environment which can result in offspring phenotype changes following birth. The developmental programming of hypertension has been reported to possibly involve oxidative stress at the cellular level. Ionizing radiation produces oxidative stress, even at low doses, and irradiation of animals is often coupled with potential sources of maternal stress such as transportation of animals or repeated handling. Materials and methods: Pregnant C57Bl/6J mice were irradiated on gestational day 15 with 5-1000 mGy 137Cs gamma radiation. Post-natal weight, blood pressure (BP) and heart rate (HR) were measured. Radiation had minimal effects at doses ≤300 mGy, but 1000 mGy caused a significant reduction in HR in male pups and growth reduction at 16 weeks of age in both genders. The sham-irradiation protocol included repeated transportation in order to acclimate animals to transport. However, it may have resulted in programming, as sham-irradiation alone resulted in elevated BP measures compared to the offspring of animals that were never transported. Results and conclusions: Overall, there were minimal effects on cardiovascular measures or offspring weight due to irradiation except at 1000 mGy. The presence of maternal stress, a known trigger of developmental programming, may have confounded any potential irradiation effects.

Re-evaluation of the linear no-threshold (LNT) model using new paradigms and modern molecular studies.

The linear no-threshold (LNT) model is currently used to estimate low dose radiation (LDR) induced health risks. This model lacks safety thresholds and postulates that health risks caused by ionizing radiation is directly proportional to dose. Therefore even the smallest radiation dose has the potential to cause an increase in cancer risk. Advances in LDR biology and cell molecular techniques demonstrate that the LNT model does not appropriately reflect the biology or the health effects at the low dose range. The main pitfall of the LNT model is due to the extrapolation of mutation and DNA damage studies that were conducted at high radiation doses delivered at a high dose-rate. These studies formed the basis of several outdated paradigms that are either incorrect or do not hold for LDR doses. Thus, the goal of this review is to summarize the modern cellular and molecular literature in LDR biology and provide new paradigms that better represent the biological effects in the low dose range. We demonstrate that LDR activates a variety of cellular defense mechanisms including DNA repair systems, programmed cell death (apoptosis), cell cycle arrest, senescence, adaptive memory, bystander effects, epigenetics, immune stimulation, and tumor suppression. The evidence presented in this review reveals that there are minimal health risks (cancer) with LDR exposure, and that a dose higher than some threshold value is necessary to achieve the harmful effects classically observed with high doses of radiation. Knowledge gained from this review can help the radiation protection community in making informed decisions regarding radiation policy and limits.

Clinical utility of endomyocardial biopsies in the diagnosis of arrhythmogenic right ventricular cardiomyopathy in children.

BACKGROUND: Histomorphometry of endomyocardial biopsies is one component of arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis, although there is a need for stricter diagnostic criteria for this disease in pediatrics. The clinical utility of biopsy analysis as a component of ARVC diagnosis was evaluated in pediatric patients. METHODS: Histomorphometric analysis of fibrofatty infiltrate was completed on pediatric right ventricular endomyocardial biopsy samples. Myocardial replacement by fat and fibrosis was quantified. ARVC diagnosis was established using the 2010 ARVC Task Force criteria, with the biopsy measures compared across various ARVC diagnoses (definite, borderline, possible, or no ARVC). Receiver-operating characteristic (ROC) curve analysis was also completed using biopsy measures. RESULTS: The greatest proportion of fat, fibrosis, and myocardial replacement was in the definite ARVC cohort, and was significantly larger than for the other diagnosis cohorts. ROC curve analysis (with the biopsy analysis removed from the diagnostic classification) produced cutoff values of 15 and 25% myocardial replacement, which is lower than current adult diagnosis criteria. CONCLUSION: We propose modifications in pediatric major and minor biopsy diagnosis criteria to allow for improved sensitivity. This study suggests that biopsy analysis in children is most significant for subjects with a more severe disease presentation.

Micronuclei formation in rainbow trout cells exposed to multiple stressors: Morpholine, heat shock, and ionizing radiation.

Discharges from industrial cooling water systems can include low levels of morpholine (a chemical pH regulator and corrosion inhibitor), as well as transiently higher temperature effluent water which present a potential source of environmental impact to aquatic biota. The effects of environmental levels of morpholine or heat shock (HS) treatment alone and in combination with a challenge high-dose of 137Cs ionizing radiation were studied using the cytokinesis block micronucleus assay in a rainbow trout cell line (RTG-2). Morpholine treatment of 10 or 100mgL-1 alone produced no significant effects, and no interaction was observed in combination with 7.75Gy radiation. A 9°C magnitude HS treatment alone significantly increased micronuclei formation. A synergistic response was observed when 9°C HS was combined with 7.75Gy radiation, with 15% more cells containing 3 or more micronuclei than the sum of each individual stressor. A synergistic increase in the average number of micronuclei was observed when morpholine and a 9°C HS were co-treated. These results indicate that morpholine at environmentally-relevant levels does not impact micronuclei formation or cell cycle progression however 9°C HS may be of potential concern both alone and in combination with other stressor treatments.

Low-Dose Ionizing Radiation Exposure, Oxidative Stress and Epigenetic Programing of Health and Disease.

Ionizing radiation exposure from medical diagnostic imaging has greatly increased over the last few decades. Approximately 80% of patients who undergo medical imaging are exposed to low-dose ionizing radiation (LDIR). Although there is widespread consensus regarding the harmful effects of high doses of radiation, the biological effects of low-linear energy transfer (LET) LDIR is not well understood. LDIR is known to promote oxidative stress, however, these levels may not be large enough to result in genomic mutations. There is emerging evidence that oxidative stress causes heritable modifications via epigenetic mechanisms (DNA methylation, histone modification, noncoding RNA regulation). These epigenetic modifications result in permanent cellular transformations without altering the underlying DNA nucleotide sequence. This review summarizes the major concepts in the field of epigenetics with a focus on the effects of low-LET LDIR (<100 mGy) and oxidative stress on epigenetic gene modification. In this review, we show evidence that suggests that LDIR-induced oxidative stress provides a mechanistic link between LDIR and epigenetic gene regulation. We also discuss the potential implication of LDIR exposure during pregnancy where intrauterine fetal development is highly susceptible to oxidative stress-induced epigenetic programing.

Ionizing Radiation Exposure During Pregnancy: Effects on Postnatal Development and Life.

Reliable human data on the effects of prenatal exposure to ionizing radiation are largely based on high-dose exposures. Exposure to low doses may produce effects that are not easily observable at birth, and may persist over the course of the offspring's postnatal life. This is important when considering fetal programing, a phenomenon characterized by changes in offspring phenotype due to a stress experienced in utero. In this review, we briefly summarize the known effects of both high- and low-dose exposure to ionizing radiation during pregnancy in humans. There is a major consensus that the atomic bomb survivors' data shows increased incidence of microcephaly and reductions in IQ of A-bomb survivors, whereas, with diagnostic radiography in utero there is no conclusive evidence of increased cancer risk. Due to the relatively limited data (particularly for low-dose exposures) in humans, animal models have emerged as an important tool to study prenatal effects of radiation. These animal models enable researchers to manipulate various experimental parameters and make it possible to analyze a wider variety of end points. In this review, we discuss the major findings from studies using mouse and rat models to examine prenatal ionizing radiation effects in postnatal development of the offspring. In addition, we broadly categorize trends across studies within three major stages of development: pre-implantation, organogenesis and fetal development. Overall, long-term effects of prenatal radiation exposure (including the possible role on the developmental programing of disease) are important factors to consider when assessing radiation risk, since these effects are of relevance even in the low-dose range.

Developmental effects of the industrial cooling water additives morpholine and sodium hypochlorite on lake whitefish (Coregonus clupeaformis).

Chemicals used in the prevention of corrosion and biofouling may be released into the environment via industrial cooling water discharges. The authors assessed the impacts of 2 commonly used chemicals, morpholine and sodium hypochlorite, on development in lake whitefish (Coregonus clupeaformis). Embryos were exposed chronically, beginning at fertilization or at the eyed stage. Acute 96-h exposures were also examined at 4 development stages. Chronic morpholine resulted in median lethal concentrations (LC50s) of 219 ± 54 mg/L when exposure began at fertilization and 674 ± 12 mg/L when exposure began at the eyed stage, suggesting that embryos are more sensitive earlier in development. Chronic morpholine exposure advanced hatching by up to 30%, and the early hatching embryos were up to 10% smaller in body length. A decrease in yolk conversion efficiency was also observed in embryos exposed to chronic morpholine concentrations of 1000 mg/L. The majority of effects from morpholine exposure manifested near hatch, possibly reflecting changes in chorion permeability at the end of embryonic development. Sodium hypochlorite only impacted survival with chronic exposure from fertilization, where the total residual chlorine LC50 was 0.52 ± 0.11 mg/L. Acute exposures to both chemicals had minimal effects up to the highest tested concentrations. Overall, the results suggest that the risk during development from exposure to morpholine and sodium hypochlorite is low under normal operating conditions. Environ Toxicol Chem 2017;36:1955-1965. © 2016 SETAC.