A biologically based mathematical model for spontaneous and ionizing radiation cataractogenesis

Sakashita, Tetsuya; Sato, Tatsuhiko; Hamada, Nobuyuki

doi:10.1371/journal.pone.0221579

Cited by 12 publications

(6 citation statements)

References 52 publications

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“…The long-term goal of this project is to develop a biophysical model for predicting cataractogenesis considering dose-rate effects. To date, the existing model for reproducing cataractogenesis allows the prediction of a relationship between dose and cataract onset at various ages 24 . Ideally, replacing the DNA repair obtained in this study would make the model more accurate.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, Sakashita et al . proposed the first biophysical model for human cataractogenesis that allows the prediction of a relationship between radiation dose and cataract onset at various ages 24 , with the model parameters (e.g., DNA damage and repair) optimized to reproduce the Beaver Dam Eye Study data 25 . For more developments, a mechanistic model with the model parameters based on actually measured biological data would be required, and in this regard, the IMK model analysis using in vitro HLEC data is a powerful approach for the study on dose-rate effects.…”

Section: Introductionmentioning

confidence: 99%

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The impact of dose rate on responses of human lens epithelial cells to ionizing irradiation

Matsuya,

Sato,

Yachi

et al. 2024

Sci Rep

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The knowledge on responses of human lens epithelial cells (HLECs) to ionizing radiation exposure is important to understand mechanisms of radiation cataracts that are of concern in the field of radiation protection and radiation therapy. However, biological effects in HLECs following protracted exposure have not yet fully been explored. Here, we investigated the temporal kinetics of γ-H2AX foci as a marker for DNA double-strand breaks (DSBs) and cell survival in HLECs after exposure to photon beams at various dose rates (i.e., 150 kVp X-rays at 1.82, 0.1, and 0.033 Gy/min, and 137Cs γ-rays at 0.00461 Gy/min (27.7 cGy/h) and 0.00081 Gy/min (4.9 cGy/h)), compared to those in human lung fibroblasts (WI-38). In parallel, we quantified the recovery for DSBs and cell survival using a biophysical model. The study revealed that HLECs have a lower DSB repair rate than WI-38 cells. There is no significant impact of dose rate on cell survival in both cell lines in the dose-rate range of 0.033–1.82 Gy/min. In contrast, the experimental residual γ-H2AX foci showed inverse dose rate effects (IDREs) compared to the model prediction, highlighting the importance of the IDREs in evaluating radiation effects on the ocular lens.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The impact of dose rate on responses of human lens epithelial cells to ionizing irradiation

Matsuya,

Sato,

Yachi

et al. 2024

Sci Rep

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“…For cancer, integration of epidemiology and biology has long been discussed (246,247), and epidemiological data have been applied to several biologically based mechanistic models (248,249). The integrative approach would also indeed be needed for cataracts (250), DCS (247) and other noncancer effects, but such studies are very limited, e.g., for cataracts (251) and DCS (252)(253)(254)(255). To this end, developments of biologically based dose response (BBDR) models would be critical to enhance the risk assessment process (by reducing uncertainty in risk estimates at low dose and low dose rate), and developments of adverse outcome pathways (AOPs) would be required to determine BBDR model parameters (247).…”

Section: Integration Of Epidemiology and Biologymentioning

confidence: 99%

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

Hamada

2023

Radiation Research

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For radiation protection purposes, noncancer effects with a threshold-type dose-response relationship have been classified as tissue reactions (formerly called nonstochastic or deterministic effects), and equivalent dose limits aim to prevent occurrence of such tissue reactions. Accumulating evidence demonstrates increased risks for several late occurring noncancer effects at doses and dose rates much lower than previously considered. In 2011, the International Commission on Radiological Protection (ICRP) issued a statement on tissue reactions to recommend a threshold of 0.5 Gy to the lens of the eye for cataracts and to the heart and brain for diseases of the circulatory system (DCS), independent of dose rate. Literature published thereafter continues to provide updated knowledge. Increased risks for cataracts below 0.5 Gy have been reported in several cohorts (e.g., including in those receiving protracted or chronic exposures). A dose threshold for cataracts is less evident with longer follow-up, with limited evidence available for risk of cataract removal surgery. There is emerging evidence for risk of normal-tension glaucoma and diabetic retinopathy, but the long-held tenet that the lens represents among the most radiosensitive tissues in the eye and in the body seems to remain unchanged. For DCS, increased risks have been reported in various cohorts, but the existence or otherwise of a dose threshold is unclear. The level of risk is less uncertain at lower dose and lower dose rate, with the possibility that risk per unit dose is greater at lower doses and dose rates. Target organs and tissues for DCS are also unknown, but may include heart, large blood vessels and kidneys. Identification of potential factors (e.g., sex, age, lifestyle factors, coexposures, comorbidities, genetics and epigenetics) that may modify radiation risk of cataracts and DCS would be important. Other noncancer effects on the radar include neurological effects (e.g., Parkinsonŉs disease and dementia) of which elevated risk has increasingly been reported. These late occurring noncancer effects tend to deviate from the definition of tissue reactions, necessitating more scientific developments to reconsider the radiation effect classification system and risk management. This paper gives an overview of historical developments made in ICRP prior to the 2011 statement and an update on relevant developments made since the 2011 ICRP statement.

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“…Neural connectivity in the ABM is established using a network of directed links through which agents send inhibitory signal to one another. A stochastic Damage Accumulation: Damage accumulation models (also known as damage-repair models) are used to describe the effects of stressors over time on the health of biological systems [36,37,38]. Previously, a pilot damage accumulation model was used to simulate the impact of noxious, external stimulations on the sensitization of excited and inhibited neurons in the CeA [10].…”

Section: Purpose and Basic Principlesmentioning

confidence: 99%

Agent-based modeling of the central amygdala and pain using cell-type specific physiological parameters

et al. 2021

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The amygdala is a brain area involved in emotional regulation and pain. Over the course of the last 20 years, multiple researchers have studied sensory and motor connections within the amygdala in trying to understand the ultimate role of this structure in pain perception and descending control of pain. A number of investigators have been using cell-type specific manipulations to probe the underlying circuitry of the amygdala. As data have accumulated in this research space, we recognized a critical need for a single framework to integrate these data and evaluate emergent system-level responses. In this manuscript, we present an agent-based computational model of two distinct inhibitory neuron populations in the amygdala, those that express protein kinase C delta (PKCδ) and those that express somatostatin (SOM). We utilized a network of neural links to simulate connectivity and the transmission of inhibitory signals between neurons. Type-specific parameters describing the response of these neurons to noxious stimuli were estimated from published physiological and immunological data as well as our own wet-lab experiments. The model outputs an abstract measure of pain, which is calculated in terms of the cumulative pro-nociceptive and anti-nociceptive activity across neurons in both hemispheres of the amygdala. Results demonstrate the ability of the model to produce changes in pain that are consistent with published studies and highlight the importance of several model parameters. In particular, we found that the relative proportion of PKCδ and SOM neurons within each hemisphere is a key parameter in predicting pain and we explored model predictions for three possible values of this parameter. We compared model predictions of pain to data from our earlier behavioral studies and found areas of similarity as well as distinctions between the data sets. These differences, in particular, suggest a number of wet-lab experiments that could be done in the future.

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A biologically based mathematical model for spontaneous and ionizing radiation cataractogenesis

Cited by 12 publications

References 52 publications

The impact of dose rate on responses of human lens epithelial cells to ionizing irradiation

The impact of dose rate on responses of human lens epithelial cells to ionizing irradiation

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

Agent-based modeling of the central amygdala and pain using cell-type specific physiological parameters

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