Dataset Information

Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation.

ABSTRACT: High levels of ionizing radiation (IR) are known to induce neurogenesis defects with harmful consequences on brain morphogenesis and cognitive functions, but the effects of chronic low to moderate dose rates of IR remain largely unknown. In this study, we aim at defining the main molecular pathways impacted by IR and how these effects can translate to higher organizational levels such as behavior. Adult zebrafish were exposed to gamma radiation for 36 days at 0.05 mGy/h, 0.5 mGy/h and 5 mGy/h. RNA sequencing was performed on the telencephalon and completed by RNA in situ hybridization that confirmed the upregulation of oxytocin and cone rod homeobox in the parvocellular preoptic nucleus. A dose rate-dependent increase in differentially expressed genes (DEG) was observed with 27 DEG at 0.05 mGy/h, 200 DEG at 0.5 mGy/h and 530 DEG at 5 mGy/h. Genes involved in neurotransmission, neurohormones and hypothalamic-pituitary-interrenal axis functions were specifically affected, strongly suggesting their involvement in the stress response behavior observed after exposure to dose rates superior or equal to 0.5 mGy/h. At the individual scale, hypolocomotion, increased freezing and social stress were detected. Together, these data highlight the intricate interaction between neurohormones (and particularly oxytocin), neurotransmission and neurogenesis in response to chronic exposure to IR and the establishment of anxiety-like behavior.

SUBMITTER: Cantabella E

PROVIDER: S-EPMC9367516 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation.

Cantabella Elsa E Camilleri Virginie V Cavalie Isabelle I Dubourg Nicolas N Gagnaire Béatrice B Charlier Thierry D TD Adam-Guillermin Christelle C Cousin Xavier X Armant Oliver O

Cancers 20220804 15

High levels of ionizing radiation (IR) are known to induce neurogenesis defects with harmful consequences on brain morphogenesis and cognitive functions, but the effects of chronic low to moderate dose rates of IR remain largely unknown. In this study, we aim at defining the main molecular pathways impacted by IR and how these effects can translate to higher organizational levels such as behavior. Adult zebrafish were exposed to gamma radiation for 36 days at 0.05 mGy/h, 0.5 mGy/h and 5 mGy/h. R ...[more]

PMID: 35954455

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Project description:Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses.

Project description:Following nuclear accidents and the increasing use of radionuclides, environmental radiation radiological protection is a source of major concern, particularly in the context of low doses. Ionizing radiation (IR) may lead to genetic mutations, chromosomal rearrangements and epigenetic modifications. The present study focuses on the in vivo effects of low to moderate doses of IR on zebrafish early embryonic development. The effects of IR on the transcriptome were studied at the shield stage (6 hours post-fertilization, hpf) and at dose rates from 50 mGy/h to 0.005 mGy/h. The effects on the methylome by whole genome bisulfite sequencing were investigated at the same stage and at dose rates of 50 mGy/h and 5 mGy/h.IR exposure impacted the expression of genes involved in germ layers specification during gastrulation of zebrafish embryos. Moreover, changes in mitochondrial energetic metabolism were detected at all dose rates. Different transcriptomic responses were observed between groups irradiated at the two highest dose rates, 50 mGy/h and 5 mGy/h and those irradiated at the three lower dose rates. However, the transcriptomic analysis revealed an impact of IR on development, neurogenesis and muscular development at 50 mGy/h, 5 mGy/h and 0.5 mGy/h. The global level of methylation was not changed after exposure to IR, and no widespread changes in transposable elements were detected. Rather, we observed that IR induced loci specific demethylation in the promoter of genes involved in development, neurogenesis and myogenesis. Interestingly, this promoter hypomethylation was equally associated with a change in gene expression. In this study, both DMR and gene expression analysis pointed toward a specific deregulation of genes involved in development, neurogenesis and myogenesis. The modification of the methylation pattern in promoters of genes involved in central nervous system development and muscle development seems to be responsible of transcriptomic changes. This study confirms previous results obtained at later developmental stages, showing that neurogenesis and muscle development were also impacted at 50 mGy/h, 5 mGy/h and 0.5 mGy/h with phenotypic alterations in terms of muscle histology and swimming behaviour. This suggests that early developmental perturbations are predictive of functional defects at later developmental stages.

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Dataset Information

Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation.

Publications

Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation.

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