SEARCHRCTradiation biology, neurology

RCT·radiation biology, neurology, orthopedics, animal science, oxidative stress·PMC10779003

Delayed Reaction of Radiation on the Central Nervous System and Bone System in C57BL/6J Mice

International Journal of Molecular Sciences · 12 authors, 1 centre

AI SUMMARY

FIDELITY 88%

POPULATIONMale C57BL/6J mice (20 ± 2 g)

INTERVENTIONSingular total body irradiation (5 Gy at 109 cGy/min) or fractional total body irradiation (5 Gy × 2, 30 days apart, cumulative 10 Gy)

COMPARISONNon-irradiated control group

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This study shows that both singular (5 Gy) and fractional (10 Gy) total body irradiation in C57BL/6J mice cause delayed cognitive and motor deficits, with the fractional dose leading to irreversible damage. The mechanisms involve DNA damage-induced oxidative stress and apoptosis, downregulation of BDNF and Tau in the brain, and increased osteoclast activity with reduced RUNX2, sclerostin, and β-catenin in bone. The fractional 10 Gy model provides a stable platform for studying multi-organ radiation injury and testing anti-radiation therapies.

Full summary

2,516 CHARS

**Background:** Ionizing radiation (IR) is widely used in medicine, but delayed reactions—occurring weeks to months after exposure—remain poorly understood. This study aimed to establish a mouse model of delayed radiation injury to the central nervous system and bone, and to identify underlying mechanisms.

**Methods:** Male C57BL/6J mice were divided into three groups (n=7 each): control (no irradiation), singular 5 Gy total body irradiation (TBI), and fractional 10 Gy TBI (5 Gy × 2, 30 days apart). Sixty days after the first exposure, behavior was assessed using the open field test (OFT) and Morris water maze (MWM). Brain and femur tissues were collected for histology (HE, Nissl, TRAP staining), micro-CT scanning, RNA sequencing (RNA-Seq), and Western blot analysis of key proteins.

**Key Results:** - **Behavior:** Both IR groups showed reduced activity and spatial memory. The singular 5 Gy group partially recovered over time, while the fractional 10 Gy group did not. - **Brain:** HE and Nissl staining revealed neuronal damage (loose arrangement, crinkled neurons, necrosis) in the hippocampal dentate gyrus, especially in the fractional 10 Gy group. RNA-Seq identified 540 DEGs in the singular group (252 up, 288 down) and 438 DEGs in the fractional group (138 up, 300 down). Downregulated genes were enriched in neuron differentiation and calcium transport; upregulated genes were linked to immune/inflammatory responses. Western blot confirmed increased γH2AX (DNA damage), decreased BDNF and increased p-Tau (cognition), reduced Nrf2 and HO-1 (oxidative stress), and increased p53, bax, and caspase3 (apoptosis). - **Bone:** Micro-CT showed decreased trabecular bone volume (BV/TV) and bone mineral density (BMD) in the fractional 10 Gy group, with reduced trabecular number and increased spacing. TRAP staining revealed significantly more osteoclasts in irradiated groups. Western blot showed reduced RUNX2, sclerostin, and β-catenin (osteogenesis), along with increased oxidative stress and apoptosis markers.

**Clinical Implications:** This study demonstrates that delayed radiation injury involves persistent oxidative stress and apoptosis driven by DNA damage, leading to cognitive decline and bone loss. The fractional 10 Gy TBI model produces stable, multi-organ damage and is suitable for screening anti-radiation drugs. These findings highlight the need for long-term monitoring and therapeutic strategies targeting oxidative stress and apoptosis in patients undergoing radiotherapy.

PICO

PPOPULATION

Male C57BL/6J mice (20 ± 2 g)

IINTERVENTION

Singular total body irradiation (5 Gy at 109 cGy/min) or fractional total body irradiation (5 Gy × 2, 30 days apart, cumulative 10 Gy)

OOUTCOME

Spatial memory (MWM), activity (OFT), brain histopathology (HE, Nissl), bone microarchitecture (micro-CT), osteoclast number (TRAP), expression of DNA damage, oxidative stress, apoptosis, and bone/cognition-related proteins (WB, RNA-Seq)

STUDY TYPE

RCT

SPECIALTY

radiation biology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

88% · B

ORIGINAL PAPER

PMC10779003

Delayed Reaction of Radiation on the Central Nervous System and Bone System in C57BL/6J Mice

International Journal of Molecular Sciences

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ABSTRACT

The aim of this study was to provide a suitable mouse model of radiation-induced delayed reaction and identify potential targets for drug development related to the prevention and treatment of radiation injury. C57BL/6J mice were subjected to singular (109 cGy/min, 5 Gy*1) and fractional (109 cGy/min, 5 Gy*2) total body irradiation. The behavior and activity of mice were assessed 60 days after ionizing radiation (IR) exposure. After that, the pathological changes and mechanism of the mouse brain and femoral tissues were observed by HE, Nissl, Trap staining micro-CT scanning and RNA sequencing (RNA-Seq), and Western blot. The results show that singular or fractional IR exposure led to a decrease in spatial memory ability and activity in mice, and the cognitive and motor functions gradually recovered after singular 5 Gy IR in a time-dependent manner, while the fractional 10 Gy IR group could not recover. The decrease in bone density due to the increase in osteoclast number may be relative to the down-regulation of RUNX2, sclerostin, and beta-catenin. Meanwhile, the brain injury caused by IR exposure is mainly linked to the down-regulation of BNDF and Tau. IR exposure leads to memory impairment, reduced activity, and self-recovery, which are associated with time and dose. The mechanism of cognitive and activity damage was mainly related to oxidative stress and apoptosis induced by DNA damage. The damage caused by fractional 10 Gy TBI is relatively stable and can be used as a stable multi-organ injury model for radiation mechanism research and anti-radiation medicine screening.

CITATION EXPORT

Yi Ru, Xianxie Zhang, Baoying Shen et al.. Delayed Reaction of Radiation on the Central Nervous System and Bone System in C57BL/6J Mice. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms25010337

AUTHORS

12 · 1 CENTRES

Yi Ru, Xianxie Zhang, Baoying Shen, Chunqi Yang, Huijing Yu, Zuoxu Liu, Xiangjun Wu, Fangyang Li, Jialu Cui, Chengcai Lai, Yuguang Wang, Yue Gao

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; [email protected] (Y.R.); [email protected] (X.Z.); [email protected] (B.S.); [email protected] (C.Y.); [email protected] (H.Y.); [email protected] (Z.L.); [email protected] (X.W.); [email protected] (F.L.); [email protected] (J.C.); [email protected] (C.L.)

EDITOR / REVIEWER

Alvaro Galli