Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC–MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells.

关于人类产前长期暴露于低剂量 (LD) 电离辐射的影响的可靠数据缺失。人们担心不利的长期影响可能会持续到后代的整个出生后生活。由于其缓慢的细胞周期动力学和在生物体中的终生停留时间，间充质干细胞 (MSC) 更容易受到外源性多重 LD 事件引起的低水平遗传毒性应激。本研究的目的是调查产前慢性 LD 伽马射线照射对 MSC 日后生物学的影响。 C3H 小鼠在子宫内接受 10 mGy/天的慢性产前照射，持续 3 周。两年后，从骨髓中分离出间充质干细胞，并在体外分析其放射敏感性、细胞衰老以及第二次急性伽玛射线照射后的 DNA 双链断裂识别。除了这些细胞测定之外，还使用 ​​HPLC-MS/MS 测量蛋白质表达的变化，并使用生物信息学识别失调的分子信号传导途径。与未受辐射的对照组相比，我们观察到子宫内受辐射小鼠后代的 MSC 中辐射诱导的蛋白质组变化（导致所有检测到的蛋白质中约 9.4% 上调或下调）。蛋白质组变化与细胞外基质、氧化应激反应和 Wnt 信号通路相关的调节通路相关。此外，慢性产前 LD 照射会导致生命后期体外辐射诱导的衰老率增加，并导致 4 Gy 照射后残留 DNA 双链断裂数量增加，这表明体内辐射与第二次急性剂量的体外辐射。 这项研究首次深入了解产前电离辐射暴露造成的持续性 MSC 损伤反应的分子机制，并将有助于预测干细胞临床应用的治疗安全性和有效性。