Abstract
Prenatal brain development is a complex and sensitive process, highly susceptible to environmental influences such as pollutants, stress, malnutrition, drugs, tobacco exposure, or ionizing radiation (IR). Disturbances in development may cause life-long disabilities and diseases, such as ADHD, childhood cancers, cognitive problems, depression, anxiety and more severe developmental disabilities. Due to increasing medical imaging, radiation therapy, natural terrestrial radiation, radioactive pollution and long-distance flights, humans are increasingly exposed to IR. However, data on impact of IR on very early human brain development are scarce, particularly in the very first weeks of gestation. Here we investigated the effects of low-dose X-ray IR (1 Gy) in a 3D early brain developmental model derived from human pluripotent stem cells. In this model very early neural stem cells, neuroectodermal progenitor cells (NEP), were exposed to low-dose IR and direct as well as delayed effects were investigated. Expression of 20 different marker genes crucial for normal neural development was determined 48 h and 9 days post IR (pIR). All but one of the analyzed marker genes were reduced 48 h after IR, and all but seven genes normalized their expression by day 9 pIR. Among the seven markers were genes involved in neurodevelopmental and growth abnormalities. Moreover, we could show that stemness of the NEP was reduced after IR. We were thus able to identify a significant impact of radiation in cells surviving low-dose IR, suggesting that low-dose IR could have a negative impact on the early developing human brain, with potential later detrimental effects.
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Acknowledgements
This work was supported by Grant 02NUK025B from the German Ministry for Education and Research (BMBF), AK and ES were supported by the InViTe PhD program from the Baden-Wuerttemberg Ministry for Science, Research and Art (MWK Baden-Württemberg). We also thank George Daley, Harvard Medical School/Children’s Hospital Boston, for providing the human iPSC, and Maria Moreno-Villanueva and Thilo Sindlinger, University of Konstanz, for very helpful input with the irradiation experiments.
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Klatt, A., Salzmann, E., Schneider, LJ. et al. Toxicity of ionizing radiation (IR) in a human induced pluripotent stem cell (hiPSC)-derived 3D early neurodevelopmental model. Arch Toxicol 93, 2879–2893 (2019). https://doi.org/10.1007/s00204-019-02553-z
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DOI: https://doi.org/10.1007/s00204-019-02553-z