Wu Yijen L, Christodoulou Anthony G, Beumer Jan H, Rigatti Lora H, Fisher Renee, Ross Mark, Watkins Simon, Cortes Devin R E, Ruck Cody, Manzoor Shanim, Wyman Samuel K, Stapleton Margaret C, Goetzman Eric, Bharathi Sivakama, Wipf Peter, Tan Tuantuan, Eiseman Julie L, Christner Susan M, Guo Jianxia, Lo Cecilia W Y, Epperly Michael W, Greenberger Joel S
bioRxiv. 2024 Feb 14:2024.02.13.580105. doi: 10.1101/2024.02.13.580105.
Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.
Mitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.
辐射恐怖事件的受害者将包括孕妇和未出生的胎儿。线粒体功能障碍和氧化应激是胎儿辐射损伤的关键致病因素。本临床前研究的目的是探讨母体给予线粒体靶向短杆菌肽S（GS）-氮氧化物辐射缓解剂JP4-039减轻胎儿辐射损伤的疗效。怀孕的雌性C57BL/6NTac小鼠在妊娠中期胚胎第13.5天（E13.5）接受3 Gy全身电离辐射（TBI）。使用新型的时间和运动分辨4D磁共振成像（4D-uMRI），我们发现TBI对胎儿大脑造成了广泛损伤，包括脑出血、脑组织丢失和脑脊液（CSF）过度积聚导致的脑积水。胎儿小鼠大脑的组织病理学显示脑血管破裂和凋亡增加。进一步使用能够探测完整大脑中线粒体功能的新型4D氧小波MRI显示，3 Gy TBI后胎儿大脑中线粒体功能显著降低。这通过奥罗波若斯线粒体呼吸测定法得到验证。TBI后一天（E14.5）母体给予JP4-039，其可穿过胎盘屏障，显著减少胎儿大脑辐射损伤并改善胎儿大脑线粒体呼吸。这也保留了大脑组织的完整性，减少了脑出血和细胞死亡。由于给予JP4-039并未改变窝仔数或胎儿活力，这些发现共同表明JP4-039可作为一种安全有效的缓解剂，用于减轻妊娠中期子宫内电离辐射暴露对胎儿造成的辐射损伤。
线粒体靶向短杆菌肽S（GS）-氮氧化物JP4-039是妊娠中期胎儿辐射损伤的安全有效辐射缓解剂。
