{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:55:20Z","timestamp":1791248120509,"version":"4.1.0"},"reference-count":83,"publisher":"Radiation Research Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2024,7,30]]},"abstract":"<jats:p>Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation 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 irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D in utero 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 in vivo mitochondrial function in intact brain revealed a significant reduction of mitochondrial function in the fetal brain after 3 Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. One day after TBI (E14.5) maternal administration of JP4-039, which passes through the placenta, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. Treatment also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. JP4-039 administration following irradiation resulted in increased survival of pups. These findings indicate that JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.<\/jats:p>","DOI":"10.1667\/rade-24-00095.1","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T20:01:16Z","timestamp":1722283276000},"page":"565-579","source":"Crossref","is-referenced-by-count":6,"title":["Mitigation of Fetal Radiation Injury from Mid-Gestation Total-body Irradiation by Maternal Administration of Mitochondrial-Targeted GS-Nitroxide JP4-039"],"prefix":"10.1667","volume":"202","author":[{"given":"Yijen L.","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony G.","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.","family":"Beumer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lora H.","family":"Rigatti","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Resources (DLAR), University of Pittsburgh, Pittsburgh, Pennsylvania 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin R. E.","family":"Cortes","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Ruck","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanim","family":"Manzoor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel K.","family":"Wyman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret C.","family":"Stapleton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Goetzman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakama","family":"Bharathi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wipf","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuantuan","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Christner","sequence":"additional","affiliation":[{"name":"Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxia","family":"Guo","sequence":"additional","affiliation":[{"name":"Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia W. Y.","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Epperly","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel S.","family":"Greenberger","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"10","doi-asserted-by":"crossref","unstructured":"MVC Greenberg, J Glaser, M Borsos, et al.  \"Nat Genet.\"  49, \"Transient transcription in the early embryo sets an epigenetic state that programs postnatal growth.\" 110 (2017)","DOI":"10.1038\/ng.3718"},{"key":"72","doi-asserted-by":"crossref","unstructured":"E Khodamoradi, M Hoseini-Ghahfarokhi, P Amini, et al.  \"Cell Mol Life Sci.\"  77, \"Targets for protection and mitigation of radiation injury.\" 3129 (2020)","DOI":"10.1007\/s00018-020-03479-x"},{"key":"69","doi-asserted-by":"crossref","unstructured":"LB Russell  and WL Russell  \"J Cell Physiol Suppl.\"  43, \"An Analysis Of The Changing Radiation Response Of The Developing Mouse Embryo.\" 103 (1954)","DOI":"10.1002\/jcp.1030430407"},{"key":"81","doi-asserted-by":"crossref","unstructured":"MW Epperly, T Smith, X Zhang, et al.  \"Gene Ther.\"  18, \"Modulation Of In Utero Total Body Irradiation Induced Newborn Mouse Growth Retardation By Maternal Manganese Superoxide Dismutase-Plasmid Liposome (Mnsod-PL) Gene Therapy.\" 579 (2011)","DOI":"10.1038\/gt.2010.178"},{"key":"44","doi-asserted-by":"crossref","unstructured":"MW Epperly, T Smith, X Zhang, et al.  \"Gene Ther.\"  18, \"Modulation Of In Utero Total Body Irradiation Induced Newborn Mouse Growth Retardation By Maternal Manganese Superoxide Dismutase-Plasmid Liposome (Mnsod-PL) Gene Therapy.\" 579 (2011)","DOI":"10.1038\/gt.2010.178"},{"key":"41","doi-asserted-by":"crossref","unstructured":"J Steinman, M Epperly, W Hou, et al.  \"Radiat Res.\"  189, \"Improved total-body irradiation survival by delivery of two radiation mitigators that target distinct cell death pathways.\" 68 (2018)","DOI":"10.1667\/RR14787.1"},{"key":"6","doi-asserted-by":"crossref","unstructured":"S Sreetharan, C Thome, S Tharmalingam, et al.  \"Radiat Res.\"  187, \"Ionizing radiation exposure during pregnancy: Effects on postnatal development and life.\" 647 (2017)","DOI":"10.1667\/RR14657.1"},{"key":"5","doi-asserted-by":"crossref","unstructured":"T Verreet, M Verslegers, R Quintens, et al.  \"Neural Plast.\"  2016, \"Current evidence for developmental, structural, and functional brain defects following prenatal radiation exposure.\" 1243527 (2016)","DOI":"10.1155\/2016\/1243527"},{"key":"22","doi-asserted-by":"crossref","unstructured":"RL. 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