3,3'-diindolylmethane mitigates total body irradiation-induced hematopoietic injury in mice.
We have reported that hematopoietic system injury induced by total body irradiation (TBI) leads to generation of intracellular reactive oxygen species (ROS) and DNA damage, which are ameliorated by antioxidant agents. In the present study, we reported that administration of DIM, a potent antioxidant agent, not only protected mice against TBI-induced lethality, also ameliorated TBI-induced hematopoietic injury. The latter effect was probably attributable to DIM's inhibition of TBI-induced increases in ROS production in hematopoietic stem cells (HSCs) and the phosphorylation of histone H2AX (γ-H2AX). In particular, DIM led to significant improvements in bone marrow (BM) HSC frequency, hematopoietic progenitor cell (HPC) clonogenic function, and multilineage engraftment after transplantation. A downregulation of NADPH oxidase 4 (NOX4) and an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression were observed following DIM treatment. Notably, the anti-apoptotic potential of DIM was correlated with increased expression of the anti-apoptotic protein Bcl-2 and decreased expression of the pro-apoptotic protein Bax. These findings suggest that DIM attenuates TBI-induced hematopoietic injury through the inhibition of both oxidative stress in HSCs and hematopoietic cell apoptosis. Furthermore, we demonstrated that DIM protected BM hematopoietic cells against ionizing radiation and led to increased clonogenicity in vitro. Therefore, DIM has the potential to be used as an effective radioprotectant to ameliorate TBI-induced hematopoietic injury.
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. Electronic address: lulu@irm-cams.ac.cn.
Lu
L
Lu
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Jiali
J
Dong
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Deguan
D
Li
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Junling
J
Zhang
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. Electronic address: fansaijun@irm-cams.ac.cn.
Saijun
S
Fan
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000528:radiation effects; D006085:Graft Survival / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014916:Whole-Body Irradiation; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D051547:Heme Oxygenase-1; D006657:Histones; D007211:Indoles; D008565:Membrane Proteins; D000074663:NADPH Oxidase 4; D051267:NF-E2-Related Factor 2; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C494827:Bax protein, mouse; C495636:Nfe2l2 protein, mouse; C052617:Bcl2 protein, mouse; C496542:Hmox1 protein, mouse; C422943:Nox4 protein, mouse; C016392:3,3'-diindolylmethane; C475961:gamma-H2AX protein, mouse
3,3′-diindolylmethane; Hematopoietic stem/progenitor cells; Oxidative stress; Radioprotection