Keywords
hematopoietic stem
progenitor cells
hematotoxicity
myelotoxicity
lineage-dependent
How to Cite
Abstract
Benzene exposure has been associated with hematotoxicity and leukemogenicity. However, the impact of benzene exposure on complex microenvironment of Hematopoetic Stem Cells (HSCs) niche, comprising of HSCs and lineage-specific progenitors remains elusive. Thus, a study on benzene-targeting HSCs niche could uncover mechanism linking benzene to HSCs niche alteration. This study evaluates the lineage-specific responses following exposure to a benzene metabolite, namely hydroquinone (HQ) in targeting HSCs and myeloid-committed progenitors. Freshly isolated murine bone marrow cells (BMCs) were exposed to HQ at series of concentrations (0 – 50 µM) for 24 hours; followed by cell viability analysis using MTT assay. Chromosomal aberration (CA) status was determined using karyotyping analysis. Expression of surface antigen for HSCs (Sca-1) was confirmed by flow cytometer. Lineage-specific myelotoxicity was studied using the colony-forming unit (CFU) assay for the following myeloid progenitors: CFU granulocyte /erythrocyte /macrophage /megakaryocyte (CFU-GEMM), CFU-granulocyte/macrophage (CFU-GM), CFU-granulocyte (CFU-G), CFU-macrophage (CFU-M), CFU-erythroid (CFU-E) and Burst-forming unit erythroid (BFU-E). HQ reduced (p<0.05) viability of BMCs at 25 µM and 50 µM with the IC10, IC25, and IC50 were at 17 µM, 23 µM and 35 µM, respectively. Increased (p<0.05) frequency of CA was observed in HQ-treated group as compared to control. Reduced (p<0.05) Sca-1+ cells at 17 µM, 23 µM and 35 µM indicates cytotoxic effect of HQ targeting HSCs population. Reduced (p<0.05) total colony counts were noted following HQ exposure at 6.25 µM and a complete inhibition of colony growth were observed at higher concentration (12.5 µM). HQ reduced (p<0.05) the growth of CFU-GEMM, CFU-GM and CFU-G at 6.25 µM, while the growth of CFU-M, CFU-E and BFU-E were not remarkably affected at lower concentrations (1.56 µM and 6.25 µM). Conclusively, HQ induces chromosomal aberration and cytotoxicity on HSCs with notable lineage-specific responses in governing benzene-mediated myelotoxicity targeting HSCs niche.
References
Atkinson TJ. A review of the role of benzene metabolites and mechanisms in malignan transformation: Summative evidence for a lack of research in nonmyelogenous cancer types. Int. J. Hyg. Environ. Health 2009;212:1-10.
https://doi.org/10.1016/j.ijheh.2007.09.013
Bird MG, Greim H, Kaden DA, Rice JM, Snyder R. Benzene 2009- Health effects and mechanisms of bone marrow toxicity: Implications for t-AML and the mode of action framework. Chem.-Biol. Interact 2010;1843-6.
https://doi.org/10.1016/j.cbi.2009.12.001
Chow PW, Abdul Hamid Z, Chan KM, Salmaan Hussain Inayat Hussain, Rajab NF. Lineage related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells. Toxicology and Applied Pharmacology 2015;284:8-15.
https://doi.org/10.1016/j.taap.2015.01.016
Chow P.W., Rajab N.F., Chua K.H., Chan K.M., Abd Hamid Z. 2018. Differential responses of lineages-committed hematopoietic progenitors and altered expression of self-renewal and differentiation-related genes in 1,4-benzoquinone (1,4-BQ) exposure. Toxicology in Vitro 46: 122-128.
https://doi.org/10.1016/j.tiv.2017.10.001
Faiola B, Fuller ES, Wong VA, Pluta L, Abernethy DJ, Rose J, Recio L. Exposure of hematopoietic stem cells to benzene or 1,4-benzoquinone induces gender-specific gene expression. Stem Cell 2004; 22:750-758.
https://doi.org/10.1634/stemcells.22-5-750
Green JD, Snyder CA, LoBue J, Goldstein BD, Albert RE. Acute and chronic dose/response effect of benzene inhalation on the peripheral blood, bone marrow, and spleen cells of CD-1 male mice. Toxicology and Applied Pharmacology 1981;59:2204-214.
https://doi.org/10.1016/0041-008X(81)90191-5
Hazel BA, Baum C, Kalf GF. Hydroquinone, a bioreactive metabolite of benzene, inhibits apoptosis in myeloblasts. Stem Cells 1996;14:6730-742.
https://doi.org/10.1002/stem.140730
IARC. Monograph Supplement 7. 1987a. Benzene. IARC. International Agency for Research on Cancer 1987.
Ji, Z., Zhang, L., Guo, W., McHale, C.M & Smith, M.T. 2009. The benzene metabolite, hydroquinone and etoposide both induce endoreduplication in human lymphoblastoid TK6 cells. Mutagenesis 24: 367-372.
https://doi.org/10.1093/mutage/gep018
Khan HA. Short Review: Benzene's toxicity: a consolidated short review of human and animal studies. Human & experimental toxicology 2007;26:9677-685.
https://doi.org/10.1177/0960327107083974
Malerba I, Casati S, Diodovich C, Parent-Massin D, Gribaldo L. Inhibition of CFU-E/BFU-E and CFU-GM colony growth by Cyclophosphamide, 5-Fluorouracil and Taxol: development of a high-throughput in vitro method. Toxicol. In vitro 2004;18:293-300.
https://doi.org/10.1016/j.tiv.2003.09.001
Parent-Massin, D. Relevance of clonogenic assays in hematotoxicity. Cell Biol Toxicol 2001;17:287-94.
https://doi.org/10.1023/A:1010906104558
Smith, M.T., Zhang, L., Wang, Y., Hayes, R.B., Li, G., Wiemels, J., Dosemeci, M., Titenko-Holland, N., Xi, L., Kolachana, P., Yin, S. & Rothman, N. 1998. Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene. Cancer Research 58(10): 2176-2181.
Smith, M.T. 2010. Advances in understanding benzene health effects and susceptibility. Annual Review of Public Health 31: 133-148.
https://doi.org/10.1146/annurev.publhealth.012809.103646
Snyder R. Benzene's toxicity: a consolidated short review of human and animal studies by HA Khan. Hum. Exp. Toxicol 2007; 26:687-696.
https://doi.org/10.1177/0960327107083975
Snyder R, Hedli CC. An overview of benzene metabolism. Environmental health perspectives 1996; 104: 61165.
https://doi.org/10.2307/3433158
Snyder R, Witz G, Goldstein BD. The toxicology of benzene. Environmental health perspectives 1993;100: 293.
https://doi.org/10.1289/ehp.93100293
Sun, R., Zhang, J., Xiong, M., Wei, H., Tan, K., Yin, L. & Pu, Y. 2015. Altered expression of genes in signaling pathways regulating proliferation of hematopoietic stem and progenitor cells in mice with subchronic benzene exposure. International Journal of Environmental Research and Public Health 12(8): 9298-9313.
https://doi.org/10.3390/ijerph120809298
Wang L, He X, Bi Y, Ma Q. Stem cell and benzene-induced malignancy and hematotoxicity. Chem. Res. Toxicol 2012; 25:71303-1315.
https://doi.org/10.1021/tx3001169
Zhang, L., Rothman, N., Wang, Y., Hayes, R.B., Yin, S., Titenko-Holland, N., Dosemeci, M., Wang, Y.Z., Kolachana, P., Lu, W., Xi, L., Li, G.L. & Smith, M.T. 1999. Benzene increases aneuploidy in the lymphocytes of exposed workers: a comparison of data obtained by fluorescence in situ hybridization in interphase and metaphase cells. Environ. Mol. Mutagen. 34(4): 260-268.
https://doi.org/10.1002/(SICI)1098-2280(1999)34:4<260::AID-EM6>3.0.CO;2-P
Zhang, L., Lan, Q., Guo, W., Hubbard, A.E., Li, G., Rappaport, S.M., McHale, C.M., Shen, M., Ji, Z., Vermeulen, R., Yin, S., Rothman, N. & Smith, M.T. 2011. Chromosome-wide aneuploidy study (CWAS) in workers exposed to an established leukemogen, benzene. Carcinogenesis 32(4): 605-612.
https://doi.org/10.1093/carcin/bgq286
Zhang L, Lan Q, Ji Z, Li G, Shen M, Vermeulen R, Guo W, Hubbard AE, McHale CM, Rappaport SM, Hayes RB, Linet MS, Yin S, Smith MT, Rothman N. Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers. Leukemia 2012; 26: 2494-2498.
https://doi.org/10.1038/leu.2012.143
Zhu, J., Wang, H., Yang, S., Guo, L., Li, Z., Wang, W., Wang, S., Huang, W., Wang, L., Yang, T., Ma, Q. & Bi, Y. 2013. Comparison of toxicity of benzene metabolite hydroquinone in hematopoietic stem cells derived from murine embryonic yolk sac and adult bone marrow. PLoS One 8(8): e71153.
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