Benzene exposure affects the hematopoietic system and leads to the occurrence of various types of leukemia and hematotoxicity. It has been confirmed that active metabolites of benzene, including 1,4-benzoquinone (1,4-BQ), can induce reactive oxygen species (ROS) and apoptosis in the bone marrow, and recent studies have also suggested that benzene exposure can affect mitochondrial function in both experimental animals and cell lines. However, the potential relationship among ROS production, mitochondrial damages, and subsequent apoptosis following benzene exposure has not been well studied in detail. In the present study, we utilized HL-60 cells, a well-characterized human myeloid cell line, as an in vitro model and examined the effects of 1,4-BQ on intracellular ROS formation, mitochondria damage, and the occurrence of apoptotic events with or without using the ROS scavenger N-acetyl-l-cysteine (NAC). The results demonstrated that 1,4-BQ could dose-dependently induce production of ROS and mitochondrial damage as characterized by mitochondrial membrane potential disruption, mitochondrial ultrastructure alteration, and induced apoptosis and activated caspase-3 and caspase-9. Preincubation of HL-60 cells with NAC prior to 1,4-BQ treatment could block 1,4-BQ-induced production of ROS and the occurrence of apoptosis. These results demonstrated that 1,4-BQ induced apoptosis in HL-60 cells through a ROS-dependent mitochondrial-mediated pathway.
BahadarHMostafalouSAbdollahiM (2014) Current understandings and perspectives on non-cancer health effects of benzene: a global concern. Toxicology and Applied Pharmacology276(2): 83–94.
2.
BurnsAShinJMUniceKM. (2017) Combined analysis of job and task benzene air exposures among workers at four US refinery operations. Toxicology and Industrial Health33(3):193–210.
3.
CarugnoMPesatoriACDioniL. (2012) Increased mitochondrial DNA copy number in occupations associated with low-dose benzene exposure. Environmental Health Perspectives120(2): 210–215.
4.
ChandrasekaranKSwaminathanKChatterjeeS. (2010) Apoptosis in HepG2 cells exposed to high glucose. Toxicology In Vitro24(2): 387–396.
5.
ChenYSunPBaiW. (2016) Mir-133a regarded as a potential biomarker for benzene toxicity through targeting Caspase-9 to inhibit apoptosis induced by benzene metabolite (1,4-benzoquinone). Science of the Total Environment571: 883–891.
6.
ElmoreS (2007) Apoptosis: a review of programmed cell death. Toxicologic Pathology35(4): 495–516.
7.
FaiolaBFullerESWongVA. (2004) Exposure of hematopoietic stem cells to benzene or 1,4-benzoquinone induces gender-specific gene expression. Stem Cells22(5): 750–758.
8.
GalbraithDGrossSAPaustenbachD (2010) Benzene and human health: a historical review and appraisal of associations with various diseases. Critical Reviews in Toxicology40(Suppl 2): 1–46.
9.
HalasiMWangMChavanTS. (2013) ROS inhibitor N-acetyl-l-cysteine antagonizes the activity of proteasome inhibitors. Biochemical Journal454(2): 201–208.
10.
HanDWilliamsECadenasE (2001) Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochemical Journal353(Pt 2): 411–416.
11.
JiangLDaiHSunQ. (2011) Ambient particulate matter on DNA damage in HepG2 cells. Toxicology and Industrial Health27(1): 87–95.
12.
KimA (2014) A panoramic overview of mitochondria and mitochondrial redox biology. Toxicology Research30(4): 221–234.
13.
LanQZhangLLiG. (2004) Hematotoxicity in workers exposed to low levels of benzene. Science306(5702): 1774–1776.
14.
LingYLuNGaoY. (2009) Endostar induces apoptotic effects in HUVESs through activation of Caspase-3 and decrease of Bcl-2. Anticancer Research29(1): 411–417.
15.
LyJDGrubbDRLawenA (2003) The mitochondrial membrane potential (Deltapsi(m)) in apoptosis: an update. Apoptosis8(2): 115–128.
16.
McHaleCMZhangLSmithMT (2012) Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment. Carcinogenesis33(2): 240–252.
17.
PeterMEHeufelderAEHengartnerMO (1997) Advances in apoptosis research. Proceedings of the National Academy of Sciences of the United States of America94(24): 12736–12737.
18.
RossD (2000) The role of metabolism and specific metabolites in benzene-induced toxicity: evidence and issues. Journal of Toxicology and Environmental Health -Part A-Current Issues61(5–6): 357–372.
19.
SaelensXFestjensNVande WalleL. (2004) Toxic proteins released from mitochondria in cell death. Oncogene23(16): 2861–2874.
20.
ScarlettJLSheardPWHughesG. (2000) Changes in mitochondrial membrane potential during staurosporin-induced apoptosis in Jurkat cells. FEBS Letters475(3): 267–272.
21.
ShenMZhangLBonnerMR. (2008) Association between mitochondrial DNA copy number, blood cell counts, and occupational benzene exposure. Environmental and Molecular Mutagenesis49(6): 453–457.
22.
ShenYShenHMShiCY. (1996) Benzene metabolites enhance reactive oxygen species generation in HL60 human leukemia cells. Human & Experimental Toxicology15(5): 422–427.
23.
SmithMTYagerJWSteinmetzKL. (1989) Peroxidase-dependent metabolism of benzene’s phenolic metabolites and its potential role in benzene toxicity and carcinogenicity. Environmental Health Perspectives82: 23–29.
24.
StokesSEWinnLM (2014) Nf-κb signaling is increased in HD3 cells following exposure to 1,4-benzoquinone: role of reactive oxygen species and p38-MAPK. Toxicological Sciences137(2): 303–310.
25.
SunRCaoMZhangJ. (2016) Benzene exposure alters expression of enzymes involved in fatty acid β-oxidation in male C3H/He mice. International Journal of Environmental Research and Public Health13(11): 1068.
26.
SunYLZhuHZZhouJ. (1999) Menadione-induced apoptosis and the degradation of lamin-like proteins in tobacco protoplasts. Cellular and Molecular Life Sciences55(2): 310–316.
27.
TianJFPengCHYuXY. (2012) Expression and methylation analysis of p15 and p16 in mouse bone marrow cells exposed to 1,4-benzoquinone. Human & Experimental Toxicology31(7): 718–725.
28.
WangGHazraTKMitraS. (2000) Mitochondrial DNA damage and a hypoxic response are induced by CoCl(2) in rat neuronal PC12 cells. Nucleic Acids Research28(10): 2135–2140.
29.
WangQLuoWZhangW. (2007) Iron supplementation protects against lead-induced apoptosis through MAPK pathway in weanling rat cortex. Neurotoxicology28(4): 850–859.
30.
WilburSWohlersDPaikoffS. (2008a) ATSDR evaluation of health effects of benzene and relevance to public health. Toxicology and Industrial Health24(5–6): 263–398.
31.
WilburSWohlersDPaikoffS. (2008b) ATSDR evaluation of potential for human exposure to benzene. Toxicology and Industrial Health24(5–6): 399–442.
32.
WiemelsJSmithMT (1999) Enhancement of myeloid cell growth by benzene metabolites via the production of active oxygen species. Free Radical Research30(2): 93–103.
33.
ZhangGGurtuVKainSR. (1997) Early detection of apoptosis using a fluorescent conjugate of annexin V. Biotechniques23(3): 525–531.
34.
ZhangLRobertsonMLKolachanaP. (1993) Benzene metabolite, 1,2,4-benzenetriol, induces micronuclei and oxidative DNA damage in human lymphocytes and HL60 cells. Environmental and Molecular Mutagenesis21(4): 339–348.
35.
ZhangYZhouLBaoYL. (2010) Butyrate induces cell apoptosis through activation of JNK MAP kinase pathway in human colon cancer RKO cells. Chemico-Biological Interactions185(3): 174–181.
36.
ZhuJWangHYangS. (2013) Comparison of toxicity of benzene metabolite hydroquinone in hematopoietic stem cells derived from murine embryonic yolk sac and adult bone marrow. PloS One8(8): e71153.
