Abstract
ABSTRACTBenzene exposure is associated with various hematological disorders, in particular leukemia. The reactive metabolite of benzene, 1,4-benzoquinone (BQ), generated in bone marrow, is suggested to be a key molecule in mediating benzene-induced hematotoxicity and carcinogenicity. However, its pathogenic role remains largely unknown due to a lack of suitable vertebrate whole-organism models. Here, we present an in vivo study to reveal the effect of BQ exposure on hematotoxicity in zebrafish. From embryonic stages to adulthood, BQ exposure suppressed erythroid and lymphoid hematopoiesis but led to abnormal accumulation of myeloid cells and precursors, which resembles benzene-induced cytopenia and myeloid dysplasia in humans. This myeloid expansion is caused by granulocyte, but not macrophage, lineage, emphasizing the significant role of lineage specificity in BQ-mediated hematopoietic toxicity. Analysis of the c-myb (also known as myb)-deficient mutant cmybhkz3 revealed that BQ induced neutrophilia in a c-myb-dependent manner, demonstrating that c-myb is a key intrinsic mediator of BQ hematotoxicity. Our study reveals that BQ causes lineage-specific hematotoxicity in zebrafish from embryonic stages to adulthood. Since c-myb is indispensable for BQ to induce neutrophilia, c-myb could serve as a potential drug target for reversing BQ hematotoxicity.
Highlights
Epidemiological studies have found that occupational and environmental exposure to benzene can have harmful effects on the immunological, neurological, reproductive and, especially, hematological systems, causing cytopenia, aplastic anemia and leukemia (Wilbur et al, 2007)
Embryotoxicity and teratogenicity of BQ in zebrafish To investigate the effect of BQ on hematopoiesis, zebrafish embryos were treated with BQ
BQ is a reactive metabolite of benzene that is produced in bone marrow (BM)
Summary
Epidemiological studies have found that occupational and environmental exposure to benzene can have harmful effects on the immunological, neurological, reproductive and, especially, hematological systems, causing cytopenia, aplastic anemia and leukemia (Wilbur et al, 2007). Son et al (2016) analyzed the impact that BQ exposure has on DNA-repair-defective mouse embryonic stem cells. Previous in vitro studies have shown that exposure of murine hematopoietic stem and progenitor cells (HSPCs) to BQ interferes with their physiological properties and changes their clonogenic potency by altering genes for apoptosis, DNA repair, cell cycle, self-renewal and differentiation (Chow et al, 2018; Faiola et al, 2004). They proposed that BQ suppresses type 1 topoisomerases to inhibit replication fork restart and progression, leading to chromosomal instability that has the potential to cause hematopoietic disorders. There is no vertebrate model for hematological toxicity of BQ exposure, which limits the investigation at the whole-organism level
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