PUBLICATION

Establishment of a zebrafish hematological disease model induced by 1,4-benzoquinone

Authors

Zhang, A., Wu, M., Tan, J., Yu, N., Xu, M., Yu, X., Liu, W., Zhang, Y.

ID

ZDB-PUB-190323-2

Date

2019

Source

Disease models & mechanisms 12(3): (Journal)

Registered Authors

Wu, Mei, Xu, Mengchang, Zhang, Yiyue

Keywords

1,4-benzoquinone, Hematotoxicity, Neutrophilia, Zebrafish, c-myb

MeSH Terms

Disease Models, Animal
Animals
Benzoquinones/toxicity*
Mutation/genetics
Hematopoiesis/drug effects
Biomarkers/metabolism
Zebrafish/embryology
Zebrafish/metabolism*
Neutrophils/metabolism
Neutrophils/pathology
Kaplan-Meier Estimate
Teratogens/toxicity
Hematologic Diseases/chemically induced*
Hematologic Diseases/pathology*
Proto-Oncogene Proteins c-myb/metabolism
Embryo, Nonmammalian/cytology
Embryo, Nonmammalian/drug effects
Embryo, Nonmammalian/metabolism
Myeloid Cells/drug effects
Myeloid Cells/metabolism

(all 20)

PubMed

30898970 Full text @ Dis. Model. Mech.

Abstract

Benzene exposure is associated with various hematological disorders, especially leukemia. The reactive metabolite of benzene, 1,4-Benzoquinone (BQ), generated in bone marrow (BM), is suggested to be a key molecule in mediating benzene-induced hematotoxicity and carcinogenicity. Yet, its pathogenic role remains largely unknown due to 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 abnormally accumulated 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-deficient mutant cmyb^hkz3 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 may serve as a potential drug target for reversing BQ hematotoxicity.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
DsRed2	nz50Tg	control	Protruding-mouth		neutrophil	IFL	Fig. 3
DsRed2	nz50Tg	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth		neutrophil	IFL	Fig. 3
hbbe1.1	WT	chemical treatment by environment: 1,4-benzoquinone	Day 5		caudal hematopoietic tissue	ISH	Fig. 2
hbbe1.1	WT	control	Day 5		erythroid lineage cell	ISH	Fig. 2
hbbe1.1	WT	chemical treatment by environment: 1,4-benzoquinone	Day 5		erythroid lineage cell	ISH	Fig. 2
lcp1	WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth		caudal hematopoietic tissue	ISH	Fig. 2
lcp1	WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth		myeloid cell	ISH	Fig. 2
lcp1	WT	control	Protruding-mouth		myeloid cell	ISH	Fig. 2
lyz	myb^hkz3/hkz3	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	Not Detected	caudal hematopoietic tissue	ISH	Fig. 5
lyz	myb^hkz3/hkz3	control	Protruding-mouth	Not Detected	caudal hematopoietic tissue	ISH	Fig. 5

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: 1,4-benzoquinone	Prim-25	ventral wall of dorsal aorta myb expression increased amount, abnormal	Fig. 4
WT	chemical treatment by environment: 1,4-benzoquinone	Long-pec	whole organism myb expression increased amount, abnormal	Fig. 4
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	caudal hematopoietic tissue lcp1 expression increased amount, abnormal	Fig. 2
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	caudal hematopoietic tissue lyz expression increased amount, abnormal	Fig. 2
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	caudal hematopoietic tissue lyz expression increased amount, abnormal	Fig. 5
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	caudal hematopoietic tissue mfap4.1 expression decreased amount, abnormal	Fig. 2
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	caudal hematopoietic tissue mpx expression increased amount, abnormal	Fig. 2
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	caudal hematopoietic tissue mpx expression increased amount, abnormal	Fig. 5
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	lymphoid progenitor cell decreased amount, abnormal	Fig. 2
WT	chemical treatment by environment: 1,4-benzoquinone	Protruding-mouth	macrophage decreased amount, abnormal	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hkz3		Point Mutation	myb
nz50Tg	Tg(lyz:DsRed2)	Transgenic Insertion
nz117Tg	Tg(lyz:EGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
hematopoietic system disease			TAS

Sequence Targeting Reagents

Fish

Fish
myb^hkz3/hkz3
nz50Tg
nz117Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed2	EFG	DsRed2
EGFP	EFG	EGFP

Mapping

Zhang et al., 2019 ZDB-PUB-190323-2 PMID:30898970

Establishment of a zebrafish hematological disease model induced by 1,4-benzoquinone

Zhang et al., 2019

ZDB-PUB-190323-2
PMID:30898970