Abstract
Dysfunction of histone acetylation inhibits topoisomerase IIα (Topo IIα), which is implicated in benzene-induced hematotoxicity in patients with chronic benzene exposure. Whether histone deacetylase (HDAC) inhibitors can relieve benzene-induced hematotoxicity remains unclear. Here we showed that hydroquinone, a main metabolite of benzene, increased the HDAC activity, decreased the Topo IIα expression and induced apoptosis in human bone marrow mononuclear cells in vitro, and treatment with two HDAC inhibitors, namely trichostatin A (TSA) or a mixture of ribosome-inactivating proteins MCP30, almost completely reversed these effects. We further established a benzene poisoning murine model by inhaling benzene vapor in a container and found that benzene poisoning decreased the expression and activity of Topo IIα, and impaired acetylation of histone H4 and H3. The analysis of regulatory factors of Topo IIα promoter found that benzene poisoning decreased the mRNA levels of SP1 and C-MYB, and increased the mRNA level of SP3. Both TSA and MCP30 significantly enhanced the acetylation of histone H3 and H4 in Topo IIα promoter and increased the expression and activity of Topo IIα in benzene poisoning mice, which contributed to relieve the symptoms of hematotoxicity. Thus, treatment with HDAC inhibitors represents an attractive approach to reduce benzene-induced hematotoxicity.
Highlights
Benzene, a ubiquitous environmental pollutant due to its wide range of practical applications as an industrial solvent or as a starting material in making other chemicals worldwide, is an established human hematotoxicant and leukemogen
We demonstrated that HQ increased the histone deacetylase (HDAC) activity, decreased the expression of Topo IIα, and induced apoptosis in human bone marrow mononuclear cells, and trichostatin A (TSA) or MCP30 treatment almost completely reversed these effects
TSA or MCP30 treatment decreases the activity of HDAC, increases the expression of Topo IIα and reduces apoptosis in human bone marrow mononuclear cells induced by HQ
Summary
A ubiquitous environmental pollutant due to its wide range of practical applications as an industrial solvent or as a starting material in making other chemicals worldwide, is an established human hematotoxicant and leukemogen. Chronic exposure to benzene commonly causes bone marrow suppression that often initially manifests clinically decreased peripheral blood cell counts, and leads to the onset of various disorders, including. Benzene is metabolized in the liver and bone marrow, and its metabolites can damage hematopoietic cells through multiple mechanisms, including apoptosis, gene-expression alteration, and epigenetic regulation [5,6]. Accumulating evidences have demonstrated that active metabolites of benzene including hydroquinone (HQ) inhibit Topo IIα and subsequently lead to DNA damage, cell apoptosis or aberration, and eventually carcinogenesis [8,9,10,11]. Our previous study has demonstrated that the expression and activity of Topo IIα are reduced in patients with chronic benzene exposure [12], supporting the notion that benzene can induce hematotoxicity through inhibition of Topo IIα
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