Global Identification of HIF-1α Target Genes in Benzene Poisoning Mouse Bone Marrow Cells.

Zhaodi Man,Xing Meng,Yuepu Pu,Juan Zhang,Yunqiu Pu,Kai Xu,Rongli Sun,Lihong Yin,Fengxia Sun

doi:10.3390/ijerph15112531

Abstract

Benzene is a hematopoietic toxicant, and hematopoietic cells in bone marrow (BM) are one of the main targets for its action, especially hematopoietic stem cells (HSCs). Hypoxia-inducible factor-1α (HIF-1α) is associated with the metabolism and physiological functions of HSCs. We previously found that the mechanism of regulation of HIF-1α is involved in benzene-induced hematopoietic toxicity. In this study, chromatin immunoprecipitation sequencing (ChIP-Seq) technologies were used to analyze the genome-wide binding spectrum of HIF-1α in mouse BM cells, and specific HIF-1α target genes and pathways associated with benzene toxicity were screened and validated. By application of the ChIP-Seq technique, we identified target genes HIF-1α directly binds to and regulates. Forty-two differentially down-regulated genes containing the HIF-1α specific binding site hypoxia response element (HRE) were found, of which 25 genes were with biological function. Moreover, the enrichment analysis of signal pathways indicated that these genes were significantly enriched in the Jak-STAT signaling pathway, Natural killer cell mediated cytotoxicity, the Fc epsilon RI signaling pathway, Pyrimidine metabolism, the T cell receptor signaling pathway, and Transcriptional misregulation in cancer. After verification, 11 genes involved in HSC self-renewal, cell cycle, differentiation, and apoptosis pathways were found to be significantly reduced, and may participate in benzene-induced hematotoxicity. Our study provides a new academic clue for the mechanism of benzene hematotoxicity.

Highlights

Benzene, a ubiquitous environmental pollutant and a recognized human carcinogen [1,2,3,4], enters the human body through the respiratory tract and skin, which leads to chronic benzene poisoning and hematopoietic dysfunction
The following chip samples of the benzene exposure group were selected for the low benzene (LB) group
Benzene exposure may destroy the bone marrow microenvironment and decrease the expression of Hypoxia-inducible factor-1α (HIF-1α), indicating that Hypoxia inducible factors (HIFs)-1α plays an important role in benzene-induced hematopoietic damage

Summary

Introduction

A ubiquitous environmental pollutant and a recognized human carcinogen [1,2,3,4], enters the human body through the respiratory tract and skin, which leads to chronic benzene poisoning and hematopoietic dysfunction. The main manifestations of its hematotoxicity are low bone marrow (BM) hyperplasia and peripheral blood cell count [5]. It is believed that the toxicity of benzene is mainly caused by the metabolites of benzene. Benzene and its metabolites can cause hematopoietic toxicity through many mechanisms, such as oxidative damage, gene mutation, and epigenetic change [5,6]. The metabolites of benzene include phenol, hydroquinone, catechol, and 1,4-benzoquinone [7]. 1,4-benzoquinone can combine directly with biomolecules to produce reactive oxygen species (ROS), cause lipid peroxidation, and eventually result in acute oxidative damage [8,9,10,11]. Hematopoietic stem cells (HSCs) exist in hematopoietic niches. The hypoxic microenvironment helps to maintain their energetic metabolism mainly based on anaerobic glycolysis, which is necessary

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