A comparison of the cytogenetic alterations and global DNA hypomethylation induced by the benzene metabolite, hydroquinone, with those induced by melphalan and etoposide

Abstract

Specific cytogenetic alterations and changes in DNA methylation are involved in leukemogenesis. Benzene, an established human leukemogen, is known to induce cytogenetic changes through its active metabolites including hydroquinone (HQ), but the specific alterations have not been fully characterized. Global DNA hypomethylation was reported in a population exposed to benzene, but has not been confirmed in vitro. In this study, we examined cytogenetic changes in chromosomes 5, 7, 8, 11 and 21, and global DNA methylation in human TK6 lymphoblastoid cells treated with HQ for 48 h, and compared the HQ-induced alterations with those induced by two well-known leukemogens, melphalan, an alkylating agent, and etoposide, a DNA topoisomerase II inhibitor. We found that rather than inducing cytogenetic alterations distinct from those induced by melphalan and etoposide, HQ induced alterations characteristic of each agent. HQ induced global DNA hypomethylation at a level intermediate to melphalan (no effect) and etoposide (potent effect). These results suggest that HQ may act similar to an alkylating agent and also similar to a DNA topoisomerase II inhibitor in living cells, both of which may be potential mechanisms of benzene toxicity. In addition to cytogenetic changes, global DNA hypomethylation may be another mechanism underlying the leukemogenicity of benzene.

Hydroquinone Increases 5-Hydroxymethylcytosine Formation through Ten Eleven Translocation 1 (TET1) 5-Methylcytosine Dioxygenase

“…Epidemiologic and laboratory data suggest a negative correlation between DNA methylation and benzene exposures (9,22). We investigated the mechanism to account for the decrease by examining the effects of the major benzene metabolite, HQ, in HEK293 cells.…”

“…HQ is one of the most abundant metabolites of benzene (17,18) and has been shown to increase levels of reactive oxygen species (ROS) (19,20), induce mitotic arrest (21), and promote apoptosis (20). Although benzene and benzene metabolite exposures have also been shown to be associated with loss of genomic methylation (9,22), no mechanisms have been described to explain the observed decreases.…”

Environmental Epigenomics: Applications of Epigenetic Biomarkers to Investigate Epigenetic Alterations from Environmental Exposures

“…Promoter methylation was elevated in p15 (+0.35 %) and reduced in MAGE -1 (−0.49 %) with increasing airborne benzene levels (Bollati et al 2007 ). An in vitro study using human TK6 lymphoblastoid cells found that the active benzene metabolite hydroquinone induced global DNA hypomethylation (Ji et al 2010 ). In another study using lymphoblastoid cell line F32, benzene dramatically decreased mRNA expression and increased methylation of PARP -1 , a DNA repair gene (Gao et al 2010 ).…”

Benzene Induces Cytotoxicity without Metabolic Activation

“…Global DNA hypomethylation may play an important role in human leukemogenesis contributing to carcinogenesis through the generation of chromosomal instability, reactivation of transposable elements, and loss of imprinting 21) . Ji et al reported that hydroquinone, a metabolite of benzene, induced global DNA hypomethylation in TK6 lymphoid cells 14) . However, in our study, benzene did not induce global DNA hypomethylation at all (Fig.…”

“…Recent studies have indicated that occupational exposure to low levels of benzene is associated with altered DNA methylation patterns in the peripheral blood leukocytes of gas station attendants and traffic police officers 13) . However, no previous studies have evaluated the epigenetic changes caused by benzene through the use of myeloid cell lines 14) . In this study, we examined the effects of benzene on global DNA methylation in a human myeloid cell line, HL-60.…”