Human CD34-Positive Hematopoietic Stem Cells Constitute Targets for Carcinogenic Polycyclic Aromatic Hydrocarbons

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are major carcinogenic environmental contaminants known to exert bone marrow toxicity and to induce leukemias, suggesting that these chemicals target hematopoietic stem cells. To investigate this hypothesis, we studied the effects of PAHs on cell proliferation and differentiation in human hematopoietic CD34ϩ cell cultures. Benzo(a)pyrene (BP), a prototypical PAH, was shown to markedly impair CD34ϩ cell expansion and to inhibit CD34ϩ cell differentiation into various hematological cell lineages, including erythroid, granulomacrophagic, and megakaryocytic lineages. This was associated with the induction of a caspaseand mitochondrion-related apoptosis process. CD34ϩ progenitor cells were found to exhibit functional expression of the aryl hydrocarbon receptor (AhR), and the use of the pure AhR antagonist 3Ј-methoxy-4Ј-nitroflavone partially counteracted the deleterious effects of BP in CD34ϩ cell cultures, underlining the involvement of AhR in BP toxicity. Additional events such as CYP1A1/1B1-dependent PAH metabolism and adduct formation were also required since 1) 2,3,7,8-tetrachlorodibenzo-pdioxin, a very potent ligand of the AhR that is poorly metabolized and therefore does not generate reactive metabolites in contrast to PAHs, failed to affect CD34ϩ cell expansion; 2) the CYP1A1/1B1 inhibitor ␣-naphthoflavone blocked both BP adduct formation and BP toxicity; and 3) benzo(a)pyrene-trans-7,8-dihydrodiol-9,

The Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-dioxin Alters the Circadian Rhythms, Quiescence, and Expression of Clock Genes in Murine Hematopoietic Stem and Progenitor Cells

“…This is particularly important because of the tightly regulated and critical interactions between hematopoietic precursors and the nonhematopoietic stroma. These findings, along with measurable levels of AhR mRNA and protein in these cells (van Grevenynghe et al, 2005), indicate that the AhR may have some normal function in HSC. In addition, human HSCs are AhR-dependent targets for carcinogenic polycyclic aromatic hydrocarbons (van Grevenynghe et al, 2005).…”

Hematotoxicity: In Vitro and Ex Vivo Compound Profiling

“…The AhR is expressed in bone marrow stromal cells [14] and human hematopoietic stem cells [15] and upon agonist binding the receptor translocates to the nucleus, resulting in altered transcriptional expression such as increased CYP1A1 [16] and resulting in reactive oxygen species [17]. Nonpharmaceutical compounds such as TCDD, benzo(a)pyrene and benzene have been shown to induce hematotoxicity using this mechanism in vivo and in vitro [18,19].…”

Use of Molecular Testing to Identify a Cluster of Patients with Polycythemia Vera in Eastern Pennsylvania

“…However, aside from proximity, there is at present no direct evidence to indicate that these sources played a role in the current polycythemia vera cluster. Recent reports suggest that polycyclic aromatic hydrocarbons might potentially contribute to the generation of polycythemia vera and thus a cluster such as the one seen in this geographic area (30)(31)(32)(33)(34)(35). These compounds constitute ubiquitous environmental contaminants, are potent carcinogenic and immunotoxic agents, and are also present in waste-coal emissions and at most of the Superfund sites associated with area T. The aryl hydrocarbon receptor, for which polycyclic aromatic hydrocarbon serves as a ligand, is present in the cytoplasm of human hematopoietic stem and progenitor cells (30)(31)(32).…”

“…Recent reports suggest that polycyclic aromatic hydrocarbons might potentially contribute to the generation of polycythemia vera and thus a cluster such as the one seen in this geographic area (30)(31)(32)(33)(34)(35). These compounds constitute ubiquitous environmental contaminants, are potent carcinogenic and immunotoxic agents, and are also present in waste-coal emissions and at most of the Superfund sites associated with area T. The aryl hydrocarbon receptor, for which polycyclic aromatic hydrocarbon serves as a ligand, is present in the cytoplasm of human hematopoietic stem and progenitor cells (30)(31)(32). This might serve as a potential target for environmental contaminants, leading to a multistep process culminating in the development of a hematologic malignancy such as polycythemia vera (31)(32)(33)(34)(35).…”

“…These compounds constitute ubiquitous environmental contaminants, are potent carcinogenic and immunotoxic agents, and are also present in waste-coal emissions and at most of the Superfund sites associated with area T. The aryl hydrocarbon receptor, for which polycyclic aromatic hydrocarbon serves as a ligand, is present in the cytoplasm of human hematopoietic stem and progenitor cells (30)(31)(32). This might serve as a potential target for environmental contaminants, leading to a multistep process culminating in the development of a hematologic malignancy such as polycythemia vera (31)(32)(33)(34)(35). Suggestions of a specific environmental cause for this cluster are, however, purely hypothetical because the development of polycythemia vera has not been previously associated with exposure to any particular substance.…”