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TOXICOLOGY

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

Institut National de la Santé et de la Recherche Médicale U620, Faculté de Pharmacie, Rennes, France (J.v.G., S.L., O.F.); Etablissement Français du Sang, Rennes, France (C.L.B.); and Service d'Hématologie Clinique (M.B.) and Laboratoire d'Hématologie-Immunologie (T.F., O.F.), Hôpital Pontchaillou–Centre Hospitalier Universitaire, Rennes, France

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 CD34+ cell cultures. Benzo(a)pyrene (BP), a prototypical PAH, was shown to markedly impair CD34+ cell expansion and to inhibit CD34+ cell differentiation into various hematological cell lineages, including erythroid, granulomacrophagic, and megakaryocytic lineages. This was associated with the induction of a caspase- and mitochondrion-related apoptosis process. CD34+ progenitor cells were found to exhibit functional expression of the aryl hydrocarbon receptor (AhR), and the use of the pure AhR antagonist 3'-methoxy-4'-nitroflavone partially counteracted the deleterious effects of BP in CD34+ 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-p-dioxin, 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 CD34+ 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-9,10-epoxide, a highly reactive BP metabolite, exerted a marked toxicity toward CD34+ cell cultures. Overall, these data indicate that human hematopoietic CD34+ cells can bioactivate chemical carcinogens such as PAHs and, in this way, constitute targets for such carcinogenic environmental contaminants.

Address correspondence to: Dr. Olivier Fardel, INSERM U620, Faculté de Pharmacie, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France. E-mail: olivier.fardel{at}univ-rennes1.fr

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