Assessing underlying mechanisms of quinoid-induced hematopoietic cell toxicity.

Abstract

Within the bone marrow are a number of cell populations that can serve as potential targets of xenobiotics and/or their metabolites (Trush et al., 1996). These include the hematopoietic and lymphopoietic stem cells, committed progenitors, mature functional blood cells and the cells that comprise the bone marrow stromal microenvironment. The altered function of different populations probably results in the manifestation of different toxicities. Two environmental chemicals that have been linked with toxicity to the bone marrow are benzene and benzo(a)pyrene (BP). There is continued concern about human exposure to benzene arising from a variety of sources including certain occupational settings, hazardous waste sites, automobiles and cigarette smoking. Exposure of humans to benzene is associated with the development of aplastic anemia and leukemia. Polycyclic aromatic hydrocarbons (PAHs), such as BP, have been shown to be myelotoxic in animals (Legraverend et. al., 1983). For example DBA/2 mice, with the Ahd/Ahdgenotype, develop an aplastic anemia-like condition and leukemia in response to orally administered benzo(a)pyrene. In this regard, diet is considered a major route of exposure to PAHs in humans (Buckley and Lioy, 1992). Whether dietary PAHs pose a risk to human bone marrow in poorly investigated from either an experimental or an epidemiologic perspective. The bone marrow toxicity of both benzene and BP has been linked to their biotransformation. Interestingly, both compounds are metabolized to quinone derivatives: benzene to hydroquinone; BP to 1,6-, 3,6-, and 6,12-quinone. Because of the importance of the bone marrow stromal microenvironment, we have studied the toxicity of hydroquinone and BP-derived quinones to stromal cells obtained from DBA/2 mice (Twerdok et al., 1992; Zhu et al., 1995).