Uch as hematopoietic stem/progenitor cells [34,35,36]. Therefore, the toxic response of immature cells is the main cause of benzene-induced hematotoxicity [34]. When different amounts of PS-1145 web benzene were administered by gavage to Hu-NOG mice, the number of human hematopoietic stem/progenitor cells in the bone marrow was reduced in a dose-dependent manner (Fig. 2). Benzene also affected the numbers of human leukocytes in the peripheral blood and hematopoietic 18325633 organs (Fig. 4A). Thus, benzene-induced hematotoxicity was detected in a human-like hematopoietic lineage established in NOG mice. Human lymphoid cells showed higher sensitivity to benzene than myeloid cells in Hu-NOG mice (Fig. 4B). In a previous report on benzene-treated mice [37], the same effects on peripheral blood lymphoid and myeloid cells were observed. Microarray data indicate that benzene downregulates the expression of MEF2c [34], which encodes a transcription factor. Mef2c deficiency isassociated with profound defects in the production of lymphoid cells and an enhanced myeloid output [38]. Moreover, analysis of the thymic T cell profile of Hu-NOG mice showed that doublepositive (DP) pre-T cells were more strongly affected by benzene than T cells at other stages of differentiation (Fig. 4C). It has been reported that only the numbers of DP pre-T cells in the thymus are reduced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [36,39], and TCDD-induced hematotoxicity is also mediated by AhR signaling [40]. Although the molecular mechanism of benzene toxicity in Hu-NOG mice could not be inferred by these results alone, we did observe a normal 
response to benzene by HuNOG mice 11089-65-9 web harboring a human-like hematopoietic lineage. We conclude, therefore, that the human-like hematopoietic lineage was sensitive to at least 1 hematotoxicant, benzene, and that HuNOG mice promise to provide a powerful tool for assessing the in vivo response of human hematopoietic cells to known and suspected toxicants. Moreover, Hu-NOG mice can contribute to basic research on human hematopoietic cells, particularly with respect to 
internal tissues and organs. It is important to note that the LOAEL of benzene-induced hematotoxicity in Hu-NOG mice was approximately equivalent to that established for humans [25]. Sensitivity to benzene differs across species, and humans are more susceptible than mice [20,21]. The cause of interspecies differences in benzene-induced hematotoxicity likely involves differences in the affinity of benzene and the AhR [41] and the amounts and properties of benzene metabolites [20,42,43]; however, this has not been proven. In this study, we established chimeric mice, named Mo-NOG mice, by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice. Then, we compared the toxic responses of donor cell-derived human and mouse 23388095 hematopoietic lineage in NOG mice (Fig. 5A). In a previous report, Cai et al. [44] discussed the sensitivity of donorderived human hematopoietic cells to toxicants by comparison with host-derived immunodeficient mouse cells. However, we are skeptical about this comparison between donor-derived cells and irradiated host cells. In this study, a simple and direct comparison was enabled by equalizing the transplant environment of donor cells. It is also important to note that we used C57BL/6 mice, a strain generally used for toxicity tests. Differences in the benzene sensitivities of donor-derived cells from Hu- and Mo-NOG mice undoubtedly indicated that toxic respon.Uch as hematopoietic stem/progenitor cells [34,35,36]. Therefore, the toxic response of immature cells is the main cause of benzene-induced hematotoxicity [34]. When different amounts of benzene were administered by gavage to Hu-NOG mice, the number of human hematopoietic stem/progenitor cells in the bone marrow was reduced in a dose-dependent manner (Fig. 2). Benzene also affected the numbers of human leukocytes in the peripheral blood and hematopoietic 18325633 organs (Fig. 4A). Thus, benzene-induced hematotoxicity was detected in a human-like hematopoietic lineage established in NOG mice. Human lymphoid cells showed higher sensitivity to benzene than myeloid cells in Hu-NOG mice (Fig. 4B). In a previous report on benzene-treated mice [37], the same effects on peripheral blood lymphoid and myeloid cells were observed. Microarray data indicate that benzene downregulates the expression of MEF2c [34], which encodes a transcription factor. Mef2c deficiency isassociated with profound defects in the production of lymphoid cells and an enhanced myeloid output [38]. Moreover, analysis of the thymic T cell profile of Hu-NOG mice showed that doublepositive (DP) pre-T cells were more strongly affected by benzene than T cells at other stages of differentiation (Fig. 4C). It has been reported that only the numbers of DP pre-T cells in the thymus are reduced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [36,39], and TCDD-induced hematotoxicity is also mediated by AhR signaling [40]. Although the molecular mechanism of benzene toxicity in Hu-NOG mice could not be inferred by these results alone, we did observe a normal response to benzene by HuNOG mice harboring a human-like hematopoietic lineage. We conclude, therefore, that the human-like hematopoietic lineage was sensitive to at least 1 hematotoxicant, benzene, and that HuNOG mice promise to provide a powerful tool for assessing the in vivo response of human hematopoietic cells to known and suspected toxicants. Moreover, Hu-NOG mice can contribute to basic research on human hematopoietic cells, particularly with respect to internal tissues and organs. It is important to note that the LOAEL of benzene-induced hematotoxicity in Hu-NOG mice was approximately equivalent to that established for humans [25]. Sensitivity to benzene differs across species, and humans are more susceptible than mice [20,21]. The cause of interspecies differences in benzene-induced hematotoxicity likely involves differences in the affinity of benzene and the AhR [41] and the amounts and properties of benzene metabolites [20,42,43]; however, this has not been proven. In this study, we established chimeric mice, named Mo-NOG mice, by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice. Then, we compared the toxic responses of donor cell-derived human and mouse 23388095 hematopoietic lineage in NOG mice (Fig. 5A). In a previous report, Cai et al. [44] discussed the sensitivity of donorderived human hematopoietic cells to toxicants by comparison with host-derived immunodeficient mouse cells. However, we are skeptical about this comparison between donor-derived cells and irradiated host cells. In this study, a simple and direct comparison was enabled by equalizing the transplant environment of donor cells. It is also important to note that we used C57BL/6 mice, a strain generally used for toxicity tests. Differences in the benzene sensitivities of donor-derived cells from Hu- and Mo-NOG mice undoubtedly indicated that toxic respon.
