Inity of buy GGTI298 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 Tenofovir alafenamide web mouse-derived bone marrow cells into NOG mice. Then, we compared the toxic responses of donor cell-derived human and mouse 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 responses within Hu-NOG mice reflected interspecies differences in benzene-induced hematotoxicity. The toxicity of benzene in leukocytes in the peripheral blood is induced mainly by benzene metabolites produced in organs such as the liver [45,46]. Because Hu-NOG and Mo-NOG mice obviously possess the same organs, we predicted that the degree of peripheral blood leukocyte toxicity would be almost the same in both. However, there was a significant difference in the number of peripheral blood leukocytes between Hu-NOG and Mo-NOG mice in response to low levels of benzene. This difference may be attributed to differences in the amounts of cells supplied from the bone marrow, spleen, and thymus. In fact, the difference in the number of leukocytes in Hu-NOG and Mo-NOG mice was most significant in lymphoid organs (Fig. 5B). Moreover, in analyses targeting the bone marrow and peripheral blood, differences inIn Vivo Tool for Assessing Hematotoxicity in HumanIn Vivo Tool for Assessing Hematotoxicity in HumanFigure 5. Comparison of benzene toxicity in Hu-NOG and Mo-NOG mice. (A) Ratios of donor cell-derived human or mouse leukocytes 1655472 in HuNOG (Hu) and Mo-NOG (Mo) mice after benzene administration. Each ratio was calculated based on the mean number of leukocytes in untreated HuNOG or Mo-NOG mice. (B) Ratios of myeloid (upper) and lymphoid (lower) cells in the bone marrow and peripheral blood of Hu-NOG (Hu) and MoNOG (Mo) mice after benzene administration. Each ratio was calculated based on the mean number of myeloid and lymphoid cell in untreated HuNOG or Mo-NOG mice. Mouse myeloid cells in Mo-NOG mice were identified as mCD45.2+mCD45.12mLy6C/6Ghi/mid. Mouse lymphoid cells in MoNOG mice were identified as mCD45.2+mCD45.12mLy6C/6Glo/2. The box plot shows the maximum (top of the vertical line), 75th percentile (top of the box), median (middle line in the box), 25th percentile (bottom of the box), and minimum (bottom of vertical line) values of data (n = 6?). * p,0.10 represents marginally significant differences between Hu-NOG and Mo-NOG mice, as determined by Mann-Whitney U tests. ** p,0.05 and *** p,0.01 represent significant differences. doi:10.1371/journal.pone.0050448.gsusceptibilities to benzene tended to be greater in lymphoid cells than in myeloid cells. These results suggested that interspecies differences in benzene-induced hematotoxicity are mainly due to differences in toxic responses in lymphoid cells, in the regulation of benzene in lymphoid devel.Inity 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 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 responses within Hu-NOG mice reflected interspecies differences in benzene-induced hematotoxicity. The toxicity of benzene in leukocytes in the peripheral blood is induced mainly by benzene metabolites produced in organs such as the liver [45,46]. Because Hu-NOG and Mo-NOG mice obviously possess the same organs, we predicted that the degree of peripheral blood leukocyte toxicity would be almost the same in both. However, there was a significant difference in the number of peripheral blood leukocytes between Hu-NOG and Mo-NOG mice in response to low levels of benzene. This difference may be attributed to differences in the amounts of cells supplied from the bone marrow, spleen, and thymus. In fact, the difference in the number of leukocytes in Hu-NOG and Mo-NOG mice was most significant in lymphoid organs (Fig. 5B). Moreover, in analyses targeting the bone marrow and peripheral blood, differences inIn Vivo Tool for Assessing Hematotoxicity in HumanIn Vivo Tool for Assessing Hematotoxicity in HumanFigure 5. Comparison of benzene toxicity in Hu-NOG and Mo-NOG mice. (A) Ratios of donor cell-derived human or mouse leukocytes 1655472 in HuNOG (Hu) and Mo-NOG (Mo) mice after benzene administration. Each ratio was calculated based on the mean number of leukocytes in untreated HuNOG or Mo-NOG mice. (B) Ratios of myeloid (upper) and lymphoid (lower) cells in the bone marrow and peripheral blood of Hu-NOG (Hu) and MoNOG (Mo) mice after benzene administration. Each ratio was calculated based on the mean number of myeloid and lymphoid cell in untreated HuNOG or Mo-NOG mice. Mouse myeloid cells in Mo-NOG mice were identified as mCD45.2+mCD45.12mLy6C/6Ghi/mid. Mouse lymphoid cells in MoNOG mice were identified as mCD45.2+mCD45.12mLy6C/6Glo/2. The box plot shows the maximum (top of the vertical line), 75th percentile (top of the box), median (middle line in the box), 25th percentile (bottom of the box), and minimum (bottom of vertical line) values of data (n = 6?). * p,0.10 represents marginally significant differences between Hu-NOG and Mo-NOG mice, as determined by Mann-Whitney U tests. ** p,0.05 and *** p,0.01 represent significant differences. doi:10.1371/journal.pone.0050448.gsusceptibilities to benzene tended to be greater in lymphoid cells than in myeloid cells. These results suggested that interspecies differences in benzene-induced hematotoxicity are mainly due to differences in toxic responses in lymphoid cells, in the regulation of benzene in lymphoid devel.
