Lymphoid cells than in myeloid cells (Fig. 5B). Moreover, 0, 30, and 300 mg benzene/kg-b.w./day was administered to C56BL/6 mice in same manner, and the degree of benzene-induced hematotoxicity of the hematopoietic lineage within C56BL/6 mice was evaluated. The rate of decrease in leukocyte numbers in the peripheral blood and hematopoietic organs of C56BL/6 mice, depending on the amount of benzene, was not significantly Tazemetostat different for Mo-NOG mice (p.0.10).DiscussionHere, we evaluated the toxic response of a human-like hematopoietic lineage established in NOG mice using the hematotoxicant benzene [28,29,30]. Benzene-induced hematotoxicity is known to be transmitted by the aryl hydrocarbon receptor (AhR) [31]. Benzene metabolism is mediated by signals transmitted through interactions between AhR and benzene, benzene metabolites, or both, and the resulting benzene metabolites and reactive oxygen species induce cell damage [32,33]. In hematopoietic cells, the AhR is expressed selectively by immature cells, such 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 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 1655472 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 Etomoxir site 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 aff.Lymphoid cells than in myeloid cells (Fig. 5B). Moreover, 0, 30, and 300 mg benzene/kg-b.w./day was administered to C56BL/6 mice in same manner, and the degree of benzene-induced hematotoxicity of the hematopoietic lineage within C56BL/6 mice was evaluated. The rate of decrease in leukocyte numbers in the peripheral blood and hematopoietic organs of C56BL/6 mice, depending on the amount of benzene, was not significantly different for Mo-NOG mice (p.0.10).DiscussionHere, we evaluated the toxic response of a human-like hematopoietic lineage established in NOG mice using the hematotoxicant benzene [28,29,30]. Benzene-induced hematotoxicity is known to be transmitted by the aryl hydrocarbon receptor (AhR) [31]. Benzene metabolism is mediated by signals transmitted through interactions between AhR and benzene, benzene metabolites, or both, and the resulting benzene metabolites and reactive oxygen species induce cell damage [32,33]. In hematopoietic cells, the AhR is expressed selectively by immature cells, such 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 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 1655472 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 aff.
