Abstract
Despite recent advancements, it is still difficult to evaluate in vivo responses to toxicants in humans. Development of a system that can mimic the in vivo responses of human cells will enable more accurate health risk assessments. A surrogate human hematopoietic lineage can be established in NOD/Shi-scid/IL-2Rγnull (NOG) mice by transplanting human hematopoietic stem/progenitor cells (Hu-NOG mice). Here, we first evaluated the toxic response of human-like hematopoietic lineage in NOG mice to a representative toxic agent, benzene. Flow cytometric analysis showed that benzene caused a significant decrease in the number of human hematopoietic stem/progenitor cells in the bone marrow and the number of human leukocytes in the peripheral blood and hematopoietic organs. Next, we established chimeric mice by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice (Mo-NOG mice). A comparison of the degree of benzene-induced hematotoxicity in donor-derived hematopoietic lineage cells within Mo-NOG mice indicated that the toxic response of Hu-NOG mice reflected interspecies differences in susceptibilities to benzene. Responses to the toxic effects of benzene were greater in lymphoid cells than in myeloid cells in Mo-NOG and Hu-NOG mice. These findings suggested that Hu-NOG mice may be a powerful in vivo tool for assessing hematotoxicity in humans, while accounting for interspecies differences.
Highlights
Health risk assessment of various factors is evaluated based on results from epidemiologic surveys, animal testing, cytotoxicity studies, or a combination thereof
We carried out flow cytometric enumerations of Lin2hCD382hCD34+ cells contained in the bone marrow of Hu-NOG mice (Fig. 2A), which were highly enriched in the population of human hematopoietic stem/progenitor cells
Human leukocytes were identified in the peripheral blood and hematopoietic organs of Hu-NOG mice by double staining with anti-hCD45 and anti-mCD45 antibodies
Summary
Health risk assessment of various factors is evaluated based on results from epidemiologic surveys, animal testing, cytotoxicity studies, or a combination thereof. The influence on human health can be evaluated directly [1]. Animal testing, which is used as a substitute for epidemiological surveys, allows for quantifiable assessment under controlled conditions [2]. Experimental animals have been used to assess the risks of various agents, they may not reflect the responses seen in humans. Responses of human cells to potentially toxic agents can be evaluated using cytotoxicity assays [3]. To perform more accurate health risk assessments, the development of an in vivo evaluation system that can reproduce human responses to toxic factors would be an important breakthrough
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