Benzene-induced hematopoietic toxicity transmitted by AhR in wild-type mouse and nullified by repopulation with AhR-deficient bone marrow cells: Time after benzene treatment and recovery
Introduction
Recent studies have shown that the aryl hydrocarbon receptor (AhR) in primitive cells transmits negative signals for the proliferation of such cells (Hirabayashi et al., 2003, Garrett and Gasiewicz, 2005). This observation may require further detailed studies, because previous in vitro studies showed that AhR promotes cellular proliferation on one hand (Ma and Whitlock, 1996, Shimba et al., 2002), but rather suppress on the other hand (Fong et al., 2005). As we previously reported, AhR-knockout (KO) mice showed an increase in number of primitive hematopoietic progenitor cells; on the other hand, a decrease in number of relatively mature progenitor cells in a homeostatic manner (Hirabayashi et al., 2003). Therefore, there are two possibilities: one is the hierarchic positional effect of cellular differentiation and the other is a particular cell-proliferative gene alteration in in vitro cell lines.
We have reported that benzene-induced hematopoietic toxicity is transmitted by AhR (Yoon et al., 2002). We also found that cytochrome P450 2E1 (CYP2E1) that is, related to benzene metabolism is also up-regulated following benzene exposure in the bone marrow (BM) (Yoon et al., 2003). Therefore, it is of interest to hypothesize the important role of BM cells in hematopoietic toxicity with respect to AhR function. Accordingly, on the basis of the latest studies presented at the 25th International Dioxin Symposium, benzene-induced hematopoietic toxicity was evaluated in wild-type (Wt) mice after whole-body irradiation at a lethal dose followed by repopulation with BM cells that lack AhR or, vice versa, in AhR-KO mice after repopulation with Wt BM cells. As for the results, a one-day examination on day 12 after benzene exposure showed that the xenobiotic response of CYP2E1 up-regulation mediated by AhR for benzene hematotoxicity was metabolized specifically in the BM (Hirabayashi et al., 2005a). In this article, the detailed changes in blood parameters during the benzene exposure duration and their recovery three days after the cessation of exposure are shown.
Section snippets
Animals
The establishment of homozygous AhR-KO (AhR−/−) mice originating from the 129/SvJ strain has been described elsewhere (Mimura et al., 1997, Yoon et al., 2002). The crossing of heterozygous AhR-KO (AhR+/−) males with AhR+/− females generated wild-type (AhR+/+), AhR+/−, and AhR−/−mice. The neonates were genotyped by PCR screening of DNA from the tail. Male AhR-KO (AhR−/−) mice and their Wt littermates (12 weeks old) were used in the study as donors. Eight-week-old C57BL/6 male mice from Japan SLC
Results and discussion
As previously reported, the AhR-KO mice showed a significantly higher WBC counts than the Wt mice (Fig. 1a). This was also consistent with the high number of myeloid progenitor cells, that is, CFU-S-9 and CFU-S-13, observed in the AhR-KO mice (Fig. 1b). Thus, steady-state hemopoiesis in the Wt mice, on the other hand, is presumed to be suppressed by AhR signaling because of the possible presence of a physiological ligand, which is not readily observed in the AhR-KO mice. In contrast, the
Conclusions
Mice that had been lethally irradiated and repopulated with BM cells from AhR-KO mice essentially did not show any benzene-induced hematotoxicity. The present study elucidated the following: first, benzene-induced decrease in BM cellularity was clearly nullified by BM cells in mice that had been repopulated with AhR-KO BM cells. Second, we observed some differences in toxicologic phenotypes depending on the exposure route, that is, intraperitoneal, used in the previous study, or intragastric,
Acknowledgments
This work was supported in part by a Grant-in-Aid for Scientific Research C, 15510064 and also by the MHLW-Research Fund (H16-Chemistry 003), National Institute of Health Sciences.
We thank Ms. E. Tachihara, Ms. Y. Usami, Ms. Y. Shinzawa, and Ms. M. Uchiyama for excellent technical assistance, and Ms. N. Kikuchi, M. Yoshizawa, and Ms. M. Hojo for secretarial assistance.
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Present address: Department of Veterinary Medicine, College of Animal Resource, Kangwon National University, Kangwon-Do 200-701, Republic of Korea.