Abstract
Formaldehyde (FA), an economically important and ubiquitous chemical, has been classified as a human carcinogen and myeloid leukemogen. However, the underlying mechanisms of leukemogenesis remain unclear. Unlike many classical leukemogens that damage hematopoietic stem/progenitor cells (HSC/HPC) directly in the bone marrow, FA—as the smallest, most reactive aldehyde—is thought to be incapable of reaching the bone marrow through inhalation exposure. A recent breakthrough study discovered that mouse lung contains functional HSC/HPC that can produce blood cells and travel bi-directionally between the lung and bone marrow, while another early study reported the presence of HSC/HPC in rat nose. Based on these findings, we hypothesized that FA inhalation could induce toxicity in HSC/HPC present in mouse lung and/or nose rather than in the bone marrow. To test this hypothesis, we adapted a commercially available protocol for culturing burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte, macrophage (CFU-GM) colonies from bone marrow and spleen to also enable culture of these colonies from mouse lung and nose, a novel application of this assay. We reported that in vivo exposure to FA at 3 mg/m3 or ex vivo exposure up to 400 µM FA decreased the formation of both colony types from mouse lung and nose as well as from bone marrow and spleen. These findings, to the best of our knowledge, are the first empirically to show that FA exposure can damage mouse pulmonary and olfactory HSC/HPC and provide potential biological plausibility for the induction of leukemia at the sites of entry rather than the bone marrow.
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Acknowledgements
This project was partially supported by NIEHS Superfund research grant P42ES004705 and Chau Hoi Shuen Foundation Women in Science Program Award at University of California at Berkeley (L Zhang), as well as the National Key Research and Development Program of China (2017YFC0702700) (R Li). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIEHS and other funding agencies. We thank Dr. Zhe Liu from University of California, San Francisco (UCSF) at Dr. Looney's lab for her valuable suggestions on the protocol of lung cell extraction. YZ is a recipient of the China Scholarship Council for a graduate fellowship to UC Berkeley for 2 years (201706770048).
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Zhao, Y., Magaña, L.C., Cui, H. et al. Formaldehyde-induced hematopoietic stem and progenitor cell toxicity in mouse lung and nose. Arch Toxicol 95, 693–701 (2021). https://doi.org/10.1007/s00204-020-02932-x
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DOI: https://doi.org/10.1007/s00204-020-02932-x