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Formaldehyde induces toxicity in mouse bone marrow and hematopoietic stem/progenitor cells and enhances benzene-induced adverse effects

  • Organ Toxicity and Mechanisms
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Abstract

Formaldehyde (FA) is a human leukemogen and is hematotoxic in human and mouse. The biological plausibility of FA-induced leukemia is controversial because few studies have reported FA-induced bone marrow (BM) toxicity, and none have reported BM stem/progenitor cell toxicity. We sought to comprehensively examine FA hematoxicity in vivo in mouse peripheral blood, BM, spleen and myeloid progenitors. We included the leukemogen and BM toxicant, benzene (BZ), as a positive control, separately and together with FA as co-exposure occurs frequently. We exposed BALB/c mice to 3 mg/m3 FA in air for 2 weeks, mimicking occupational exposure, then measured complete blood counts, nucleated BM cell count, and myeloid progenitor colony formation. We also investigated potential mechanisms of FA toxicity, including reactive oxygen species (ROS) generation, apoptosis, and hematopoietic growth factor and receptor levels. FA exposure significantly reduced nucleated BM cells and BM-derived colony-forming unit-granulocyte–macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E); down-regulated GM-CSFRα and EPOR expression; increased ROS in nucleated BM, spleen and CFU-GM cells; and increased apoptosis in nucleated spleen and CFU-GM cells. FA and BZ each similarly altered BM mature cells and stem/progenitor counts, BM and CFU-GM ROS, and apoptosis in spleen and CFU-GM but had differential effects on other end points. Co-exposure was more potent for several end points. Thus, FA is toxic to the mouse hematopoietic system, including BM stem/progenitor cells, and it enhances BZ-induced toxic effects. Our findings suggest that FA may induce BM toxicity by affecting myeloid progenitor growth and survival through oxidative damage and reduced expression levels of GM-CSFRα and EPOR.

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Abbreviations

BZ:

Benzene

BM:

Bone marrow

BFU-E:

Burst-forming unit-erythroid

bw:

Body weight

CBC:

Complete blood counts

CMP:

Common myeloid progenitor

CSF:

Colony-stimulating factor

EP:

Erythroid progenitor

EPO:

Erythropoietin

EPOR:

EPO receptor

FA:

Formaldehyde

GRA:

Granulocytes

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

GM-CSFRα:

GM-CSF receptor α

GMP:

Granulocyte–monocyte progenitor

HSC:

Hematopoietic stem cells

HPC:

Hematopoietic progenitor cells

HGB:

Hemoglobin

IL-3:

Interleukin-3

IL-3Rα:

IL-3 receptor α

LYM:

Lymphocytes

MCV:

Mean corpuscular volume

MEP:

Megakaryocyte–erythroid progenitor

MON:

Monocytes

MPP:

Multipotent progenitor

PLT:

Platelets

ROS:

Reactive oxygen species

RBC:

Red blood cells

WBC:

White blood cells

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Acknowledgments

This study was supported by National Natural Science Foundation of China-Key Program (51136002) to XY, National Institute of Health (R01ES017452) to LZ, and Excellent Doctoral Dissertation Cultivation Grant from Central China Normal University (2013YBYB67) to CW.

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Author notes

  1. Chenxi Wei

    Present address: Key Laboratory of Ecological Safety Monitoring and Evaluation, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China

  2. Kun Wang

    Present address: Division of Biostatistics, Department of Population Health, School of Medicine, New York University, New York, NY, USA

Authors and Affiliations

  1. Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China

    Chenxi Wei, Huaxiao Wen, Langyue Yuan, Hui Li, Kun Wang, Junlin Yuan & Xu Yang

  2. Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, 94720, USA

    Cliona M. McHale & Luoping Zhang

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  1. Chenxi Wei
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  2. Huaxiao Wen
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  3. Langyue Yuan
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Correspondence to Xu Yang or Luoping Zhang.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors. The manuscript does not contain clinical studies or patient data.

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Wei, C., Wen, H., Yuan, L. et al. Formaldehyde induces toxicity in mouse bone marrow and hematopoietic stem/progenitor cells and enhances benzene-induced adverse effects. Arch Toxicol 91, 921–933 (2017). https://doi.org/10.1007/s00204-016-1760-5

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