title: Formaldehyde induces toxicity in mouse bone marrow and hematopoietic stem/progenitor cells and enhances benzene-induced adverse effects.
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/m3FA 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.
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China.|Key Laboratory of Ecological Safety Monitoring and Evaluation, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wei
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China.
authors.forename: Huaxiao
authors.initials: H
authors.lastname: Wen
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China.
authors.forename: Langyue
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, 94720, USA.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: McHale
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China.|Division of Biostatistics, Department of Population Health, School of Medicine, New York University, New York, NY, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China.
authors.forename: Junlin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, China. yangxu@mail.ccnu.edu.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, 94720, USA. luoping@berkeley.edu.
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001554:Benzene / Q000009:adverse effects*; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D005557:Formaldehyde / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D013154:Spleen / Q000187:drug effects; D018675:Toxicity Tests / Q000379:methods
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D017978:Receptors, Growth Factor; D005557:Formaldehyde; C505409:Casp3 protein, mouse; D053148:Caspase 3; D001554:Benzene
keywords: Benzene; Bone marrow; Formaldehyde; Hematotoxicity; Myeloid progenitor