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

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.

Effects of combined exposure to formaldehyde and benzene on immune cells in the blood and spleen in Balb/c mice.

Formaldehyde and benzene are the two major indoor air pollutants due to their prevalence and toxicity. This study aimed to explore the toxic effect on the spleen and relevant immune responses of Balb/c mice caused by exposure to a combination of formaldehyde and benzene. Balb/c mice were divided randomly into five groups (n=9/group): blank control group (Ctrl); solvent ([corn] Oil) control; formaldehyde only (FA, 3mg/m(3)); benzene only (BZ, 150mg/kg BW); and, formaldehyde+benzene group (FA+BZ). Exposures were performed for 8h/day, 5 day/week, for 2 weeks. Tail blood was collected after the final exposure; 24-h later, the mice were euthanized to permit assessment of a variety of immune endpoints. The endpoints' three areas were: (1) in living mice, body weight and delayed-type hypersensitivity (DTH) responses; (2) in blood, immune cell counts and serum antibody levels (serum hemagglutination); and, (3) in spleen samples, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), caspase-3 (cell apoptosis) levels and lymphocyte proliferation. In this study we fund (1) BZ and FA+BZ exposure can lead to the reduction in the number of some immune cells in peripheral blood; (2) Formaldehyde has certain synergistic effects on benzene-induced cytotoxicity in peripheral blood, (3) FA, BZ and FA+BZ exposure can lead to ROS and GSH depletion in spleen cells, and spleen cell apoptosis (caspase-3 increased) may be one of the downstream events, decreased splenic lymphocyte proliferation; and (4) the FA+BZ combined exposure can lead to the decreased body weight, serum antibody level (by serum hemagglutination assay).