Inhaled formaldehyde induces DNA–protein crosslinks and oxidative stress in bone marrow and other distant organs of exposed mice

Abstract

Formaldehyde (FA), a major industrial chemical and ubiquitous environmental pollutant, has been classified as a leukemogen. The causal relationship remains unclear, however, due to limited evidence that FA induces toxicity in bone marrow, the site of leukemia induction, and in other distal organs. Although induction of DNA-protein crosslinks (DPC), a hallmark of FA toxicity, was not previously detected in the bone marrow of FA-exposed rats and monkeys in studies published in the 1980s, our recent studies showed increased DPC in the bone marrow, liver, kidney, and testes of exposed Kunming mice. To confirm these preliminary results, in the current study we exposed BALB/c mice to 0, 0.5, 1.0, and 3.0 mg m(-3) FA (8 hr per day, for 7 consecutive days) by nose-only inhalation and measured DPC levels in bone marrow and other organs of exposed mice. As oxidative stress is a potential mechanism of FA toxicity, we also measured glutathione (GSH), reactive oxygen species (ROS), and malondialdehyde (MDA), in the bone marrow, peripheral blood mononuclear cells, lung, liver, spleen, and testes of exposed mice. Significant dose-dependent increases in DPC, decreases in GSH, and increases in ROS and MDA were observed in all organs examined (except for DPC in lung). Bone marrow was among the organs with the strongest effects for DPC, GSH, and ROS. In conclusion, exposure of mice to FA by inhalation induced genotoxicity and oxidative stress in bone marrow and other organs. These findings strengthen the biological plausibility of FA-induced leukemogenesis and systemic toxicity.

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

“…In contrast, some studies have reported an apparent increase in DPCs in circulating lymphocytes of humans exposed to ambient concentrations in the workplace (Shaham et al, 1996(Shaham et al, , 2003. Increased DPCs were also found in several remote tissues, such as bone marrow, liver, kidney, and testes of mice exposed to inhaled formaldehyde (Ye et al, 2013).…”

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

“…Further, we reported that FA reduced blood cell counts and induced genotoxicity, oxidative stress, inflammation and apoptosis in mouse BM in vivo (Ye et al 2013;Zhang et al 2013). In the present study, we performed a comprehensive analysis of hematopoietic toxicity, including toxicity to stem/progenitor cells in BM, in FA-exposed mice.…”

“…Previously, we examined bone marrow toxicity in mice exposed to FA by nose-only inhalation (Ye et al 2013;Zhang et al 2013) to avoid minor confounding from skin absorption (NTP 2011). However, the nose-only apparatus is inhumane in that it immobilizes the animals, causing restraint stress that can impact immune function (Irwin et al 1990;Thomson et al 2009).…”

“…ROS levels in mouse nucleated BM, spleen, CFU-GM and BFU-E cells were determined by dichloro-dihydro-fluorescein diacetate (DCFH-DA) fluorescent assay using a previously described procedure (Ye et al 2013) with minor modifications. Briefly, 1 × 10 6 cells were suspended in 300 μL of 10 μM DCFH-DA (Sigma-Aldrich) and incubated at 37 °C for 30 min.…”

“…Although FA did not induce leukemia in mice or rats exposed to life-long high levels of FA in a much earlier study (Kerns et al 1983), we have recently shown that relatively low levels of FA induces toxic effects in BM of mice exposed by short-term nose-only inhalation (Ye et al 2013;Zhang et al 2013). However, toxicity to hematopoietic stem cells (HSC) or progenitor cells (HPC) in BM, the targets for leukemogenesis, has not been demonstrated previously.…”