The Role of Mitochondrial and Oxidative Injury in BDE 47 Toxicity to Human Fetal Liver Hematopoietic Stem Cells

Abstract

The polybrominated diphenyl ethers (PBDEs) are a group of flame retardants whose residues have markedly increased in the environment and in human tissues during the last decade. Of the various congeners, BDE 47 (2,2',4,4'-tetrabromodiphenyl ether) is typically the predominant congener observed in fish and wildlife samples, as well as in human tissues. Several studies indicate in utero transfer of PBDEs during pregnancy with residues accumulating in fetal tissues, and thus the potential for BDE 47-mediated injury in utero is of concern. In this study, we examined the mechanisms of BDE 47-mediated injury to primary human fetal liver hematopoietic stem cells (HSCs), which comprise a large proportion of fetal hepatic cells and play a key role in hematopoiesis during fetal development. Incubation of fetal liver HSCs with BDE 47 led to a loss of mitochondrial membrane potential and the onset of apoptosis. These effects were observed in the low micromolar range of BDE 47 exposures. At higher concentrations, BDE 47 elicited a loss of viability, which was accompanied by the generation of reactive oxygen species and peroxidation of HSC lipids. Preincubation of fetal liver HSCs with N-acetylcysteine, a glutathione (GSH) precursor, caused an increase in cellular GSH concentrations, restored mitochondrial redox status, and ameliorated the toxicity of BDE 47. BDE 47-mediated cytotoxicity or oxidative injury was not evident at the lower concentrations (< 1microM). Collectively, these data support a role for oxidative stress in the cytotoxicity of BDE 47 and indicate that oxidative stress-associated biomarkers may be useful in assessing the sublethal effects of BDE 47 toxicity in other models. However, the fact that BDE 47 undergoes a concentration-dependent accumulation in other primary cells in media that can underestimate cellular concentrations (W. R. Mundy et al., 2004, Toxicol. Sci. 82, 164-169) suggests that the HSC cell injury observed in our study may be of less relevance to human in utero PBDE exposures.

Alterations in retinoid status after long-term exposure to PBDEs in zebrafish (Danio rerio)

“…In terms of PBDE toxicity, it has also been proposed that one of mechanisms is an increased formation of reactive oxygen species (ROS). Studies have demonstrated that PBDEs can induce oxidative stress in neuronal cells (Costa and Giordano, 2007), in addition to mammals, bird and fish hepatocytes (Fernie et al, 2005;Raldúa et al, 2008;Shao et al, 2008;Albina et al, 2010;Zhao et al, 2011). Consequently, oxidative stress could contribute to the alternation of retinoids and increase the utilization of retinol as an antioxidant.…”

Cytotoxicity and apoptosis induction on RTG-2 cells of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and decabrominated diphenyl ether (BDE-209)

“…cells (He et al, 2008a,b;Shao et al, 2008). However, little information exists about the possible toxic mechanisms induced by of PBDEs.…”

“…There is supporting evidence for the ability of PBDEs to induce oxidative stress. BDE-47 was reported to cause oxidative stress in different cells, such as human neutrophil granulocytes (Reistad and Mariussen, 2005), human neuroblastoma cells (He et al, 2008b), hippocampal neurons (He et al, 2008a), and human fetal hematopoietic cells (Shao et al, 2008). While BDE-209 was shown to increase oxidative stress in human hepatoma cells Hep G2 (Hu et al, 2007).…”

The selective cytotoxicity of the alkenyl glucosinolate hydrolysis products and their presence in Brassica vegetables.

“…Oxidative stress was determined fluorometrically using diclorofluorescein (DCF) (Said et al 2007); (Shao et al 2008 nm and emission at 520 nm) were taken from 0.5 h -24 h using a BMG Polarstar fluorimetric plate reader. Measurements were recorded for 4 independent cultures.…”