In Utero Exposure to Benzene Disrupts Fetal Hematopoietic Progenitor Cell Growth via Reactive Oxygen Species

Abstract

It is hypothesized that the increasing incidence of childhood leukemia may be due to in utero exposure to environmental pollutants, such as benzene, but the mechanisms involved remain unknown. We hypothesize that reactive oxygen species (ROS) contribute to the deregulation of fetal hematopoiesis caused by in utero benzene exposure. To evaluate this hypothesis, pregnant C57Bl/6N mice were exposed to benzene or polyethylene glycol-conjugated catalase (PEG-catalase) (antioxidative enzyme) and benzene. Colony formation assays on fetal liver cells were performed to measure erythroid and myeloid progenitor cell growth potential. The presence of ROS in CD117(+) fetal liver cells was measured by flow cytometric analysis. Oxidative cellular damage was assessed by Western blot analysis of 4-hydroxynonenol (4-HNE) and nitrotyrosine products, as well as reduced to oxidized glutathione ratios. Alterations in the redox-sensitive signaling pathway nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kappaB) were measured by Western blot analysis of Inhibitor of NF-kB-alpha (IkappaB-alpha) protein levels in fetal liver tissue. In utero exposure to benzene caused a significant increase in ROS production and significantly altered fetal liver erythroid and myeloid colony numbers but did not increase the levels of 4-HNE or nitrotyrosine products or alter reduced to oxidized glutathione ratios. However, in utero exposure to benzene did cause a significant decrease in fetal liver IkappaB-alpha protein levels, suggesting activation of the NF-kappaB pathway. Benzene-induced ROS formation, abnormal colony growth, and decreased IkappaB-alpha levels were all abrogated by pretreatment with PEG-catalase. These results suggest that ROS play a key role in the development of in utero-initiated benzene toxicity potentially through disruption of hematopoietic cell signaling pathways.

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

“…Once absorbed, CYA is extensively metabolized in the liver and intestine, producing a number of metabolites, with BDCYA (1,4-bisdesoxycyadox) being the main metabolite and designated as the marker residue in some jurisdictions (Liu et al, 2009;Xu et al, 2012;Wu et al, 2012). BDCYA, the N-oxide reduction product of CYA, is formed by reducing oxygen on both the N1 and N4 sites on the benzene moiety which would lead to DNA damage by intermediate radical production Badham et al, 2010). Hence, BDCYA could be a potential toxic metabolite of CYA, and should be considered together with the parent drug for food safety concerns.…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…reduced numbers of bone marrow cells, erythrocytes and lymphocytes) have been reported in 4 in vivo benzene studies Farris et al, 1997;Niculescu & Kalf, 1995;Robinson et al, 1997). Lastly, oxidative stress such as ROS generation (Badham & Winn, 2010b;Kolachana et al, 1993), nitrosative stress such as nitric oxide generation (Chen et al, 2005b;Laskin et al, 1995;Punjabi et al, 1994) have been mentioned to contribute to the benzene-mediated haematotoxicity.…”

“…The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. Winn, 2010aWinn, , 2010bLau et al, 2009). For inhalation studies, a range of 10-400 ppm has been used for subchronic/chronic exposure studies (i.e.…”

“…fluctuations of myeloid or erythroid colonies) is the most commonly reported downstream key event associated with benzene exposure (6 out of 24 studies) regardless of the exposure route Badham & Winn, 2010a, 2010bNiculescu & Kalf, 1995;Sun et al, 2015;Yoon et al, 2002). In particular, in utero exposure of benzene altered the foetal liver and erythroid colony numbers in the offspring, which might have increased susceptibility of developing haematopoietic as well as hepatic tumours later in life Badham & Winn, 2010a, 2010b. Genotoxicity (e.g.…”

Determination of cadmium and zinc levels and oxidative status in cadmium treated developing chick embryonic liver

“…The cellular redox status and antioxidant defense mechanisms are more sensitive and lower in the embryo compared to adults [9][10][11][12][13]. Antioxidant defense mechanisms against free radical-induced oxidative damage include the following (i) catalytic removal of free radicals and reactive species by factors such as CAT, SOD, peroxidase and thiol-specific antioxidants; (ii) binding of proteins (e.g., transferrin, metallothionein, haptoglobins, ceruloplasmin) to pro-oxidant metal ions, such as iron and copper; (iii) protection against macromolecular damage by proteins such as stress or heat shock proteins; and (iv) reduction of free radicals by electron donors, such as GSH, vitamin E, vitamin C, bilirubin and uric acid [14][15][16][17][18][19][20].…”