Benzene-initiated oxidative stress: Effects on embryonic signaling pathways.
Approximately 90% of childhood cancers are of unknown etiology; however, it is hypothesized that in utero carcinogen exposure may contribute. Epidemiological studies have correlated parental exposure to benzene with an increased incidence of childhood leukemias. However, mechanisms of benzene-induced carcinogenesis following in utero exposure remain unknown. We hypothesize that in utero exposure to benzene causes alterations in the redox-sensitive signaling pathways involving c-Myb, Pim-1, AKT, ERK-MAPK, p38-MAPK, and NF-kappaB via the production of reactive oxygen species (ROS) as a possible mechanism of in utero-initiated carcinogenesis. Using a CD-1 mouse model we have shown increased oxidative stress in fetal tissue from embryos exposed in utero to benzene by measuring reduced to oxidized glutathione ratios, and increased levels of ROS in male fetuses using flow cytometry and the ROS sensitive fluorescent probe dichlorofluoroscein diacetate (DCFDA). In addition, using Western blotting techniques we observed increased expression of fetal Pim-1, Pim-1 phosphorylation, c-Myb, and phosphorylated p38-MAPK (activated form) and lower protein levels of IkappaBalpha, while phosphorylated ERK-MAPK and AKT protein levels did not change. Interestingly, we found male fetuses more susceptible to benzene-induced oxidative stress, which is in agreement with the literature suggesting that males are more susceptible to benzene toxicity. Further studies evaluating the reason for this gender difference are ongoing.
Badham
Helen J
HJ
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Renaud
Stephen J
SJ
Wan
Joanne
J
Winn
Louise M
LM
D000818:Animals; D001554:Benzene / Q000009:adverse effects*; D002273:Carcinogens / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002273:Carcinogens; D016328:NF-kappa B; D020598:Proto-Oncogene Proteins c-myb; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D048051:p38 Mitogen-Activated Protein Kinases; D001554:Benzene