Investigating the role of reactive oxygen species in transplacental benzene carcinogenesis

The incidence of childhood leukemia is increasing, especially in urbanized areas. It is hypothesised that transplacental exposure to environmental carcinogens, such as benzene, plays a role in the etiology of childhood cancers. The studies in this thesis investigated mechanisms of transplacental benzene tumourigenesis focusing on the role of reactive oxygen species (ROS). Initially, we investigated the effect of maternal benzene exposure on fetal erythroid progenitor cell number and the role of ROS in benzene metabolite-induced dysregulation of erythropoiesis. In the CD-1 mouse, in utero benzene exposure caused significant alterations in female fetal liver erythroid progenitor cell numbers at gestational day 16 and postnatal day 2. Using an in vitro chicken erythroblast cell line capable of erythropoiesis, we found that hydroquinone significantly inhibited erythropoiesis and this effect was prevented by pretreatment with PEG-superoxide dismutase. The second objective investigated the role of ROS in dysregulated fetal hematopoietic progenitor cell growth after maternal benzene exposure in C57Bl/6N mice. In utero exposure to benzene caused changes in fetal hematopoietic progenitor cell numbers, an increase in levels of fetal liver intracellular ROS, and a decrease in IkappaB-alpha protein levels, which were all prevented by pretreatment with PEG-catalase. The final objective determined the incidence of cancer in offspring transplacentally exposed to benzene. This study compared two strains of mice (C57Bl/6N and CD-1), as well as male and female offspring. This study also measured levels of benzene and benzene metabolites present in maternal blood and fetal liver tissue after maternal benzene exposure. Transplacental exposure to benzene induced hepatic and hematopoietic tumours in male and female CD-1 mice, respectively. Interestingly, there were no significant changes in tumour incidence in C57Bl/6N mice demonstrating a significant strain difference in susceptibility to transplacental benzene carcinogenesis. Levels of fetal liver benzene metabolites also differed between genders and strains of mice suggesting that the gender and strain differences in tumour formation may be dependent on fetal benzene metabolism capability. In conclusion, this thesis supports the hypothesis that benzene exposure to pregnant women contributes to the etiology of childhood cancers and highlights ROS and fetal benzene metabolism as potential mechanisms.