Critical windows of transplacental carcinogenesis : identifying efficacious approaches to chemoprevention with dietary phytochemicals

Graduation date: 2009Polycyclic aromatic hydrocarbons (PAHs) are a re-emerging class of environmental pollutants. The persistent nature of these highly toxic compounds along with their ubiquity in the environment creates an unavoidable route of exposure. The developing fetus and neonate are a particularly susceptible population due to their incomplete complement of xenobiotic metabolizing enzymes and limited DNA repair capacity. We’ve previously found that administration of dibenzo[a,l]pyrene (15 mg/kg), a potent PAH, late in gestation results in the induction of lymphoma, lung and liver cancer in the subsequent offspring.\ud Considering the lipophilicity of DBP, the relative contribution of in utero and lactational exposure in DBP-dependent carcinogenesis warranted investigation. We adopted a cross-foster design; litters born to DBP-treated dams were exchanged at birth with litters from control dams. Exposure to DBP in utero (~2 days) incurred more risk, resulting in increased lymphoma mortality and lung tumor multiplicity compared to exposure only through breast milk. To elucidate the enzymes\ud responsible for DBP bioactivation, we incorporated a strain of mice with the targeted disruption of the cyp1b1 gene. In support of our hypothesis concerning the role of fetal cyp1b1 in DBP transplacental carcinogenesis, we observed a clear pattern of decreasing survival time with increasing cyp1b1 gene dosage. More importantly, we have utilized this model to provide evidence that addition of phytochemicals to the maternal diet can ameliorate these DBP-dependent cancers. Incorporation of green tea in drinking water provided evidence that caffeine has a major role in the protective effects of green tea. Epigallocatechin-3-gallate was also effective in limiting the lung tumor burden in the offspring. However, the most effective protocol of all was co-administration of chlorophyllin (CHL). Incorporating CHL in the maternal diet had no impact of DBP transplacental carcinogenesis, yet if it was administered concurrently with DBP there was a 50% increase in lymphoma survival and nearly a 50% reduction in lung tumor multiplicity, further supporting a mechanism involving complex-mediated reduction in carcinogen uptake. These results present a new paradigm of dietary cancer chemoprevention which focus on early stages of development and also provides a strategy to potentially lessen tumor burden later in adult life