Translational Studies of the High Molecular Weight Polycyclic Aromatic Hydrocarbon, Dibenzo[ def,p] Chrysene; Carcinogenesis and Metabolism

Graduation date: 2016The objective of this work is to add to the body of translational data between high dose animal model research and the environmentally relevant human metabolism of the persistent pollutant dibenzo[def,p]chrysene (DBC). We furthered the knowledge of gene/exposure interactions by determining the carcinogenesis risk based on Cyp1b1 genotype following in utero DBC exposure in mice, finding no difference in lung carcinogesis by genotype. Cyp1b1 wild-type mice suffered mortality due to aggressive T-Cell Accute Lymphoblastic Leukemia (T-ALL), while Cyp1b1 null and CYP1B1 transgenic mice lack susceptibility to T-ALL. We also determined a link for Cyp1b1 status and fertility status, with a particular vulnerability in Cyp1b1 wild-type male mice fetally exposed to DBC. Female mice were found to have depleted primordial and primary follicle reserves in both Cyp1b1 wild-type and Cyp1b1 null mice. Further research will determine if the extent of depletion is similar across genotypes. \ud \ud In addition, sensitive accelerator mass spectrometry (AMS) was utilized to detect the metabolism of DBC (and BaP) by human volunteers following environmentally relevant exposures. The human PK of DBC validated rodent based PB/PK models generated to represent human metabolism for risk assessment. DBC appeared quickly in plasma, with the majority eliminated quickly over 24 hours and a slower elimination period to 72 hours. The PD of DBC provided evidence that DBC is rapidly biotransformed to metabolites circulating in plasma. The products of three or more bio-transformations (tetrols and beyond) were not present in the plasma, indicating that they are quickly converted to conjugated species and eliminated from the plasma compartment. Urine contained primarily DBC metabolites that had undergone two transformations or more (diols, tetrols, and a putative dione). The majority of these species exist as conjugated metabolites in urine. \ud \ud This body of work furthers the field of PAH translation by addressing disease and disease prevention endpoints from PAH exposure in rodent laboratory research models. Additionally, we are addressing human risk by removing the translation element and directly measuring PAH metabolism in humans from the oral route of exposure by taking a FDA IND "phase 0" approach to pharmacokinetics and pharmacodynamics