Still a Threat: Polychlorinated Biphenyl (PCB) Metabolism in Cells & Formation of Cancer-Causing DNA Adducts
Chang, Wei-Ann; Taveras, Alwany Angeles; Saadatmand, Bahareh; Gaul, Larissa
Despite PCBs having been banned from manufacturing processes for decades, polychlorinated biphenyls or PCBs can still enter the environment through various means, such as improper waste disposal methods, and wreak havoc. Current PCB-containing products are those that predate the ban but persistent health risks still exist due to the PCB chemical stability in the environment. Exposure to PCBs through inhalation, ingestion, increase risk of developing multiple medical problems, particularly cancer. Once PCBs diffuse into a cell, metabolites are produced by a cascade of reactions. PCB metabolites can then bind to DNA to create DNA adducts. This process results in mutations that can gradually develop into cancer. We hope to gain a better understanding of the impact of PCB exposure by modeling cellular PCB metabolism and DNA adduct formation with COMSOL Multiphysics 5.5. Mass transfer modules (including reaction, partitioning, and diffusion) were used to model PCB and PCB metabolite movement and accumulation in a cell over time. We modelled one spherical cell with 1D axisymmetric geometry divided into five distinct domains. Factors including temperature, pH level, and organelle interactions (besides the nucleus) were disregarded. We also assumed a uniform enzyme concentration of 0.25 𝞵M for all enzymatic reactions. Key parameters including diffusion coefficients, some rate constants, and partitioning coefficients were referenced from similar work by Chaudhry et al. and the SABIO-RK database. Damage to the cell was quantified via the number of DNA adducts formed. Model validation was done by comparing the DNA adducts concentration of our COMSOL model, with published literature values. The final number of DNA adducts calculated by our COMSOL model was 104 times greater than the DNA adducts values from literature. The sensitivity analysis found the DNA adduct formation rate constant to be the most sensitive rate constant impacting the final DNA adduct concentration. It is possible that an incorrect DNA adduct formation rate could result in deviation from experimental results. It is also possible for incorrect rate constants to have a comparatively smaller effect on final DNA adduct values. Accurate quantification of DNA adducts formed from a specified PCB exposure time and concentration may allow quantification of a cancer risk from DNA adduct formation. If a specified level of acceptable DNA adduct formation and cancer risk was selected, maximum allowable exposure time and concentration will be known. Maximum allowable concentration can act as a design constraint for water treatment, soil remediation, and other treatment efforts. Accurate quantification of DNA adduct formation may further replace or supplement in vitro experimentation requiring 32P-post labeling or high performance liquid chromatography (HPLC), as well as in vivo experimentation, saving resources involved with live cell experiments.
DNA Adducts, PCBs, Polychlorinated Biphenyls, Mass Transfer, COMSOL
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