The use of a pharmacogenetic mouse model to assess maternal and fetal susceptibility to the carcinogenic effects of coal tar.

摘要

Polycyclic Aromatic Hydrocarbons (PAH) have been demonstrated to bind to the aryl hydrocarbon (Ah) receptor, thereby eliciting the expression of enzymes responsible for their metabolism. The development of mouse strains that differ genetically in their inducibility of these enzymes can be used to evaluate how differential enzyme expression can modulate PAH metabolism, and therefore, their carcinogenic potency. Using the C57 x DBA mouse model, both maternal and fetal susceptibility to the carcinogenic effects of a complex mixture of PAH was determined.; An initial study evaluated susceptibility to the genotoxic effects of PAH as a function of Ah responsiveness following ingestion of coal tar. C57BL/6J and DBA/2J mice were fed a diet containing 0.3% coal tar for 14 days. Urine was collected during the last 24h of diet administration for metabolite analysis. Lung and liver tissues were evaluated for chemical:DNA adduct formation using 32P-postlabeling. Differences in urinary metabolite excretion were detected between the two strains, as well as tissue differences in PAH:DNA adduct formation. Additional studies were designed to evaluate the role of maternal and fetal Ah phenotype on PAH:DNA adduct formation following exposure to coal tar.; Pregnant B6D2F1/J and DBA/2J mice were dosed either orally or topically with coal tar. Dams and their pups were killed at the time of birth, and maternal and fetal tissues were evaluated for PAH:DNA adducts. Total adducts were greater in lung of B6D2F1/J compared with DBA/2J dams, while the opposite was true of liver. Total adducts were greater in tissues of pups from B6D2F1/J compared with pups of DBA/2J dams. These results are contrary to those obtained from studies in which dams were dosed topically with coal tar, and indicate a maternal influence on DNA adduct formation in fetal tissues that is modified by the route of exposure.; A subsequent study evaluated tumor formation in mice one year following exposure to coal tar in utero. Neoplasms, primarily of the lung, were detected in DBA/2J dams and the incidence of neoplasms was also greater for their pups. Together, these studies demonstrate maternal Ah genotype and route of exposure as contributing factors that influence biological outcome following transplacental exposure to a complex mixture.