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ADDITIVITY OF IN VIVO MUTATION INDUCTION BY CUMULATIVE EXPOSURES TO BENZO[A]PYRENE OR DIBENZO[A,L]PYRENE
Citation:
LEAVITT, S. A., T. MOORE, M. H. GEORGE, AND J. A. ROSS. ADDITIVITY OF IN VIVO MUTATION INDUCTION BY CUMULATIVE EXPOSURES TO BENZO[A]PYRENE OR DIBENZO[A,L]PYRENE. Presented at International Society for Polycyclic Aromatic Compounds , Toronto, ON, CANADA, August 21 - 26, 2005.
Description:
Dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P) are polycyclic aromatic hydrocarbons (PAH) found in cigarette smoke condensate, coal combustion processes and in some environmental pollutants. In this study, we investigated the effect of dosing regimen on the mutagenicity of DB[a,l]P and B[a]P in vivo using the Big Blue. transgcnic mouse system. Six animals per treatment group were dosed ip either with 6mg/kg DB[a,l]P once, or 1.2mg/kg DB[a,l]P on five consecutive days, or with 200mg/kg B[a]P once, or 40mg/kg B[a]P on five consecutive days. Animals were sacrificed 31 days after final administration of PAH and lungs were removed. DNA extracted from the lungs was assayed for the presence of mutations in the lacI gene. Both PAHs tested were mutagenic in the Big Blue. mouse lung. DNA isolated from the lungs of solvent treated control mice exhibited a mutant frequency of 3.18 x 10-5. A 2.4- fold increase in mutant frequency was observed in the lungs of mice given a single injection of DB[a,l]P . For mice receiving daily injections of DB[a,l]P for five days, a 2.8-fold increase in mutant frequency was observed. The difference in mutant frequency between the treatment regimens for DB[a,l]P was not statistically significant (P=0.16). The mice receiving a single injection of B[a]P showed a 15.3-fold increase in mutant frequency relative to the control value, while those receiving daily injections of B[a]P for five days had a 16.1-fold increase in mutant frequency. There was no statistically significant difference between the treatment regimens for B[a]P (P=0.71)
The most prevalent mutation class recovered from control mice was G:C to A:T transitions (82%). The mutation spectrum recovered from mice treated with 6mg/kg DB[a,l]P contained G:C to A:T transitions (30%), G:C to T:A transversions (28%) and A:T to T:A transversions (12%). For mice treated with 1.2mg/kg DB[a,l]P for five days, G:C to A:T transitions (24%), G:C to T:A transversions (12%) and A:T to T:A (19%) transversions dominated the mutation spectrum. The mutation spectrum obtained from mice treated with 200mg/kg B[a]P exhibited high incidences of G:C to T:A transversions (50%) and G:C to A:T transitions (21 %). For mice treated with 40mg/kg B[a]P for five days, the prevalent types of mutations were G:C to T:A transversions (44%), G:C to A:T transitions (20%), and G:C to C:G transversions (13%). These data demonstrate that for these PAH, the cumulative induction of mutations by multiple exposures in this model system are reasonably predicted by the mutations induced by a comparable single exposure.