Prolonged benzo[
6 affiliations
- 1Department of Biology, University of Ottawa, Ottawa, Canada
- 2Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada
- 3Department of Biology, University of Ottawa, Ottawa, Canada; Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada
- 4Pharmaceutical Sciences, pRED Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
- 5Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada; Department of Biology, Carleton University, Ottawa, Canada; Corresponding author at: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada.
- 6Department of Biology, University of Ottawa, Ottawa, Canada; Corresponding author at: Department of Biology, University of Ottawa, Ottawa, Canada.
Abstract
Chronic exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with increased risk of cancer through a mutagenic mode of action. We investigated how exposure duration influences mutagenicity in bone marrow (BM) and liver of MutaMouse males orally exposed to increasing doses of benzo[ b ]fluoranthene (BbF), a priority PAH, for 28, 90, or 180 days. We applied Duplex Sequencing (DS) across 20 endogenous loci to assess dose- and time-dependent effects on mutation frequency, clonal expansion of mutant cells, mutation distribution, and spectra. Mutation frequencies increased with BbF dose and exposure duration in both tissues. After 90 and 180 days of exposure to 25 mg/kg/day BbF, mutation frequency was 1.7x and 2.1x higher in BM, and 3.8x and 8.6x higher in liver, than 28-day exposures. Clonally derived mutations increased significantly with exposure duration in BM but not liver. Intergenic loci incurred more mutations than genic regions in both tissues across all exposure durations. Mutation spectra were dominated by C:G > A:T transversions and were enriched in SBS4, the mutation signature associated with tobacco-induced human lung cancer. Benchmark dose (BMD 50 ) modeling showed increasing BbF potency with longer exposures. BMD 50 decreased from 8.2 (28d) to 3.7 (90d) and 3.0 (180d) mg/kg/day in BM; in liver, BMD 50 shifted from 14.3 (28d) to 4.3 (90d) and 3.9 (180d) mg/kg/day. The observed tissue-specific responses may be attributed to differences in proliferation rate, metabolic activity, and cellular lifespan. Our findings provide insights into the mutagenic impacts of prolonged PAH exposure and highlight tissue-specific differences in mutation susceptibility.
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BibTeX
@article{schuster2026prolonged,
title = {{Prolonged benzo[}},
author = {D.M. Schuster and D.P.M. LeBlanc and G. Zhou and M.J. Meier and A.E. Dodge and P.A. White and A. Zeller and A. Williams and D.C. Eickmeyer and S. Kehm and J. Funk and F. Marchetti and C.L. Yauk},
journal = {Environment International},
year = {2026},
month = oct,
doi = {10.1016/j.envint.2026.110516},
url = {https://doi.org/10.1016/j.envint.2026.110516},
note = {CC BY},
}
RIS
TY - JOUR
TI - Prolonged benzo[
AU - D.M. Schuster
AU - D.P.M. LeBlanc
AU - G. Zhou
AU - M.J. Meier
AU - A.E. Dodge
AU - P.A. White
AU - A. Zeller
AU - A. Williams
AU - D.C. Eickmeyer
AU - S. Kehm
AU - J. Funk
AU - F. Marchetti
AU - C.L. Yauk
PY - 2026
DA - 2026/10/24
JO - Environment International
DO - 10.1016/j.envint.2026.110516
UR - https://doi.org/10.1016/j.envint.2026.110516
AB - Chronic exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with increased risk of cancer through a mutagenic mode of action. We investigated how exposure duration influences mutagenicity in bone marrow (BM) and liver of MutaMouse males orally exposed to increasing doses of benzo[ b ]fluoranthene (BbF), a priority PAH, for 28, 90, or 180 days. We applied Duplex Sequencing (DS) across 20 endogenous loci to assess dose- and time-dependent effects on mutation frequency, clonal expansion of mutant cells, mutation distribution, and spectra. Mutation frequencies increased with BbF dose and exposure duration in both tissues. After 90 and 180 days of exposure to 25 mg/kg/day BbF, mutation frequency was 1.7x and 2.1x higher in BM, and 3.8x and 8.6x higher in liver, than 28-day exposures. Clonally derived mutations increased significantly with exposure duration in BM but not liver. Intergenic loci incurred more mutations than genic regions in both tissues across all exposure durations. Mutation spectra were dominated by C:G > A:T transversions and were enriched in SBS4, the mutation signature associated with tobacco-induced human lung cancer. Benchmark dose (BMD 50 ) modeling showed increasing BbF potency with longer exposures. BMD 50 decreased from 8.2 (28d) to 3.7 (90d) and 3.0 (180d) mg/kg/day in BM; in liver, BMD 50 shifted from 14.3 (28d) to 4.3 (90d) and 3.9 (180d) mg/kg/day. The observed tissue-specific responses may be attributed to differences in proliferation rate, metabolic activity, and cellular lifespan. Our findings provide insights into the mutagenic impacts of prolonged PAH exposure and highlight tissue-specific differences in mutation susceptibility.
SN - 0160-4120
ER -