ENVIRONMENTAL POLYCYCLICS--METABOLISM AND ACTIVATION

Project Details

Description

The objective of this research program is to determine the
mechanisms) by which several nonalternant polycyclic aromatic
hydrocarbons (PAH) are activated to carcinogens. This research
program will focus on the environmental pollutants:
benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)fluoranthene,
indeno-(1,2,3-cd)pyrene, and 2- and 3-methylfluoranthene. Several new methods will be developed for elucidating the
mechanism(s) of action of these nonalternant PAH. We will use a
combination of the classical fluorine-probe approach with 32P post-
labelling of DNA adducts as formed in vivo in mouse skin to
determine those positions in these molecules which are critically
associated with their genotoxic activity. With synthetic standards
and 32P post-labelling, we will determine the extent to which
suspect proximate and ultimate carcinogenic metabolites contribute
to the DNA adducts formed from their parent hydrocarbon. The
chemical nature of the post-labelled DNA adducts formed will be
partially established by their chromatographic properties on HPLC
and their retention using immobilized boronate chromatography. The
possibility that differences in DNA adduct formation or persistence
are correlated with know sex differences in tumorigenic activity
will also be determined. Bioassays in newborn mice and initiation
promotion bioassays on mouse skin will be among the principal in
vivo bioassays which will be employed to evaluate suspect proximate
and ultimate carcinogenic metabolites. This research program will provide data essential for analysis of
their DNA adducts in peripheral lymphocytes as well as establish
the appropriate methodology for the analysis of the principal
hemoglobin bound adducts of these nonalternant PAH. The methods
which developed in this research program will be of general use in
elucidating the mechanism of action of other genotoxic agents and
in developing suitable indices of human exposure.
StatusFinished
Effective start/end date12/5/782/28/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $209,381.00
  • National Institutes of Health: $259,525.00
  • National Institutes of Health: $207,322.00
  • National Institutes of Health: $239,561.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Environmental Science(all)
  • Medicine(all)

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