NITROAROMATICS--CARCINOGENITY AND METABOLISM

Project: Research project

Description

1-Nitropyrene (1-NP) is considered one of the major components found in
numerous environmental sources and is tumorigenic in mouse lung and liver,
in rat mammary glands in hamster trachea and lung. 6-Nitrochrysene (6-NC),
which is carcinogenic in newborn mouse lung and liver, is the most active
compound tested in this assay, more active than benzo[a]pyrene. In rat
mammary glands and in newborn mouse liver and lung, multiple DNA adducts
were detected following administration of 1-NP. In contrast one major
adduct was detected in newborn mouse liver and lung following
administration of 6-NC. Based on our results we hypothesized that the
major metabolic activation pathway of 1-NP in newborn mice occurs via
nitroreduction and in Sprague-Dawley rats via ring oxidation; both pathways
are essential for the metabolic activation of 6-NC in newborn mice. In
order to clearly define the biological activities of these compounds,
assess the possible risks associated with human exposure, and test our
hypothesis our aims are: 1) Elucidate the structures of the major DNA
adducts detected in newborn mouse liver and lung and in rat liver and
mammary glands following the administration of 1-NP; 2) Compare the
tumorigenic activity of 1-NP and its ring oxidized metabolites in a)
Newborn mice, b) Newborn female Sprague-Dawley rats; 3) Develop sensitive
analytical methods for detecting urinary metabolites of 1-NP in humans; 4)
Compare the tumorigenic activities of 6-NC and its metabolites derived from
nitroreduction and ring oxidation in newborn female Sprague-Dawley rats; 5)
Compare the tumorigenic activities of
1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-aminochrysene
(1,2-DHD-3,4-oxide-6-AC) and
1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (1,2-DHD-3,4-oxide-C) in
newborn mice; 6) Establish the relationship between the levels of DNA
adducts in newborn mouse lung and liver and the capacity for tumor
induction by 1,2-DHD-3,4-oxide-6-AC and 1,2-DHD-3,4-oxide-C.
StatusFinished
Effective start/end date7/1/837/31/13

Funding

  • National Institutes of Health: $203,066.00
  • National Institutes of Health: $240,111.00
  • National Institutes of Health: $295,970.00
  • National Institutes of Health: $304,309.00
  • National Institutes of Health: $356,452.00
  • National Institutes of Health
  • National Institutes of Health: $20,790.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $143,420.00
  • National Institutes of Health: $107,999.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $292,895.00
  • National Institutes of Health: $333,404.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $13,409.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $22,247.00
  • National Institutes of Health: $293,198.00
  • National Institutes of Health: $295,970.00
  • National Institutes of Health
  • National Institutes of Health: $276,609.00
  • National Institutes of Health: $291,763.00
  • National Institutes of Health: $295,970.00
  • National Institutes of Health: $113,981.00
  • National Institutes of Health: $137,963.00
  • National Institutes of Health: $88,988.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

1-nitropyrene
Breast Neoplasms
DNA Adducts
Breast
Carcinogens
Aromatic Hydrocarbons
Mutation Rate
p53 Genes
Lung
6-nitrochrysene
Carcinogenesis
Liver
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
DNA Repair
Rodentia
Oxides
Human Mammary Glands
Sprague Dawley Rats
Mutation
Reporter Genes