1999 Progress Report: Mechanism of Carcinogenesis of Thia-PAHs

EPA Grant Number: R826192
Title: Mechanism of Carcinogenesis of Thia-PAHs
Investigators: Kumar, Subodh
Current Investigators: Kumar, Subodh , Sikka, Harish C.
Institution: The State University of New York at Buffalo
EPA Project Officer: Hahn, Intaek
Project Period: November 3, 1997 through November 2, 2000
Project Period Covered by this Report: November 3, 1998 through November 2, 1999
Project Amount: $500,827
RFA: Exploratory Research - Human Health (1997) RFA Text |  Recipients Lists
Research Category: Health Effects , Human Health , Health

Objective:

Exposure to a wide variety of complex chemical mixtures such as in automobile exhaust, soot, coal tar and pitch, mineral oils, shale oil, coal-gasification residues, and cigarette smoke has been associated with an increased incidence of cancer. These complex mixtures contain a number of polycyclic aromatic hydrocarbons (PAHs), and their heterocyclic analogues (especially aza-PAHs and thia-PAHs), many of which are carcinogens. To fully understand the risk that various carcinogenic chemicals in a complex mixture may present to human health, it is important that these chemicals be studied for their mechanism of carcinogenic action. Most of the studies conducted in the past involved predominantly PAHs and, to some extent, aza-PAHs. In contrast, thia-PAHs have been studied very little for their mechanism of carcinogenic action, despite observations that: (1) these thia-PAHs are present in up to 50 percent of the total hydrocarbons in some of the environmental samples, and (2) thia-PAHs are known to be more persistent, bioaccumulated, and carcinogenic compared to their homocyclic analogues (PAHs). The objective of the proposed research is to investigate whether thia-PAHs are activated by the mechanism similar to that of PAHs, or whether they follow a different metabolic activation pathway(s) due to the presence of sulfur heteroatom. The purpose of the proposed research is to identify the metabolic activation pathway(s) of benzo[b]phenanthro[2,3-d]thiophene (BPT), a model thia-PAH, known to be more carcinogenic than its PAH isoster dibenz[a,h]anthracene. To accomplish the project objectives, we propose to: (1) study the metabolism of BPT by liver microsomes from induced or uninduced mice and rats, and identify the metabolites formed; (2) assess the mutagenicity of BPT and its metabolites; and (3) characterize the DNA adducts produced in mouse skin treated with BPT.

Progress Summary:

During the second year of the project period, we developed the synthesis that enabled us to prepare BPT-trans-3,4-diol (a potential mutagenic/carcinogenic metabolite of BPT) in pure form. Our metabolism studies from liver microsomes prepared from control mice and rats, and from mice and rats induced with dibenz[a,h]anthracene (DBA), 3-MC, PB or Araclor-1254 indicated that mouse liver is better in metabolizing BPT than rat liver. Among identifiable metabolites, BPT-trans-3,4-diol was always the major metabolite compared to BPT sulfoxide or BPT sulfone, except for the liver microsomes from PB-induced mice and 3-MC-induced rats. With these microsomes, BPT sulfoxide was the major metabolite compared to BPT-trans-3,4-diol. In addition to these identifiable metabolites, additional metabolites also were produced. The formation of many of these unknown metabolites was significantly inhibited in the presence of epoxide hydrolase inhibitor, 3,3,3-trichloropropylene-1,2-epoxide (TCPO), in the incubation mixture, suggesting that these unknown metabolites of BPT are either isomeric dihydrodiols or dihydrodiol-derived. Our preliminary data also have suggested that, under in vitro conditions, the major BPT-DNA adducts are derived via BP-trans-3,4-diol. The involvement of sulfoxide or sulfone in the formation of BPT-DNA adducts does not appear to be very significant.

Future Activities:

Future activities include: (1) characterization of unknown BPT metabolites, especially those which require epoxide hydrolase activity in their formation; (2) continued characterization of BPT-DNA adducts produced in vitro (liver microsomes) and in vivo (mouse skin); and (3) mutagenicity studies of BPT and its various metabolites.

Journal Articles:

No journal articles submitted with this report: View all 8 publications for this project

Supplemental Keywords:

PAHs, thia-PAHs, metabolism, DNA adducts., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, Waste, air toxics, Genetics, Environmental Chemistry, Health Risk Assessment, chemical mixtures, Risk Assessments, Biochemistry, Physical Processes, complex mixtures, cumulative risk, furnace emissions, mutagenic properties, heterocyclic analogues, sulfur heteroatom, exposure and effects, automobile exhaust, mineral oils, exposure, cigarette smaoke, PAH, DNA adducts, metabolic activation, human exposure, cigarette smoke, cancer risk, carcinogenic

Progress and Final Reports:

Original Abstract
  • 1998 Progress Report
  • Final Report