Mechanism of Carcinogenesis of Thia-PAHsEPA 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 Amount: $500,827
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health , Health
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 considered to be associated with increased incidence of cancer in human populations. 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. In order 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 mechanistic studies conducted in the past involved predominantly PAHs, and to some extent aza-PAHs. In contrast, thia-PAHs have been studied very little in spite of the observations that these thia-PAHs are present up to 50% of the total hydrocarbons in some of the crude oils and emissions from coal-fired residential furnaces. In addition, thia-PAHs are also known to be more persistent, bioaccumulated and carcinogenic compared to their homocyclic analogues (PAHs). Thus, despite the potential biohazard associated with thia-PAHs, there is extremely limited information available on the mechanism by which they induce their carcinogenic effects. The objective of the proposed research is to investigate whether thia-PAHs are activated by the mechanism similar to that of PAHs, or follow a different metabolic activation pathway(s) due do 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.
In order to accomplish the project objectives, we propose: (i) To study the metabolism of BPT by mouse liver microsomes from induced or uninduced mice and identify the metabolites formed; (ii) To assess the mutagenicity of BPT and its metabolites; (iii) to characterize the DNA adducts produced in mouse skin treated with BPT.
The long term goal of this project is to understand the mechanism of carcinogenesis using isosteric PAHs and their heterocyclic analogues as model carcinogens. The characterization of metabolites and DNA adducts of BPT may be useful in developing biomarkers of exposure and consequently assessing the risk BPT and other thia-PAHs may present to human health.