Abstract 3094: Effects of aryl hydrocarbon receptor and estrogen receptor beta crosstalk on benzo(a)pyrene induced AhR target genes

Abstract

Abstract Colorectal cancer (CRC) is the third most common diagnosed cancer and the third leading cause of cancer-related deaths in the United States. Epidemiological evidence show estrogen might influence the incidence of CRC in women by acting in a protective role via estrogen receptor beta (ERβ) but the mechanism of action is not known. Benzo(a)pyrene [B(a)P], a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds is a well-characterized environmental toxicant that has been proven to be a major contributor to the development of sporadic colon cancer. Literature provides evidence of crosstalk between Aryl Hydrocarbon Receptor (AhR), a receptor for B(a)P, and estrogen receptors (ERs) which negatively affect ER-mediated transcription. This study aims to elucidate the effect of AhR/ERB crosstalk on B(a)P-induced expression of AHR target genes in adult Polyposis In the Rat Colon (PIRC) model. We hypothesize that estrogen inhibits B(a)P-induced expression of AHR target genes and attenuates the formation of colon polyps in female PIRC rats. Groups of female and male PIRC rats (n = 8) received sub-chronic exposure to 25, 50 and 100 µg B(a)P/kg body wt. via oral gavage for 60 days. Female PIRC rats that received 25, 50 and 100 µg B(a)P/kg body wt. showed significant decrease in total polyp count when compared to males with respective treatments. Polyp sizes of female PIRC rats receiving 25, 50 and 100 µg B(a)P/kg body wt. were increased when compared to males respectively. Histopathological analysis of colon polyps revealed that female animals exhibited low-grade to no dysplasia while high-grade dysplasia was recorded in male animals treated with corresponding doses. As expected B(a)P increased expression of Cytochrome P450 isoform 1A1 (CYP1A1), CYP1B1, Sulfotransferase Family 1A Member 1 (SULT1A1), and Glutathione S-transferases (GST) in the colon of PIRC rats. Female PIRC rats show increase in CYP1B1, SULT1A1 and GST when compared to males in various treatment groups. It is possible that the increase in Phase II enzymes may provide clearance of B(a)P, preventing polyp development in female PIRC rats. In future studies, by measuring the expression of other phase 1 and phase 2 drug metabolizing enzymes (DME), along with measuring circulating estrogen levels, analyzing [B(a)P] metabolite profile, and probing B(a)P-DNA interactions, we will provide insight into how estrogen protects females from developing colon cancer. This research was funded by NIH grants 5RO1CA142845-04, 5R25GM059994-3, and G12MD007586-29. Citation Format: Kenneth J. Harris, Kelly L. Harris, Mary K. Washington, James Amos-Landgraf, Aramandla Ramesh. Effects of aryl hydrocarbon receptor and estrogen receptor beta crosstalk on benzo(a)pyrene induced AhR target genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3094.