Abstract 4804: Sex-specific differences in Benzo(a)Pyrene [B(a)P]-induced colon carcinogenesis

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. It has also been reported that colon cancer incidence and mortality rates are higher in men than woman, but there is yet a determined mechanistic link to show the factors that underlie the sex-specific differences in CRC initiation and progression. 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. Published studies indicate that Aryl Hydrocarbon Receptor (AhR), a receptor for [B(a)P], bind to estrogen receptor (ER) and negatively affect AhR-target gene transcription. This study aims to elucidate the sex-specific differences in B(a)P-induced colon cancer in adult Polyposis In the Rat Colon (PIRC) model. We hypothesize that sex-specific differences in B(a)P biotransformation modulates the formation of colon tumors in 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 and male rats that received no [B(a)P] treatment served as controls. [B(a)P] was shown to have no significant effect on body weight of these rats and 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. Phase 1 enzyme, Cytochrome P450 isoform 1A1 (CYP1A1), and phase 2 enzyme, Sulfotransferase Family 1A Member 1 (SULT1A1), were downregulated in colon tissue of female PIRC rats receiving 25, 50 and 100 µg B(a)P/kg body wt. when compared to male counterparts. 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 if and how estrogen receptor 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. Sex-specific differences in Benzo(a)Pyrene [B(a)P]-induced colon carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4804. doi:10.1158/1538-7445.AM2017-4804