Abstract 4312: Preneoplastic activity of dietary poly unsaturated fatty acid (PUFA) regulation of organ and tissue microenvironments in an iso-caloric pair-fed mouse model

Diets containing omega-3 (ω3) PUFAs have health benefits due to their anti-inflammatory activity and lower risk of chronic conditions including cardiac, autoimmune and neoplastic diseases. This contrasts with ω6 PUFA containing Western diets, which are pro-inflammatory. Balancing the dietary ω6:ω3 ratio has been suggested to have cancer preventive and potentially therapeutic activity; however, the majority of these studies have not differentiated dietary PUFA content from obesity. Herein we examined the effects of the ω6:ω3 ratio in iso-caloric diets that were pair fed. These diets had 35.5% of calories from fat with an ω6:ω3 ratio in the ω6 and ω3 based diets of 42:1 and 1:1 respectively (confirmed by gas chromatography-mass spectrometry) using the liquid, Lieber DeCarli diet and fish oil substituting for 70% of olive oil. The ω3 diet contained eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid at a 3:1 ratio, while the ω6 diet contained linoleic acid as the predominant ω6 PUFA and a low level of the ω3 PUFA, linolenic acid. After establishing female BALB/c mice on these diets, weight gain and diet consumption were monitored for 12 weeks, the mice sacrificed and the dietary effects on mammary gland and hepatic histopathology, leukocyte phenotypes and organ and tissue lipidomics determined. In association with pair feeding there were no differences in diet consumed (ω-3 diet used as baseline) and weight gain between cohorts. The cohort on the ω6 diet had depressed numbers of marrow progenitor cells and increased splenic subcapsular extramedullary hematopoiesis consistent with an inflammatory response, increased hepatocyte lipidosis, hypertrophy and multinucleation and increased hepatic vascularity with thicker intima. The ω-6 dietary cohort also had mammary fat pads (MFPs) with increased adipocytes in the tubular epithelium, stromal cellularity and epithelial tissue density. These mammary gland and hepatic histopathologic changes and subclinical inflammation are consistent with pre-neoplastic lesions and were accompanied by organ specific lipodemic changes. This included significant increases in arachidonic acid (AA) in the plasma, spleen and liver, but not MFPs, of the ω-6 cohort, and a significant increase in EPA and DHA levels in the plasma, spleen, MFPs and liver of the ω-3 cohort. In addition, the liver and MFPs had a significant increase in the ω3 PUFA, docosapentaenoic acid. In summary, our studies demonstrate that the dietary ratio of ω6:ω3, independent of obesity can regulate mammary gland and hepatocyte proliferation and subclinical inflammation in association with significant, organ specific increases in AA levels contributing to microenvironmental preneoplastic hyperplasia. Citation Format: Saraswoti Khadge, Paul Black, Concetta DiRusso, Geoff Thiele, Lynell W. Klassen, J Graham Sharp, Timothy R. McGuire, Michael J. Duryee, Holly C. Britton, Alicia Dafferner, Jordan Beck, James E. Talmadge. Preneoplastic activity of dietary poly unsaturated fatty acid (PUFA) regulation of organ and tissue microenvironments in an iso-caloric pair-fed mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4312.