The Effects of Omega-3 Supplementation and Doxorubicin-Based Chemotherapy on the Murine Brain Lipidome

Abstract Objectives To determine how omega-3 (n3-FA) supplementation may confer protection against lipid modifications following doxorubicin-based chemotherapy (DOX). Methods Ovariectomized C57BL/6 mice consumed a diet with 0% or 2% kcal supplemental EPA + DHA for 4 weeks, followed by two injections of either DOX (9 mg/kg) + cyclophosphamide (90 mg/kg), or vehicle. In study 1, animals were sacrificed at 4, 7, and 14 days after the last injection (n = 120) and in study 2, at 10 days after the last injection (n = 40). Whole brain from study 1 were analyzed by targeted methods (UHPLC-MS/MS), to quantify specialized pro-resolving mediators resolvin D1 (RvD1), resolvin D2 (RvD2), resolvin D3 (RvD3), resolvin D5 (RvD5), resolvin E1 (RvE1), maresin (MaR1), and protectin (PD1). In study 2, lipidomics analyses were performed on hippocampus to determine changes in the lipidome after n3-FA supplementation and chemotherapy injection. Results Study 1 results: RvD1 was present in all samples, but no significant differences in concentration were observed regardless of treatment or dietary group. RvD3, PD1 and MaR1 were detected in a subset of samples. Study 2 results: EPA + DHA (2%) supplementation favorably altered lipids associated with cognitive function (i.e., PE (P-16:0/20:5), PE (P-18:0/22:6, with adjusted p-value equal to 0.003 and 0.04 respectively), which have been previously negatively correlated with Alzheimer's and Parkinson's disease. Chemotherapy treatment increases omega-9 fatty acids (i.e., nervonic, gadoleic and mead acid) previously positively correlated with diseases of cognitive decline (e.g., Alzheimer's, Parkinson's). No chemo*n3-FA interaction was observed (p-value > 0.05). Conclusions N3-FA supplementation favorably altered lipids associated with cognitive function. DOX increased lipids associated with diseases of cognitive decline. Future investigations will determine if the same biomarkers of n-3 FA consumption and chemotherapy are observed in human breast cancer patients. Funding Sources This research was supported by a Foods for Health Discovery Themes Initiative SEEDS grant, NIH R01CA189947, NIH Award Number Grant P30 CA016058, OSU, and OSUCCC.