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The notorious environmental carcinogen 2,3,7,8‐tetrachlorodivenzo‐p‐dioxin (TCDD) stimulates tumor progression in mice fed high levels of omega‐6 polyunsaturated fatty acids (PUFA), but inhibits tumor progression in mice fed a high omega‐3 PUFA diet

The notorious environmental carcinogen 2,3,7,8‐tetrachlorodivenzo‐p‐dioxin (TCDD) stimulates tumor progression in mice fed high levels of omega‐6 polyunsaturated fatty acids (PUFA), but inhibits tumor progression in mice fed a high omega‐3 PUFA diet

Date 
Thursday, May 26, 2016 - 12:00pm to 1:00pm
Location 
43-105 CHS
FSPH: 650 Charles E. Young DR S,
Los Angeles , CA
California US
Featuring 
Oliver Hankinson, PhD
Event Contact 
Rebecca Greenberg, rgreenberg@ph.ucla.edu, 310.206.1619
Dr. Oliver Hankinson
Dr. Oliver Hankinson
The environmental pollutant 2,3,7,8‐tetrachlorodibenzo‐ρ‐dioxin (TCDD) is the prototype of a large number of nongenotoxic environmental carcinogens, dietary phytochemicals and endogenous metabolites that act via binding the aryl hydrocarbon receptor (AHR). However, the mechanism(s) of carcinogenesis by these compounds is still unclear. We confirmed that TCDD‐liganded AHR massively upregulates CYP1A1, CYP1A2 and CYP1B1 in many mammalian organs. The roles of these enzymes in metabolizing polyunsaturated fatty acids (PUFA) in vivo has not been investigated. We demonstrated that TCDD treatment dramatically increases the levels of epoxide metabolites of both omega‐6 (ω‐6) and omega‐3 (ω‐3) PUFA in the liver, lungs and blood of mice, via the activities of the CYP1 family members. ω‐6 epoxides are known to stimulate tumor growth, angiogenesis, and metastasis in mice, while ω‐3 epoxides have the opposite effect. These observations form the basis of our hypothesis that “TCDD will impact angiogenesis, growth and metastasis of tumors in either a positive or negative way, depending on the relative levels of ω‐6 epoxides and ω‐3 epoxides generated by the induced CYP1 enzymes in the host and/or tumor cells”. To begin to address this hypothesis, mice were fed either a high ω‐6/low ω‐3 or a low ω‐6/high ω‐3 PUFA diet, treated with or without TCDD, and then injected subcutaneously with cancer cells. TCDD accelerated the growth rate of the resulting tumors in mice fed the high ω‐6 diet, but markedly retarded the growth rate of the resulting tumors fed the high ω‐3 diet. The negative effect of TCDD on tumor growth in mice fed the high ω‐3 diet was associated with enhanced apoptosis in the tumor tissue. Future experiment will investigate whether the high ω‐6 and ω‐3 PUFA diets also differentially affect the rates of TCDD‐induced metastasis. These studies may establish a novel mechanism whereby TCDD stimulates tumor progression; suggest a novel mechanism of cancer protection by ω‐3 PUFA, and suggest novel mechanisms of action of “beneficial” dietary AHR agonists and endogenous AHR ligands.