Progress 03/01/20 to 02/28/21
Outputs
Target Audience:In this project we will: (i) determine the effects of dietary fatty acids, notably linoleic acid, on colon cancer development, and (ii) elucidate the molecular mechanisms involved. The targeted audience includes: (i) general public, (ii) food industry, and (iii) scientists in bioactive lipid research field. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?This project supports the training of Jianan Zhang, who is a 5-th year PhD student in the Department of Food Science at UMass-Amherst. For this project, she has performed the animal experiments, traveled to collaborator lab at NIH/NIEHS to enhance her training in genetically engineered mouse models, and presented her finding in national meetings: ZhangJ.,EdinM.L.,YangJ.,SanidadK.Z.,ShermanH.,WangW.,MinterL.M.,HammockB.D.,ZeldinD.C.,andZhangG.Excessintakeofdietarylinoleicacidexaggeratescolontumorigenesis:rolesofcytochromeP450 (CYP)metabolitesinvolved.BioactiveLipidsinCancer,InflammationandRelatedDiseasesInternationalConference.St.Petersburg,FL, 20-23Oct.2019 (Poster). How have the results been disseminated to communities of interest?Yes, we have presented our data in conference (please see below) and are in preparation to submit the research manuscript: ZhangJ.,EdinM.L.,YangJ.,SanidadK.Z.,ShermanH.,WangW.,MinterL.M.,HammockB.D.,ZeldinD.C.,andZhangG.Excessintakeofdietarylinoleicacidexaggeratescolontumorigenesis:rolesofcytochromeP450 (CYP)metabolitesinvolved.BioactiveLipidsinCancer,InflammationandRelatedDiseasesInternationalConference.St.Petersburg,FL, 20-23Oct.2019 (Poster). What do you plan to do during the next reporting period to accomplish the goals?We have key data to support the hypothesis of our project, we are currently finishing some supporting experiments to finish the whole project and submit the research manuscript.
Impacts
What was accomplished under these goals?
Progress summary: in this project, our major goal is to test the extent to which linoleic acid (LA)-rich diet increases the risks of developing colorectal cancer, through CYP/EpOME axis-dependent mechanisms. We have obtained key data to support that our hypothesis is correct. For aim 1, we found that LA-rich diet exacerbated AOM/DSS-induced colon tumorigenesis in mice. Compared with control diet, treatment with the LA-rich diet increased tumor number and tumor size, enhanced expression of proliferating cell nuclear antigen (PCNA) and active β-catenin in colon, increased colonic infiltration of immune cells, and increased concentration of LPS in plasma. Overall, these findings demonstrate that LA-rich diet exacerbated development of AOM/DSS-induced CRC in mice. For aim 2, we used a LC-MS/MS-based lipidomics, which can measure > 100 lipid metabolites (LMs) produced by various lipid metabolizing enzymes, to systematically analyze how the LA-rich diet changed profiles of fatty acid metabolites in the plasma and colon of the AOM/DSS-induced CRC mice. We detected 50 metabolites in the plasma and 65 metabolites in the colon. We found that the concentrations of 9,10- and 12,13-EpOMEs, which are metabolites of LA produced by the actions of CYP monooxygenases, are significantly increased in both the colon and plasma of the LA-rich diet-treated mice compared with the control diet-treated mice. Additionally, among the LMs that are statistically altered, 9,10- and 12,13-EpOMEs are the most dramatically increased LMs induced by the LA-rich diet. For aim 3, we used a Cyp2c gene cluster knockout mouse, which has deletions of fourteen mouse Cyp2c genes including Cyp2c29, 2c37, 2c38, 2c39, 2c40, 2c50, 2c54, 2c55, 2c65, 2c66, 2c67, 2c68, 2c69, and 2c70, to determine the roles of CYP monooxygenases involved in the CRC-enhancing effects of LA. We found that LA-rich diet exacerbated AOM/DSS-induced CRC in Cyp2c+/+ mice, however, such effect was abolished in Cyp2c+/- mice. These results support that the Cyp2c monooxygenase pathway is required for the CRC-enhancing effect of dietary LA.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
n-3 Polyunsaturated Fatty Acids on Colonic Inflammation and Colon Cancer: Roles of Lipid-Metabolizing Enzymes Involved
M Tu, W Wang, G Zhang, BD Hammock
Nutrients 12 (11), 3301
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
Wang Y., Yang J., Wang W., Sanidad K.Z., Cinelli M.A., Wan D., Hwang S.H., Kim D., Lee K.S.S., Xiao H., Hammock B.D., and Zhang G. (2020) Soluble epoxide hydrolase is an endogenous reg-ulator of obesity-induced intestinal barrier dysfunction and bacterial translocation. PNAS 117: 8431-8436.
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
Zhang J., Tu M., Liu Z., and Zhang G. (2020) Soluble epoxide hydrolase as a therapeutic target for obesity-induced disorders: roles of gut barrier function involved. Prostaglandins, Leukotri-enes and Essential Fatty Acids, Doi: 10.1016/j.plefa.2020.102180
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
Edin M.L., Duval C., Zhang G., and Zeldin D.C. (2020) Role of linoleic acid-derived oxylipins in cancer. Submitted. Cancer Metastasis Review, Doi: 10.1007/s10555-020-09904-8.
- Type:
Journal Articles
Status:
Published
Year Published:
2020
Citation:
Zhang J., Freund M.A., Culler M., Yang R., Chen P.B., Park Y., Decker E.A., and Zhang G. (2020) How to stabilize n-3 polyunsaturated fatty acids (PUFAs) in an animal feeding study? effects of temperature, oxygen level, antioxidant on oxidative stability of n-3 PUFAs in a mouse diet. Journal of Agricultural and Food Chemistry, Doi: 10.1021/acs.jafc.9b08298.
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Wang W., Zhang J., and Zhang G. Cytochrome P450 monooxygenase eicosanoid pathway: a potential mechanistic linkage between dietary fatty acid consumption and colon cancer risk? Food Science and Human Wellness 8:337-343.
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Wang Y., Dattmore D.A., Wang W., Pohnert G., Wolfram S., Zhang J., Yang R., Decker E.A., Lee K.S.S., and Zhang G. (2019) trans, trans-2,4-decadienal, a lipid peroxidation product, induces in-flammatory responses via Hsp90- or 14-3-3?-dependent mechanisms. Journal of Nutritional Biochemistry 76:108286.
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Zhang J., Chen X., Yang R., Ma Q., Qi W., Park Y., Sanidad K.Z., Kim D., Decker E.A., and Zhang G. (2019) Thermally processed oil exaggerates colonic inflammation and colitis-associated colon tumorigenesis in mice. Cancer Prevention Research 12:741-750.
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Progress 03/01/19 to 02/29/20
Outputs
Target Audience:Audience: food and agriculture industry and general public In this research, we will study several important dietary fatty acids: linoleic acid (the most abundant polyunsaturated fatty acid in vegetable oils such as corn, soybean, safflower, and canola oils), monounsaturated fatty acid (major components in olive oil),and ω-3 polyunsaturated fatty acid (major components in fish oil). These components are of critical importance to the US agriculture and food industry. Clarification of their impacts on human health could lead to significant impact for the food industry and public health. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?The NIFA grant provides training opportunities for graduate student (Jianan Zhang), she has presented part of her data in an international meeting in 2019 "Zhang J., Edin M.L., Yang J., Sanidad K.Z., Sherman H., Wang W., Minter L.M., Hammock B.D., Zeldin D.C., and Zhang G. Excess intake of dietary linoleic acid exaggerates colon tumorigenesis: roles of cytochrome P450 (CYP) metabolites involved. Bioactive Lipids in Cancer, Inflammation and Related Diseases International Conference. St. Petersburg, FL, 20-23 Oct. 2019 (Poster)". In addition, in 2020, she will present more recent data in The 18th International Winter Eicosanoid Conference, March 15-17, Baltimore, MD. How have the results been disseminated to communities of interest?We have reported our finding in a conference poster: Zhang J., Edin M.L., Yang J., Sanidad K.Z., Sherman H., Wang W., Minter L.M., Hammock B.D., Zeldin D.C., and Zhang G. Excess intake of dietary linoleic acid exaggerates colon tumorigenesis: roles of cytochrome P450 (CYP) metabolites involved. Bioactive Lipids in Cancer, Inflammation and Related Diseases International Conference. St. Petersburg, FL, 20-23 Oct. 2019 (Poster) What do you plan to do during the next reporting period to accomplish the goals?Our current data support our hypothesis that excess intake of dietary LA increases colon cancer, through CYP pathway. We will finish this project about dietary LA, and plan to submit the research paper.
Impacts
What was accomplished under these goals?
Our research in progress showed that a high dietary intake of linoleic acid (LA) exaggerates development of colon tumorigenesis in mice, at least in part via formation ofepoxyoctadecenoic acids (EpOMEs) which are metabolites of LA produced by cytochrome P450 (CYP) monooxygenases. We found that dietary treatment with a LA-rich diet exaggerates azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in mice, with increased tumor number and tumor size, and higher infiltration of immune cells (total macrophages, M1 macrophage, neutrophils, and activated CD4+ Th1-like T cells) into colon tumor. LC-MS/MS profiling showed that 9,10- and 12,13-EpOME are the most dramatically increased eicosanoid metabolites by the LA-rich diet. Treatment with 12,13-EpOME, at nM concentrations, induces cytokine production in both macrophage and colon cancer cells via a potential GPCR-dependent mechanism; and systemic infusion with 12,13-EpOME exaggerates AOM/DSS-induced colon tumorigenesis in mice. Finally, the colon cancer-enhancing effect of the LA-rich diet was abolished by genetic ablation of Cyp2c monoxygenases. Together, our results support that a high intake of dietary LA could cause adverse effects on colon cancer through the CYP/EpOME eicosanoid pathway.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Zhang J., Sanidad K.Z., and Zhang G. (2019) Role of cytochrome P450 monooxygenase eico-sanoid pathway in pathogenesis of colorectal cancer. Oncoscience, 6:371-375
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Zhang J., Chen X., Yang R., Ma Q., Qi W., Park Y., Sanidad K.Z., Kim D., Decker E.A., and Zhang G. (2019) Thermally processed oil exaggerates colonic inflammation and colitis-associated colon tumorigenesis in mice. Cancer Prevention Research 12:741-750
- Type:
Journal Articles
Status:
Published
Year Published:
2019
Citation:
Wang W., Zhang J., and Zhang G. Cytochrome P450 monooxygenase eicosanoid pathway: a potential mechanistic linkage between dietary fatty acid consumption and colon cancer risk? Food Science and Human Wellness, 8:337-343.
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