Omega-3 polyunsaturated fatty acids enhance cytokine production and oxidative stress in a mouse model of preterm labor

Abstract Objective: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation during pregnancy remains controversial. We sought to examine the effects of ω-3 PUFA on inflammation and oxidative stress in vitro and in vivo using a model of preterm labor. Methods: In vivo. Female Swiss Webster mice were fed a normal diet or a 5% fish oil (FO) diet for 3 weeks then mated with normal-fed males. On gestational day 15, dams were injected with either saline (n=10 per group) or lipopolysaccharide (LPS, intrauterine) (n=10 per group). Maternal plasma, amniotic fluid, placentas, and uteri were collected 4 h later and assessed for cytokines; maternal plasma and amniotic fluids were analyzed for oxidative stress. In vitro. RAW264.7 mouse macrophage-like cells were treated with either: vehicle, H2O2, docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA) (0, 0.1–100 μM) and analyzed for oxidative stress. Results: In vivo. Administration of the 5% FO diet enhanced LPS-induced cytokines in the placenta (P<0.05–0.01) and increased tumor necrosis factor-α in the uterus (P<0.05) and amniotic fluid (P<0.01) when compared to LPS-treated normal-fed animals. Maternal plasma obtained from FO-fed dams showed higher LPS-induced oxidative stress than control-fed animals (P<0.035). However, no differences in oxidative stress were observed in the amniotic fluid. In vitro. Treatment of macrophage-like cells with ω-3 PUFA significantly and dose-dependently increased oxidative stress (P<0.001–0.0001). Conclusions: Supplementation with FO for prior to and during pregnancy significantly increased LPS-induced inflammation in the amniotic fluid, uterus, and placenta and significantly increased maternal systemic oxidative stress in vivo. Likewise, DHA and EPA induced oxidative stress in macrophage-like cells in vitro.

[1]  C. Metz,et al.  Maternal magnesium supplementation reduces intrauterine growth restriction and suppresses inflammation in a rat model. , 2013, American journal of obstetrics and gynecology.

[2]  P. Calder,et al.  Plasma inflammatory and vascular homeostasis biomarkers increase during human pregnancy but are not affected by oily fish intake. , 2012, The Journal of nutrition.

[3]  O. D. Rangel-Huerta,et al.  Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials , 2012, British Journal of Nutrition.

[4]  K. Breen,et al.  Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury , 2011, International Journal of Developmental Neuroscience.

[5]  M. Elovitz,et al.  The role of inflammation and infection in preterm birth. , 2011, Clinics in perinatology.

[6]  R. Lamont,et al.  Evidence regarding an effect of marine n‐3 fatty acids on preterm birth: a systematic review and meta‐analysis , 2011, Acta obstetricia et gynecologica Scandinavica.

[7]  K. Nakagawa,et al.  Long-term intake of fish oil increases oxidative stress and decreases lifespan in senescence-accelerated mice. , 2011, Nutrition.

[8]  J. Martin Preterm births - United States, 2007. , 2011, MMWR supplements.

[9]  M. Gravett,et al.  Use of nonhuman primate models to investigate mechanisms of infection‐associated preterm birth , 2011, BJOG : an international journal of obstetrics and gynaecology.

[10]  Liping Li,et al.  Role of Toll-like receptor 4 in inflammation-induced preterm delivery. , 2010, Molecular human reproduction.

[11]  Louis J Muglia,et al.  The enigma of spontaneous preterm birth. , 2010, The New England journal of medicine.

[12]  M. Klebanoff,et al.  Omega-3 Fatty Acid Supplementation to Prevent Recurrent Preterm Birth: A Randomized Controlled Trial , 2010, Obstetrics and gynecology.

[13]  A. Roman,et al.  Omega-3 Fatty acids and pregnancy. , 2010, Reviews in obstetrics & gynecology.

[14]  J. Morrow,et al.  Dietary supplementation of omega-3 fatty acid-containing fish oil suppresses F2-isoprostanes but enhances inflammatory cytokine response in a mouse model of ovalbumin-induced allergic lung inflammation. , 2009, Free radical biology & medicine.

[15]  F. Visioli,et al.  Polyunsaturated fatty acids as antioxidants. , 2008, Pharmacological research.

[16]  F. Gottrand,et al.  Dietary n-3 fatty acids have suppressive effects on mucin upregulation in mice infected with Pseudomonas aeruginosa , 2007, Respiratory research.

[17]  Dongxu Sun,et al.  Different ratios of eicosapentaenoic and docosahexaenoic omega-3 fatty acids in commercial fish oils differentially alter pro-inflammatory cytokines in peritoneal macrophages from C57BL/6 female mice. , 2007, The Journal of nutritional biochemistry.

[18]  A. Valenzuela,et al.  Ingestion of high doses of fish oil increases the susceptibility of cellular membranes to the induction of oxidative stress , 1989, Lipids.

[19]  R. Romero,et al.  Intrauterine Infection, Preterm Labor, and Cytokines , 2005, The Journal of the Society for Gynecologic Investigation: JSGI.

[20]  B. Jacobsson,et al.  Role of cytokines in preterm labour and brain injury , 2005, BJOG : an international journal of obstetrics and gynaecology.

[21]  F. Facchinetti,et al.  Polyunsaturated fatty acids and risk of preterm delivery. , 2005, European review for medical and pharmacological sciences.

[22]  M. Elovitz,et al.  Animal models of preterm birth , 2004, Trends in Endocrinology & Metabolism.

[23]  S. Ozgoçmen,et al.  Effect of fish oil supplementation on plasma oxidant/antioxidant status in rats. , 2004, Prostaglandins, leukotrienes, and essential fatty acids.

[24]  E. Chien,et al.  A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. , 2003, The American journal of pathology.

[25]  C. Weiner,et al.  Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. , 2003, American journal of obstetrics and gynecology.

[26]  P. Calder,et al.  Polyunsaturated fatty acids, inflammation, and immunity , 2001, Lipids.

[27]  J. Hauth,et al.  Intrauterine infection and preterm delivery. , 2000, The New England journal of medicine.

[28]  S. F. Olsen,et al.  Randomised clinical trials of fish oil supplementation in high risk pregnancies , 2000, BJOG : an international journal of obstetrics and gynaecology.

[29]  U. Bauer,et al.  [Centers for Disease Control and Prevention (CDC)]. , 2000, Annales de dermatologie et de venereologie.

[30]  A. Collins,et al.  The effect of increased intakes of polyunsaturated fatty acids and vitamin E on DNA damage in human lymphocytes , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  Yang C. Fann,et al.  Phenoxyl Free Radical Formation during the Oxidation of the Fluorescent Dye 2′,7′-Dichlorofluorescein by Horseradish Peroxidase , 1999, The Journal of Biological Chemistry.

[32]  E. Hirsch,et al.  Inflammatory Cytokines in a Murine Model of Infection-Induced Preterm Labor: Cause or Effect? , 1999, The Journal of the Society for Gynecologic Investigation: JSGI.

[33]  K. Wahle,et al.  Dietary intakes of polyunsaturated fatty acids and indices of oxidative stress in human volunteers , 1999, European Journal of Clinical Nutrition.

[34]  Calder,et al.  Dietary lipids modify the cytokine response to bacterial lipopolysaccharide in mice , 1999, Immunology.

[35]  E. Sanzini,et al.  Oxidative stress markers: specificity and measurement techniques. , 1999, Annali dell'Istituto superiore di sanita.

[36]  S. Chavali,et al.  Dietary alpha-linolenic acid increases TNF-alpha, and decreases IL-6, IL-10 in response to LPS: effects of sesamin on the delta-5 desaturation of omega6 and omega3 fatty acids in mice. , 1998, Prostaglandins, leukotrienes, and essential fatty acids.

[37]  J. Meer,et al.  Dietary n-3 fatty acids increase spleen size and postendotoxin circulating TNF in mice; role of macrophages, macrophage precursors, and colony-stimulating factor-1. , 1996, Journal of immunology.

[38]  Y. Shibutani,et al.  Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: a model for human preterm parturition and for assessment of the therapeutic ability of drugs against preterm delivery. , 1996, American journal of obstetrics and gynecology.

[39]  S. Meydani Effect of (n-3) polyunsaturated fatty acids on cytokine production and their biologic function. , 1996, Nutrition.

[40]  H. R. Chang,et al.  Fish oil enhances macrophage tumor necrosis factor-alpha mRNA expression at the transcriptional level. , 1995, Metabolism: clinical and experimental.

[41]  M. Monga,et al.  Intrauterine Infection and Preterm Labor , 1995, Infectious diseases in obstetrics and gynecology.

[42]  C. Dinarello,et al.  Influence of dietary fatty acids on cytokine production and its clinical implications. , 1993, Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition.

[43]  J. Brown,et al.  Effect of fish-oil and vitamin E supplementation on lipid peroxidation and whole-blood aggregation in man. , 1990, Clinica chimica acta; international journal of clinical chemistry.

[44]  T. Sayers,et al.  Interleukin-1 and tumor necrosis factor synthesis by mouse peritoneal macrophages is enhanced by dietary n-3 polyunsaturated fatty acids. , 1990, Immunology letters.