Journal of Translational Medicine and Developmental Disorders
ISSN (Print): ISSN Pending ISSN (Online): ISSN Pending Website: Editor-in-chief: Kunio Yui MD
Open Access
Journal Browser
Journal of Translational Medicine and Developmental Disorders. 2015, 2(1), 1-9
DOI: 10.12691/jtmdd-2-1-1
Open AccessArticle

Down-regulation of Signaling Mediator in Related to Increased Ratio of Docosahexaenoic Acid/Arachidonic Acid in Individuals with Autism Spectrum Disorders

Kunio Yui1, , George Imataka2, Yohei Kawasaki3 and Tsutomu Yamada3

1Research Institute of Pervasive Developmental Disorders, Ashiya University, Rokurokusocho, Ashiya, Hyogo, Japan

2Department of Pediatrics, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi, Japan

3Department of Drug Evaluation and Information, School of Pharmaceutical Science University of Shizuoka, Shizuoka, Japan

Pub. Date: September 29, 2015

Cite this paper:
Kunio Yui, George Imataka, Yohei Kawasaki and Tsutomu Yamada. Down-regulation of Signaling Mediator in Related to Increased Ratio of Docosahexaenoic Acid/Arachidonic Acid in Individuals with Autism Spectrum Disorders. Journal of Translational Medicine and Developmental Disorders. 2015; 2(1):1-9. doi: 10.12691/jtmdd-2-1-1


Background and aim: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Converging lines of research indicate that the altered composition of polyunsaturated fatty acids (PUFAs) may contribute to the pathophysiology of ASD. Methods: We examined the relationships between the plasma ratios of omega-3PUFs/arachidonic acid (AA), plasma levels of 21 fatty acid fractions, and biomarkers of AA-related signaling mediators (ceruloplasmin, transferrin and superoxide dismutase) with the behavioral symptoms of 32 individuals with ASD (mean age, 13.5 ± 4.3 years old) and 20 age- and gender-matched normal controls (mean age, 13.2 ± 5.4 years old). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). Results: Plasma levels of EPA, DPA and DHA, and the plasma ratios of docosahesaenoic acid (DHA)/AA were significantly higher while plasma levels of AA, 5,8,11,14-eicosatetraenoic acid and Cp were significantly lower in the 32 individuals with ASD compared with the 20 normal controls. The ABC scores were significantly increased in the ASD group compared to those of the control group. Discussion and Conclusion: High plasma DHA/AA ratio related to the increased plasma DHA levels and reduced plasma AA level may down-regulate mediators of AA signaling, such as Cp. Additionally, as 5,8,11,14-eicosatetraenoic acid is an arachidonate metabolite, the reduced plasma AA revels might have a pathophysiological factor in the reduced plasma Cp levels. Subsequently, reduced Cp levels may reduce the protective capacity of the brain against damage, which may cause in the pathophysiology underlying behavioral symptoms observed in individuals with ASD.

signaling mediators ceruloplasmin competitive interaction arachidonic acid docosahexaenoic acid

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Frye, R.E., Delatorre, R., Taylor, H., Slattery, J., Melnyk, S., Chowdhury, N., James, S.J. “Redox metabolism abnormalities in autistic children associated with mitochondrial disease.” Transl Psychiatry, 3, e273, 2013.
[2]  Wong, C., Crawford, D.A. Lipid signaling in the pathology of autism spectrum disorders. In: V.B. Patel, V.R. Preedy, C.R. Martin (Eds.), Comprehensive guide to autism, Springer Publishing, New York, 2014, 1259-1283, 2014.
[3]  Holowka, D., Korzeniowski,.K., Bryant, K.L., Baird, B. “Polyunsaturated fatty acids inhibit stimulated coupling between the ER Ca2+ sensor STIM1 and the Ca2+ channel protein Orai1 in a process that correlates with inhibition of stimulated STIM1 oligomerization.” Biochim Biophys, 1841, 1210-1216, 2014.
[4]  Vrablik, T.L., Watts, J.L. “Polyunsaturated fatty acid derived signaling in reproduction and development: insights from Caenorhabditis elegans and Drosophila melanogaster.” Mol Reprod Dev, 80, 244-259, 2013.
[5]  R. Crupi, A. Marino, S. Cuzzocrea, n-3 fatty acids: role in neurogenesis and neuroplasticity. Curr. Med. Chem. 20 (2013) 2953-2963.
[6]  Tamiji, J., Crawford, D.A. “The neurobiology of lipid metabolism in autism spectrum disorders.” Neurosignals, 18, 98-112, 2010.
[7]  Kurlak, L.O., Stephenson, T.J. “Plausible explanations for effects of long chain polyunsaturated fatty acids (LCPUFA) on neonates.” ArchDis Child Fetal Neonatal Ed, 80, F148-154, 1999.
[8]  Bazinet, R.P., Layé, S. “Polyunsaturated fatty acids and their metabolites in brain function and disease.” Nat Rev Neurosci, 15, 771-785. 2014.
[9]  Vancassel, S., Durand, G., Barthélémy, C. Lejeune, B., Martineau, J., Guilloteau, D., Andrès, C., Chalon, S. “Plasma fatty acid levels in autistic children.” Prostaglandins Leukot Essent Fatty Acids, 65, 1-7. 2001.
[10]  El-Anary, A.K., Bacha, A,G., Al-Ayahdi, L.Y. “Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia.” Lipids Health Dis, 10 63, 2011a. http://www.ncbi.nlm.nih. gov/pmc/articles/PMC3107801/.
[11]  Simopoulos, A.P. “Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain.” Mol Neurobiol, 44, 203-215, 2011.
[12]  Luxwolda, M.F., Kuipers, R.S., Smit, E.N., Velzing-Aarts, F.V., Dijck-Brouwer, D.A., Muskiet, F.A. “The relation between the omega-3 index and arachidonic acid is bell shaped: synergistic at low EPA+DHA status and antagonistic at high EPA+DHA status.” Prostaglandins Leukot. Essent. Fatty Acids, 8, 171-178, 2011.
[13]  Taha, A.Y., Cheon, Y., Faurot, K.F., Macintosh,B., Majchrzak-Hong, S.F., Mann, J.D., Hibbeln, J.R., Ringel, A., Ramsden, C.E. “Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.” Prostaglandins Leukot Essent Fatty Acids, 90, 151-157, 2014.
[14]  Schmitz, G., Ecker, J. “The opposing effects of n-3 and n-6 fatty acid.” Prog Lipid Res, 47, 147-155, 2008.
[15]  Janssen, C.L., Kiliaan, A.J. “Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: The influence of LCPUFA on neural development, aging, and neurodegeneration.” Prog Lipid Res, 53, 1-17, 2014.
[16]  Whelan J. “Antagonistic effects of dietary arachidonic acid and n-3 polyunsaturated fatty acids.” J Nutr, 126, 1086S-10891S, 1996.
[17]  Obajimi, O., Black, K.D., MacDonald, D.J., Boyle, R.M., Glen, I., Ross, B.M. “Differential effects of eicosapentaenoic and docosahexaenoic acids upon oxidant-stimulated release and uptake of arachidonic acid in human lymphoma U937 cells.” Pharmacol Res, 52, 183-191, 2005.
[18]  Mori, T.A., Chem, C.P., Beilin, L.J. “Omega-3 Fatty Acids and Inflammation.” Curr Atheroscler Rep, 6, 461-467, 2004.
[19]  Morbtaten, K., Haug, T.M., Kleiveland, C.R., Lea,T.”Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signaling events, but with different kinetics and intensity in Caco-2 cells.” Lipids Health Dis, 12, 101, 2013.
[20]  Calder, C.P. “Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale.” Biochimie, 91, 791-795, 2009.
[21]  Sidhu, A., Miller, P.J., Hollenbach, A.D. “FOXO1 stimulates ceruloplasmin promoter activity in human hepatoma cells treated with IL-6. Biochem. Biophys.” Res Commun, 404, 963-967, 2011.
[22]  Tsang, C.K., Liu, Y., Thoma, J., Zhang, Y., Zheng, X.F. “Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance.” Nat Commun, 5, 3446, 2014.
[23]  Jian, J., Yang, Q., Huang, X. “Src regulates Tyr (20) phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival.” J Biol Chem, 286, 35708-35715, 2011.
[24]  Barbariga, M., Curnis, F., Spitaleri, A., Andolfo, A., Zucchell, C., Lazzaro, M., Magnani, G., Musco, G., Corti, A., Alessio, M. “Oxidation-induced structural changes of ceruloplasmin foster NGR motif deamidation that promotes integrin binding and signaling.” J Biol Chem, 289, 3736-3748, 2014.
[25]  Glezer, I., Chernomoretz, A., David, S., Plante, M.M., Rivest, S. “Genes involved in the balance between neuronal survival and death during inflammation.” PLoS One, 2(3), e310, 2007.
[26]  Ayton, S., Zhang, M., Roberts, B.R., Lam, L.Q., Lind, M., McLean, C., Bush, A.I., Frugier, T., Crack, P.J., Duce, J.A. “Ceruloplasmin and β-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron.” Free Radic Biol Med, 69, 331-337, 2014.
[27]  Lazzaro, M., Bettegazzi, B., Barbariga, M., Codazzi, F., Zacchetti, D., Alessio, M. “Ceruloplasmin potentiates nitric oxide synthase activity and cytokine secretion in activated microglia.” J Neuroinflammation, 11, 164, 2014.
[28]  Fukai, T., Ushio-Fukai, M. “Superoxide dismutases: role in redox signaling, vascular function, and diseases.” Antioxid Redox Signal, 15, 1583-1606, 2011.
[29]  Moura, I.C., Hermine, O., Lacombe, C., Mayeux, P. “Erythropoiesis and transferrin receptors.” Curr Opin Hematol, 193-198, 2015.
[30]  Yorbik, O.Sayal, A., Akay, C., Akbiyik, D.I., Sohmen, T. “Investigation of antioxidant enzymes in children with autistic disorder.” Prostagland Leukot Essent Fatty Acids, 67, 341-343, 2002.
[31]  Söğüt, S., Zoroğlu, S.S., Ozyurt, H., Yilmaz, H.R., Ozuğurlu, F., Sivasli, E., Yetkin, O., Yanik, M., Tutkun, H., Savaş, H.A., Tarakçioğlu, M., Akyol, O. “Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiolgical mechanisms involved in autism.” Clin Chim Acta, 331, 111-117, 2006.
[32]  Zoroglu, S.S., Armutcu, F., Ozen, S., Gurel, A., Sivasli, E., Yetkin,O., Meram, I. “Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism.” Eur Arch Psychiatry Clin Neurosci, 254, 143-147, 2004.
[33]  Meguid, N.A., Dardir, A.A., Abdel-Raouf, E.R., Hashish, A. “Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation.” Biol Trace Elem Res, 143, 58-65, 2011.
[34]  Parellada, M., Moreno, C., Mac-Dowell, K., Leza, J.C., Giraldez, M., Bailón, C., Castro, C., Miranda-Azpiazu, P., Fraguas, D., Arango, C. “Plasma antioxidant capacity is reduced in Asperger syndrome.” J Psychiat Res, 46, 394-401, 2012.
[35]  Chauhan, A., Chauhan, V., Brown, W.T., Cohen, I. “Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin-the antioxidant proteins.” Life Sci, 75, 2539-2549, 2004.
[36]  Tórsdóttir, G., Hreidarsson, S., Kristinsson, J., Snaedal, J., Jóhannesson, T. “Ceruloplasmin, superoxide dismutase and copper in autistic patients.” Basic Clin Pharmacol Toxicol, 96, 146-148, 2005.
[37]  F.H. Tessaro, F.H., T.S. Ayala, T.S., J.Q. Martins, J.Q. “Lipid mediators are critical in resolving inflammation: a review of the emerging roles of eicosanoids in diabetes mellitus.” Biomed Res Int, 2015:568408. http://www.ncbi.nlm.nih. gov/ pmc/articles/PMC4383369/.
[38]  Hata, A.N., Breyer, R.M. “Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation.” Pharmacol Ther, 103, 147-166, 2004.
[39]  Rutter, M., Le Couteur, A., Lord, C. “ADI-R Autism Diagnostic Interview Revised Manual.” Western Psychological Services, Los Angeles, 2003, UAS.
[40]  D. Wechsler, Wechsler Intelligence Scale for Children-Revised Manual. The Psychological Corporation, New York, NY, USA (1974).
[41]  D. Wechsler. Wechsler Adult Intelligence Scale-Revised Manual. The Psychological Corporation, San Antonio, TX, USA (1981).
[42]  Koyama, T., Kamio, Y., Inada, N., Kurita, H. “Sex differences in WISC-III profiles of children with high-functioning pervasive developmental disorders.” J Autism Dev Disord 39, 135-141, 2009.
[43]  Schroeder, N., Park, Y.H., Kang, M.S., Kim, Y., Ha, G.K., Kim, H.R., Yates, A.A., Caballero. B. “A Randomized Trial on the Effects of 2010 Dietary Guidelines for Americans and Korean Diet Patterns on Cardiovascular Risk Factors in Overweight and Obese Adults.” J Acad Nutr Diet, 115, 1083-1092, 2015.
[44]  Ministry of Health, Labour and Welfare, and Ministry of Agriculture, Forestry and Fishers, “Japanese Food Guide.” Ministry of Health, Labour and Welfare, and Ministry of Agriculture, Forestry and Fishers, Tokyo, Japan, 2012.
[45]  Ministry of Health, Labour and Welfare, “Dietary Reference Intakes for Japanese. -2010-.” Ministry of Health, Labour and Welfare, Tokyo, Japan, 2010.
[46]  Ministry of Health, Labour, and Welfare. “Overview of dietary reference Intake for Japanese (2015).” Ministry of Health, Labour, and Welfare, Tokyo, Japan, 2015.
[47]  Okuda, M., Sasaki, S., Bando, N., Hashimoto, M., Kunitsugu, I., Sugiyama, S., Terao, J., Hobara, T. “Carotenoid, tocopherol, and fatty acid biomarkers and dietary intake estimated by using a brief self-administered diet history questionnaire for older Japanese children and adolescents.” J Nutr Sci Vitaminol (Tokyo), 55, 231-241, 2009.
[48]  Rojahn, J., Aman, M.G., Matson, J.L., Mayville, E. “The Aberrant Behavior Checklist and the Behavior Problems Inventory: convergent and divergent validity.” Res Dev Disabil, 24 (2003) 391-404, 2003.
[49]  Hollander, E., Chaplin, W., Soorya, L., Wasserman, S., Novotny, S., Rusoff, J., Feirsen, N., Pepa, L., Anagnostou, E. “Divalproex sodium vs. placebo for the treatment of irritability in children and adolescents with autism spectrum disorders.” Neuropsychopharmacology, 35, 990-998, 2009.
[50]  Karabekiroglu, K., Aman, M.G., “Validity of the aberrant behavior checklist in a clinical sample of toddlers.” Child Psychiatry Hum Dev, 40, 99-110, 2009.
[51]  Hamazaki, H., Itomura, M., Hamazaki, T., Sawazaki, S. “Effects of cooking plant oils on recurrent aphthous stomatitis: a randomized, placebo-controlled, double-blind trial.” Nutrition, 22, 534-536, 2006.
[52]  Bligh, E.G., Dyer, W.J. “A rapid method of total lipid extraction and purification.” Can J Med Sci, 37, 911-917, 1959.
[53]  Singh, K., Connors, S.L., Macklin, E.A., Smith, K.D., Fahey, J.W., Talalay, P., Zimmerman, A,W. “Sulforaphane treatment of autism spectrum disorder (ASD).” Proc Natl Acad Sci U S A, 111, 15550-15555, 2014.
[54]  Sublette, M.E., Bosetti, F., DeMar, J.C., Ma, K., Bell, J.M., Fagin-Jones, S., Russ, M.J., Rapoport, S.I. “Plasma free polyunsaturated fatty acid levels are associated with symptom severity in acute mania.” Bipolar Disord, 9, 759-765, 2007.
[55]  Barbariga, M., Curnis, F., Spitaleri, A., Andolfo, A., Zucchelli, C., Lazzaro, M., Magnani, G., Musco, G., Corti, A., M. Alessio, M. “Oxidation-induced structural changes of ceruloplasmin foster NGR motif deamidation that promotes integrin binding and signaling.” J Biol Chem, 289, 3736-3748, 2014.
[56]  Squitti, R., Ghidoni, R., Siott, M., Ventriglia, M., Benussi, L., Paterlini, A., Magri, M. Binetti, G., Cassetta, E., Caprara, D., Vernieri, F., Rossini, P.M., Pasqualetti, P. Value of serum Nonceruloplasmin copper for prediction of mild cognitive impairment conversion to Alzheimer disease. Ann Neurol, 75, 574-580, 2014.
[57]  Dalvi, S., Nguyen, H.H., On, N., Mitchell, R.W., Aukema, H.M., Miller, D.W., Hatch, G.M. “Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors.” J Neurochem, 2015.
[58]  Sokov, A.V., Golenkina, E.A., Kostevich, V.A., Vasilyev, V.B., Sud’ina, G.F. “Interaction of ceruloplasmin and 5-lipoxygenase.” Biochemistry (Mosc), 75, 1464-1469, 2010.
[59]  Seegmiller. A.C. “Abnormal unsaturated fatty acid metabolism in cystic fibrosis: biochemical mechanisms and clinical implications.” Int J Mol Sci, 15, 16083-16099, 2014.
[60]  Jacometo, C.B., Schmitt, E., Pfeifer, L.F., Schneider, A., Bado, F., da Rosa, F.T., Halfen, S., Del Pino, F.A., Loor, J.J., Corrêa, M.N., Dionello, N.J. “Linoleic and α-linolenic fatty acid consumption over three generations exert cumulative regulation of hepatic expression of genes related to lipid metabolism.” Genes Nutr, 9, 405, 2014.
[61]  El-Ansary, A.K., Bacha, A.G., Al-Ayahdi. L.Y. “Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia.” Lipids Health Dis, 10, 62, 2011b.
[62]  Al-Farsi, Y.M., Waly, M.I., Deth, R.C., Al-Sharbati, M.M., Al-Shafaee, M., Al-Farsi, O., Al-Khaduri, M.M., Al-Adawi, S., Hodgson, N.W., Gupta, I., Ouhtit, A, “Impact of nutrition on serum levels of docosahexaenoic acid among Omani children with autism.” Nutrition, 29, 1142-1146, 2013.
[63]  Karr, J.E., Alexander, R.G. Winningham, R.G. “Omega-3 polyunsaturated fatty acids and cognition throughout the lifespan: a review.” Nutr Neurosci, 14, 216-225, 2011.
[64]  Innis SM. Dietary (n-3) fatty acids and brain development. J Nutr, 137, 855-859, 2007.
[65]  Adel, S., Kakularam, K.R., Horn, T., Reddanna, P., Kuhn, H., Heydeck, D. “Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens.” Arch Biochem Biophys, 565, 17-24, 2015.
[66]  Zheng, W., Monnot, A.D. “Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases.” Pharmacol Ther, 133,177-188, 2012.
[67]  J.H. Chen C.J. Perry, Y.C. Tsui, M.M. Staron I.A. Parish, C.X. Dominguez, D.W. Rosenberg, S.M. Kaech, Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat. Med. 21(2015) 327- 334
[68]  Rago, B., Fu, C. “Development of a high-throughput ultra performance liquid chromatography-mass spectrometry assay to profile 18 eicosanoids as exploratory biomarkers for atherosclerotic diseases.” J Chromatogr B Analyt Technol Biomed Life Sci, 936, 25-32, 2013.
[69]  Baron-Cohen, S., Lombardo, M.V., Auyeung, B., Ashwin, E., Chakrabarti, B., Knickmeyer, R. “Why are autism spectrum conditions more prevalent in males?” PLoS Biol. 9, e1001081, 2012.