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Belyaeva L.E., Pauliukevich A.N.
The early programming of human diseases and the application of nutraceuticals for their prevention: focus on fish oil. Literature review. Part 2
Vitebsk State Order of Peoples’ Friendship Medical University, Vitebsk, Republic of Belarus

Vestnik VGMU. 2019;18(5):12-25.

In the second part of this review the results of numerous experimental, clinical and epidemiological studies devoted to the influence of ω-3 polyunsaturated fatty acids (ω-3 PUFA)-containing nutraceuticals on the characteristic and peculiarities of intrauterine development and also the effects observed in different periods of postnatal development in organisms born by mothers whose pregnancy proceeded in adverse conditions have been analyzed and discussed. The main mechanisms of prenatal stress outcomes minimization with ω-3 PUFA by their influence on the inflammatory process, oxidative stress, organization of structural cell components as well as participation in epigenetic regulation of gene expression and various disorders programming as a whole are discussed.  
Key words: omega-3 polyunsaturated fatty acids, prenatal stress, oxidative stress, systemic low grade inflammation, lipid «rafts», caveolae, epigenetic mechanisms.


1. Pirkola J, Vääräsmäki M, Ala-Korpela M, Bloigu A, Canoy D, Hartikainen AL, et al. Low-grade, systemic inflammation in adolescents: association with early-life factors, gender, and lifestyle. Am J Epidemiol. 2010 Jan;171(1):72-82. doi:
2. Pedersen JM, Mortensen EL, Christensen DS, Rozing M, Brunsgaard H, Meincke RH, et al. Prenatal and early postnatal stress and later life inflammation. Psychoneuroendocrinology. 2018 Feb;88:158-166. doi:
3. Staud F, Karahoda R. Trophoblast: The central unit of fetal growth, protection and programming. Int J Biochem Cell Biol. 2018 Dec;105:35-40. doi:
4. Kuzawa CW, Fried RL, Borja JB, McDade TW. Maternal pregnancy C-reactive protein predicts offspring birth size and body composition in metropolitan Cebu, Phillipines. J Dev Orig Health Dis. 2017 Dec;8(6):674-681. doi:  
5. Watanabe IKM, Jara ZP, Volpini RA, Franco MDC, Jung FF, Casarini DE. Up-regulation of renal renin-angiotensin system and inflammatory mechanisms in the prenatal programming by low-protein diet: beneficial effect of the post-weaning losartan treatment. J Dev Orig Health Dis. 2018 Oct;9(5):530-535. doi:
6. Peixoto AB, Rolo LC, Nardozza LMM, Araujo Júnior E. Epigenetics and preeclampsia: programming of future outcomes. Methods Mol Biol. 2018;1710:73-83. doi:
7. Tarry-Adkins JL, Fernandez-Twinn DS, Chen JH, Hargreaves IP, Neergheen V, Aiken CE, et al. Poor maternal nutrition and accelerated postnatal growth induces an accelerated aging phenotype and oxidative stress in skeletal muscle of male rats. Dis Model Mech. 2016 Oct;9(10):1221-1229.  
8. McDade TW, Ryan C, Jones MJ, MacIsaac JL, Morin AM, Meyer JM, et al. Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood. Proc Natl Acad Sci U S A. 2017 Jul;114(29):7611-7616. doi:
9. Bouwens M, van de Rest O, Dellschaft N, Bromhaar MG, de Groot LC, Geleijnse JM, et al. Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr. 2009 Aug;90(2):415-24. doi:
10. Sigal LH. Basic science for the clinician 39: NF-kappa B-function, activation, control, and consequences. J Clin Rheumatol. 2006 Aug;12(4):207-11. doi:
11. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014 Jun;510(7503):92-101. doi:
12. Grygiel-Gуrniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review. Nutr J. 2014 Feb;13:17. doi:
13. Abedi E, Sahari MA. Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties. Food Sci Nutr. 2014 Sep;2(5):443-63. doi:
14. Haast RA, Kiliaan AJ. Impact of fatty acids on brain circulation, structure and function. Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:3-14. doi:
15. Garcia-So J, Zhang X, Yang X, Rubinstein MR, Mao Y, Kitajewski J, et al. Omega-3 fatty acids suppress Fusobacterium nucleatum-induced placental inflammation originating from maternal endothelial cells. JCI Insight. 2019 Feb;4(3). pii: 125436. doi:
16. Ramalingam L, Menikdiwela KR, Clevenger S, Eboh T, Allen L, Koboziev I, et al. Maternal and postnatal supplementation of fish oil improves metabolic health of mouse male offspring. Obesity (Silver Spring). 2018 Nov;26(11):1740-1748. doi:
17. See VHL, Mas E, Prescott SL, Beilin LJ, Burrows S, Barden AE, Huang RC, et al. Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: a double-blind, randomised controlled clinical trial. Br J Nutr. 2017 Dec;118(11):971-980. doi:
18. Krauss-Etschmann S, Hartl D, Rzehak P, Heinrich J, Shadid R, Del Carmen Ramírez-Tortosa M, et al. Decreased cord blood IL-4, IL-13, and CCR4 and increased TGF-beta levels after fish oil supplementation of pregnant women. J Allergy Clin Immunol. 2008 Feb;121(2):464-470.e6. doi:
19. Thompson LP, Al-Hazan Y. Impact of oxidative stress in fetal programming. J Pregnancy. 2012;2012:582748. doi:
20. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001 Jun;30(11):1191-212. doi:
21. Eick SM, Barrett ES, van 't Erve TJ, Nguyen RHN, Bush NR, Milne G, et al. Association between prenatal psychological stress and oxidative stress during pregnancy. Paediatr Perinat Epidemiol. 2018 Jul;32(4):318-326. doi:
22. Ferreira DJS, Pedroza AA, Braz GRF, Fernandes MP, Lagranha CJ. Mitochondrial dysfunction: maternal protein restriction as a trigger of reactive species overproduction and brainstem energy failure in male offspring brainstem. Nutr Neurosci. 2018 Mar:1-11. doi:
23. Ramaiyan B, Bettadahalli S, Talahalli RR. Dietary omega-3 but not omega-6 fatty acids down-regulate maternal dyslipidemia induced oxidative stress: a three generation study in rats. Biochem Biophys Res Commun. 2016 Sep;477(4):887-894. doi:
24. Kajarabille N, Hurtado JA, Peña-Quintana L, Peña M, Ruiz J, Diaz-Castro J, et al. Omega-3 LCPUFA supplement: a nutritional strategy to prevent maternal and neonatal oxidative stress. Matern Child Nutr. 2017 Apr;13(2). doi:
25. Barden AE, Mori TA, Dunstan JA, Taylor AL, Thornton CA, Croft KD, et al. Fish oil supplementation in pregnancy lowers F2-isoprostanes in neonates at high risk of atopy. Free Radic Res. 2004 Mar;38(3):233-9.
26. Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science. 1972 Feb;175(4023):720-31.
27. Karnovsky MJ, Kleinfeld AM, Hoover RL, Klausner RD. The concept of lipid domains in membranes. J Cell Biol. 1982 Jul;94(1):1-6. doi:
28. Sonnino S, Prinetti A. Membrane domains and the «lipid raft» concept. Curr Med Chem. 2013;20(1):4-21.
29. Sohn J, Brick RM, Tuan RS. From embryonic development to human diseases: the functional role of caveolae/caveolin. Birth Defects Res C Embryo Today. 2016 Mar;108(1):45-64. doi:
30. Itokazu Y, Tsai YT, Yu RK. Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells. Glycoconj J. 2017 Dec;34(6):749-756. doi:
31. Bowen RA, Clandinin MT. Dietary low linolenic acid compared with docosahexaenoic acid alter synaptic plasma membrane phospholipid fatty acid composition and sodium-potassium ATPase kinetics in developing rats. J Neurochem. 2002 Nov;83(4):764-74.
32. Jonscher KR, Stewart MS, Alfonso-Garcia A, DeFelice BC, Wang XX, Luo Y, et al. Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. FASEB J. 2017 Apr;31(4):1434-1448. doi:
33. Kasbi-Chadli F, Ferchaud-Roucher V, Krempf M, Ouguerram K. Direct and maternal n-3 long-chain polyunsaturated fatty acid supplementation improved triglyceridemia and glycemia through the regulation of hepatic and muscle sphingolipid synthesis in offspring hamsters fed a high-fat diet. Eur J Nutr. 2016 Mar;55(2):589-599. doi:
34. Zhang W, Liu J, Hu X, Li P, Leak RK, Gao Y, et al. n-3 polyunsaturated fatty acids reduce neonatal hypoxic/ischemic brain injury by promoting phosphatidylserine formation and Akt signaling. Stroke. 2015 Oct;46(10):2943-50. doi:
35. Wassall SR, Leng X, Canner SW, Pennington ER, Kinnun JJ, Cavazos AT, et al. Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation. Biochim Biophys Acta Biomembr. 2018 Oct;1860(10):1985-1993. doi:
36. Zhaorigetu S, Bair H, Lu J, Jin D, Olson SD, Harting MT. Perturbations in endothelial dysfunction-associated pathways in the nitrofen-induced congenital diaphragmatic hernia model. J Vasc Res. 2018;55(1):26-34. doi:
37. Kozak LP, Newman S, Chao PM, Mendoza T, Koza RA. The early nutritional environment of mice determines the capacity for adipose tissue expansion by modulating genes of caveolae structure. PLoS One. 2010 Jun;5(6):e11015. doi:
38. Chen DB, Li SM, Qian XX, Moon C, Zheng J. Tyrosine phosphorylation of caveolin 1 by oxidative stress is reversible and dependent on the c-src tyrosine kinase but not mitogen-activated protein kinase pathways in placental artery endothelial cells. Biol Reprod. 2005 Oct;73(4):761-72.
39. Li Q, Zhang Q, Wang M, Liu F, Zhao S, Ma J, et al. Docosahexaenoic acid affects endothelial nitric oxide synthase in caveolae. Arch Biochem Biophys. 2007 Oct;466(2):250-9. doi:
40. Nguyen HP, Simpson RJ, Salamonsen LA, Greening DW. Extracellular vesicles in the intrauterine environment: challenges and potential functions. Biol Reprod. 2016 Nov;95(5):109. doi:
41. Makris V, Daniilidis A, Koiou A, Balaouras D, Fotinakis I, Spathopoulou S, et al. Microparticles hyperactivity in a case of intrauterine growth restriction. Clin Exp Obstet Gynecol. 2015;42(2):231-3.
42. Zhang Y, Zhao C, Wei Y, Yang S, Cui C, Yang J, et al. Increased circulating microparticles in women with preeclampsia. Int J Lab Hematol. 2018 Jun;40(3):352-358. doi:
43. Jayabalan N, Lai A, Ormazabal V, Adam S, Guanzon D, Palma C, et al. Adipose tissue exosomal proteomic profile reveals a role on placenta glucose metabolism in gestational diabetes mellitus. J Clin Endocrinol Metab. 2019 May;104(5):1735-1752. doi:
44. Wu SY, Mayneris-Perxachs J, Lovegrove JA, Todd S, Yaqoob P. Fish-oil supplementation alters numbers of circulating endothelial progenitor cells and microparticles independently of eNOS genotype. Am J Clin Nutr. 2014 Nov;100(5):1232-43. doi:
45. Phang M, Lincz L, Seldon M, Garg ML. Acute supplementation with eicosapentaenoic acid reduces platelet microparticle activity in healthy subjects. J Nutr Biochem. 2012 Sep;23(9):1128-33. doi:
46. Rudolph MC, Jackman MR, Presby DM, Houck JA, Webb PG, Johnson GC, et al. Low neonatal plasma n-6/n-3 PUFA ratios regulate offspring adipogenic potential and condition adult obesity resistance. Diabetes. 2018 Apr;67(4):651-61. doi:
47. Fan C, Fu H, Dong H, Lu Y, Lu Y, Qi K. Maternal n-3 polyunsaturated fatty acid deprivation during pregnancy and lactation affects neurogenesis and apoptosis in adult offspring: associated with DNA methylation of brain-derived neurotrophic factor transcripts. Nutr Res. 2016 Sep;36(9):1013-1021. doi:
48. Boddicker RL, Koltes JE, Fritz-Waters ER, Koesterke L, Weeks N, Yin T, et al. Genome-wide methylation profile following prenatal and postnatal dietary omega-3 fatty acid supplementation in pigs. Anim Genet. 2016 Dec;47(6):658-671. doi:
49. Lee H-S, Barraza-Villarreal A, Biessy C, Duarte-Salles T, Sly PD, Ramakrishnan U, et al. Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants. Physiol Genomics. 2014 Dec;46(23):851-7. doi:
50. van Dijk SJ, Zhou J, Peters TJ, Buckley M, Sutcliffe B, Oytam Y, et al. Effect of prenatal DHA supplementation on the infant epigenome: results from a randomized controlled trial. Clin Epigenetics. 2016 Nov;8:114.
51. Harb H, Irvine J, Amarasekera M, Hii CS, Kesper DA, Ma Y, et al. The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil. Biosci Rep. 2017 Mar;37(2). pii: BSR20160485. doi:
52. Casas-Agustench P, Fernandes FS, Tavares do Carmo MG, Visioli F, Herrera E, Dávalos A. Consumption of distinct dietary lipids during early pregnancy differentially modulates the expression of microRNAs in mothers and offspring. PLoS One. 2015 Feb;10(2):e0117858. doi:
53. Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst Rev. 2018 Nov;11:CD003402. doi:
54. Chiu YH, Karmon AE, Gaskins AJ, Arvizu M, Williams PL, Souter I, et al. Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. Hum Reprod. 2018 Jan;33(1):156-165. doi:
55. Rioux FM, Lindmark G, Hernell O. Does inadequate maternal iron or DHA status have a negative impact on an infant’s functional outcomes? Acta Paediatrica. 2006;95(2):137-44.
56. Fernstrom JD. Effects of dietary polyunsaturated fatty acids on neuronal function. Lipids. 1999 Feb;34(2):161-9.
57. Hu X, Zhang F, Leak RK, Zhang W, Iwai M, Stetler RA, et al. Transgenic overproduction of omega-3 polyunsaturated fatty acids provides neuroprotection and enhances endogenous neurogenesis after stroke. Curr Mol Med. 2013 Nov;13(9):1465-73.
58. Palsdottir V, Månsson JE, Blomqvist M, Egecioglu E, Olsson B. Long-term effects of perinatal essential fatty acid deficiency on anxiety-related behavior in mice. Behav Neurosci. 2012 Apr;126(2):361-9. doi:
59. Imhoff-Kunsch B, Briggs V, Goldenberg T, Ramakrishnan U. Effect of n-3 long-chain polyunsaturated fatty acids intake during pregnancy on maternal, infant, and child health outcomes: a systematic review. Paediatr Perinat Epidemiol. 2012 Jul;26 Suppl 1:91-107. doi:
60. Wierzejska R, Jarosz M, Wojda B, Siuba-Strzelińska M. Dietary intake of DHA during pregnancy: a significant gap between the actual intake and current nutritional recommendations. Rocz Panstw Zakl Hig. 2018;69(4):381-386.
61. Tressou J, Buaud B, Simon N, Pasteau S, Guesnet P. Very low inadequate dietary intakes of essential n-3 polyunsaturated fatty acids (PUFA) in pregnant and lactating French women: The INCA2 survey. Prostaglandins Leukot Essent Fatty Acids. 2019 Jan;140:3-10. doi:
62. Kominiarek MA, Rajan P. Nutrition recommendations in pregnancy and lactation. Med Clin North Am. 2016 Nov;100(6):1199-1215. doi:
63. Matsui F, Hecht P, Yoshimoto K, Watanabe Y, Morimoto M, Fritsche K, et al. DHA mitigates autistic behaviors accompanied by dopaminergic change in a gene / prenatal stress mouse model. Neuroscience. 2018 Feb;371:407-419. doi:
64. Gao J, Wu H, Cao Y, Liang S, Sun C, Wang P, et al. Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid. J Nutr Biochem. 2016 Sep;35:87-95. doi:
65. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics. 2003 Jan;111(1):e39-44.
66. Keenan K, Hipwell A, McAloon R, Hoffmann A, Mohanty A, Magee K. The effect of prenatal docosahexaenoic acid supplementation on infant outcomes in African American women living in low-income environments: A randomized, controlled trial. Psychoneuroendocrinology. 2016 Sep;71:170-5. doi:
67. Shysh AM, Nagibin VS, Kaplinskii SP, Dosenko VE. N-3 long chain polyunsaturated fatty acids increase the expression of PPARg-target genes and resistance of isolated heart and cultured cardiomyocytes to ischemic injury. Pharmacol Rep. 2016 Dec;68(6):1133-1139. doi:
68. Bryant J, Hanson M, Peebles C, Davies L, Inskip H, Robinson S, et al. Higher oily fish consumption in late pregnancy is associated with reduced aortic stiffness in the child at age 9 years. Circ Res. 2015 Mar;116(7):1202-5. doi:
69. Rytter D, Christensen JH, Bech BH, Schmidt EB, Henriksen TB, Olsen SF. The effect of maternal fish oil supplementation during the last trimester of pregnancy on blood pressure, heart rate and heart rate variability in the 19-year-old offspring. Br J Nutr. 2012 Oct;108(8):1475-83. doi:
70. Ottestad I, Nordvi B, Vogt G, Holck M, Halvorsen B, Brønner KW, et al. Bioavailability of n-3 fatty acids from n-3-enriched foods and fish oil with different oxidative quality in healthy human subjects: a randomised single-meal cross-over study. J Nutr Sci. 2016 Oct;5:e43. doi:                                                

Information about authors:
Belyaeva L.E. – Candidate of Medical Sciences, associate professor, head of the Chair of Pathologic Physiology, Vitebsk State Order of Peoples’ Friendship Medical University;
Pauliukevich A.N. – Master of Medical Sciences, lecturer of the Chair of Pathologic Physiology, Vitebsk State Order of Peoples’ Friendship Medical University.

Correspondence address: Republic of Belarus, 210009, Vitebsk, 27 Frunze ave., Vitebsk State Order of Peoples’ Friendship Medical University, Chair of Pathologic Physiology. E-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. – Lyudmila E. Belyaeva.

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