Skip to main content

Advertisement

SpringerLink
Log in

Association Between Neurotrophin 4 and Long-Chain Polyunsaturated Fatty Acid Levels in Mid-Trimester Amniotic Fluid

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The omega-3 long-chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) and the omega-6 LCPUFA arachidonic acid (AA) are essential nervous system components that increase in concentration throughout gestation. The neurotrophins, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) are small basic peptides crucial for fetal brain development. The DHA supplementation during pregnancy has been suggested to enhance neural development. We evaluated whether amniotic fluid DHA and AA concentrations correlated with intra-amniotic neurotrophin levels. Amniotic fluid, obtained at 15 to 19 weeks gestation from 62 women, was tested for BDNF, NGF, NT3, and NT4 by enzyme-linked immunosorbent assay. Concentrations of DHA and AA, and saturated and monounsaturated fatty acids, were determined by gas chromatography. Associations were analyzed by the Spearman rank correlation test. Median levels of AA and DHA were 2.3% and 1.3% of the total intra-amniotic fatty acids, respectively. Median neurotrophin levels (pg/mL) were 36.7 for NT3, 26.8 for BDNF, 5.2 for NT4, and 0.8 for NGF. Intra-amniotic NT4 and BDNF levels were correlated (P = .0016), while NT3 and NGF levels were unrelated to each other or to BDNF or NT4. Only NT4 was positively correlated with amniotic fluid DHA (P < .0001) and AA (P = .0003) concentrations. There were no associations between DHA, AA, or any neurotrophin and maternal age, gestational age at time of amniocentesis, amniocentesis indication, parity, or gestational age at delivery. Elevations in intra-amniotic NT4 with increasing levels of DHA and AA suggest that these LCPUFAs may specifically influence the extent of NT4-mediated fetal brain neurogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14(1):7–23.

    Article  CAS  Google Scholar 

  2. Chao MV. Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci. 2003;4(4): 299–309.

    Article  CAS  Google Scholar 

  3. Huang EJ, Reichardt LE. Neurotrophins: roles in neural development and function. Annu Rev Neurosci. 2001;24:677–736.

    Article  CAS  Google Scholar 

  4. Nikolaou KE, Malamitsi-Puchner A, Boutsikou T, et al. The varying patterns of neurotrophins changes in the perinatal period. Ann NY Acad Sci. 2006;1092:426–433.

    Article  CAS  Google Scholar 

  5. Farinas I, Cano-Jaimez M, Bellmunt E, Soriano M. Regulation of neurogenesis by neurotrophins in developing spinal sensory ganglia. Brain Res Bull. 2002;57(6):809–816.

    Article  CAS  Google Scholar 

  6. Innis SM. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr. 2003;143(4 suppl):S1–S8.

    Article  CAS  Google Scholar 

  7. Larque E, Demmelmair H, Gil-Sanchez A, et al. Placental transfer of fatty acids and fetal implications. Am J Clin Nutr. 2011; 94(6 suppl):1908S-1913S.

    Article  CAS  Google Scholar 

  8. Kitajka K, Sinclair AJ, Weisinger RS, et al. Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci USA. 2004;101(30):10931–10936.

    Article  CAS  Google Scholar 

  9. Bertrand PC, O’Kusky JR, Innis SM. Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. J Nutrition. 2006;136(6):1570–1575.

    Article  CAS  Google Scholar 

  10. Kawakita E, Hashimoto M, Shido O. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience. 2006;139(3):991–997.

    Article  CAS  Google Scholar 

  11. Bhatia HS, Agrawal R, Sharma S, Huo Y-X, Ying Z, Gomez-Pinilla F. Omega-3 fatty acid deficiency during brain maturation reduces neuronal and behavioral plasticity in adulthood. PLoS One. 2011;6(12):e28451.

    Article  CAS  Google Scholar 

  12. Sable PS, Dangat KD, Joshi AA, Joshi SR. Maternal omega 3 fatty acid supplementation during pregnancy to a micronutrientimbalanced diet protects postnatal reduction of brain neurotrophins in the rat offspring. Neuroscience. 2012;217:46–55.

    Article  CAS  Google Scholar 

  13. Dhobale M, Joshi S. Altered maternal micronutrients (folic acid, vitamin B12) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy. J Matern Fetal Med. 2012;25(4):317–323.

    Article  CAS  Google Scholar 

  14. Marx CE, Vance BJ, Jarskog F, Chescheir NC, Gilmore JH. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 levels in human amniotic fluid. Am J Obstet Gynecol. 1999;181(5 pt 1): 1125–1130.

    Google Scholar 

  15. Abdallah MW, Pearce BD, Larsen N, et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. 2012;5(6):428–433.

    Article  Google Scholar 

  16. Cho CK, Shan SJ, Winsor EJ, Diamandis EP. Proteomics analysis of human amniotic fluid. Mol Cell Proteomics. 2007;6(8): 1406–1415.

    Article  CAS  Google Scholar 

  17. Witkin SS, Skupski D, Herway C, Rudge MVC, Saito F, Harris M. Fatty acid composition of mid-trimester amniotic fluid in women of different ethnicities. J Matern Fetal Neonatal Med. 2012;25(6):818–821.

    Article  CAS  Google Scholar 

  18. Crawford MA. Placental delivery of arachidonic and docosahexaenoic acids: implications for the lipid nutrition of premature infants. Am J Clin Nutr. 2000;71(1 suppl):275S-284S.

    Article  CAS  Google Scholar 

  19. Crawford MA, Golfetto I, Ghebremeskel K, et al. The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants. Lipids. 2003;38(4):303–315.

    Article  CAS  Google Scholar 

  20. Brenna JT, Lapillonne A. Background paper on fat and fatty acid requirements during pregnancy and lactation. Ann Nutr Metab. 2009;55(1–3):97–122.

    Article  CAS  Google Scholar 

  21. Kulkarni A, Dangat K, Kale A, Sable P, Chavan-Gautam P, Joshi S. Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One. 2011;6(3):e17706.

    Article  CAS  Google Scholar 

  22. Roy S, Kale A, Dangat K, Sable P, Kulkarni A, Joshi S. Maternal micronutrient (folic acid and vitamin B12) and omega 3 fatty acids: implications for neurodevelopmental risk in the rat offspring. Brain Dev. 2012;34(1):64–71.

    Article  Google Scholar 

  23. Dhobale MV, Pisal HR, Mehendale SS, Joshi SR. Differential expression of human placental neurotrophic factors in preterm and term deliveries. Int J Dev Neurosci. 2013;31(8): 719–723.

    Article  CAS  Google Scholar 

  24. McGregor JA, Allen KGD, Harris MA, et al. The omega-3 story: nutritional prevention of preterm birth and other adverse pregnancy outcomes. Obstet Gynecol Survey. 2001;56(5 suppl 1); S1–S13.

    Article  CAS  Google Scholar 

  25. Nosrat CA, Blomlof J, ElShamy WM, Ernfors P, Olsen L. Lingual deficits in BDNF and NT3 mutant mice leading to gustatory and somatosensory disturbances, respectively. Development. 1997; 124(7): 1333–1342.

    CAS  PubMed  Google Scholar 

  26. Runge EM, Hishino N, Biehl MJ, Ton S, Rochlin MW. Neurotrophin-4 is more potent than brain-derived neurotrophic factor in promoting, attracting and suppressing geniculate ganglion neurite outgrowth. Dev Neurosci. 2012;34(5): 389–401.

    Article  CAS  Google Scholar 

  27. Bosco A, Linden R, BDNF and NT4 differentially modulate neurite outgrowth in developing retinal ganglion cells. J Neurosci Res. 1999;57(6):759–769.

    Article  CAS  Google Scholar 

  28. Fan G, Egles C, Sun Y, et al. Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat Neurosci. 2000;3(4): 350–357.

    Article  CAS  Google Scholar 

  29. Patel AV, Krimm RF. Neurotrophin-4 regulates the survival of gustatory neurons earlier in development using a different mechanism than brain-derived neurotrophic factor. Dev Biol. 2012;365(1):50–60.

    Article  CAS  Google Scholar 

  30. Liu X, Ernfors P, Wu H, Jaenisch R. Sensory but not motor neuron deficits in mice lacking BDNF and NT4. Nature. 1995; 375(6528):238–240.

    Article  CAS  Google Scholar 

  31. Shen Y, Inoue N, Heese K. Neurotrophin-4 (ntf4) mediates neurogenesis in mouse embryonic neural stems cells through the inhibition of the signal transducer and activator of transcription-3 (stat3) and the modulation of the activity of protein kinase B. Cell Mol Neurobiol. 2010;30(6):909–916.

    Article  CAS  Google Scholar 

  32. Anderson RA, Robinson LL, Brooks J, Spears N. Neurotrophins and their receptors are expressed in the human fetal ovary. J Clin Endocrinol Metab. 2002;87(2):980–897.

    Article  Google Scholar 

  33. Bagga D, Wang I, Farias-Eisner R, Glaspy JA, Reddy ST. Differential effects of prostaglandins derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci USA. 2003;100(4): 1751–1756.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division of Immunology and Infectious Diseases, Weill Cornell Medical College, 525 East 68th Street, Box 35, 10065, New York, NY, USA

    Kiesha Benn MD, Mariana Passos MD, Aswathi Jayaram MD, Ann Marie Bongiovanni AB & Steven S. Witkin PhD

  2. Department of Obstetrics and Gynecology, New York Hospital Queens, Queens, New York, NY, USA

    Kiesha Benn MD & Daniel Skupski MD

  3. Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA

    Mary Harris PhD

Authors
  1. Kiesha Benn MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariana Passos MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aswathi Jayaram MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Harris PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ann Marie Bongiovanni AB
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Skupski MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven S. Witkin PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven S. Witkin PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Benn, K., Passos, M., Jayaram, A. et al. Association Between Neurotrophin 4 and Long-Chain Polyunsaturated Fatty Acid Levels in Mid-Trimester Amniotic Fluid. Reprod. Sci. 21, 1395–1400 (2014). https://doi.org/10.1177/1933719114526474

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719114526474

Keywords

Search

Navigation