Skip to main content
Log in

Evidence of Oxidative Stress in the Brains of Fetuses with CNS Anomalies and Islet Cell Hyperplasia

  • Original article
  • Published:
Pediatric and Developmental Pathology

Abstract

Infants of diabetic mothers have an increased frequency of congenital anomalies, including CNS malformations. Fetal hyperglycemia may promote such damage via oxidative stress. Postmortem studies have shown that fetal hyperglycemia associated with maternal diabetes results in islet cell hyperplasia. Islet cell hyperplasia may correlate with the presence of oxidative stress injury in the CNS because of hyperglycemia and related metabolic derangement. This study examines 3-nitrotyrosine immunoreactivity as a marker of oxidative stress in the brains of fetuses stratified by the presence or absence of islet cell hyperplasia and CNS developmental anomalies. Fetuses with both islet cell hyperplasia and CNS developmental anomalies showed a 1.8-fold increase in semiquantitatively scored 3-nitrotyrosine immunostaining compared to negative controls. Fetuses with islet cell hyperplasia but no CNS anomalies demonstrated a 1.6-fold increase. Comparison between fetuses with islet cell hyperplasia which were stratified by presence or absence of CNS anomalies were not statistically different but did show more intense staining in those with CNS malformations. These results support the contention that hyperglycemia may contribute to CNS malformation via oxidative stress.

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

Access this article

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

Instant access to the full article PDF.

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.

Similar content being viewed by others

References

  1. S Konig M Vest M Stahl (1978) ArticleTitleInterrelation of maternal and foetal glucose and free fatty acids. The role of insulin and glucagon Eur J Pediatr 128 187–195 Occurrence Handle1:STN:280:CSeB3MvntFI%3D Occurrence Handle668726

    CAS  PubMed  Google Scholar 

  2. BG Kousseff (1999) ArticleTitleGestational diabetes mellitus (class A): a human teratogen? Am J Med Genet 83 402–408 Occurrence Handle10.1002/(SICI)1096-8628(19990423)83:5<402::AID-AJMG12>3.3.CO;2-6 Occurrence Handle1:STN:280:DyaK1M3kslOgtQ%3D%3D Occurrence Handle10232752

    Article  CAS  PubMed  Google Scholar 

  3. NG Soler CH Walsh JM Malins (1976) ArticleTitleCongenital malformations in infants of diabetic mothers Q J Med 45 303–313 Occurrence Handle1:STN:280:CSmB2crgt1A%3D Occurrence Handle781716

    CAS  PubMed  Google Scholar 

  4. A Ceriello P dello Russo P Amstad P Cerutti (1996) ArticleTitleHigh glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress Diabetes 45 471–487 Occurrence Handle1:CAS:528:DyaK28Xjs1Gjtbk%3D Occurrence Handle8603769

    CAS  PubMed  Google Scholar 

  5. R Sharma D Constantin-Teodosiu B Middleton M Willis MK Pratten (1996) ArticleTitleTeratogenic potential of free-radicals and hexokinase isoenzymes in the postimplantational “diabetic” rat conceptus Biochem Soc Trans 24 (Suppl) 235S

    Google Scholar 

  6. EA Reece CJ Homko YK Wu A Wiznitzer (1993) ArticleTitleMetabolic fuel mixtures and diabetic embryopathy Clin Perinatol 20 517–532 Occurrence Handle1:CAS:528:DyaK2cXltFagsg%3D%3D Occurrence Handle8222465

    CAS  PubMed  Google Scholar 

  7. HJ Bruyere C Viseskul JM Opitz LO Langer S Ishikawa EF Gilbert (1980) ArticleTitleA fetus with upper limb amelia, “caudal regression” and Dandy-Walker defect with an insulin-dependent diabetic mother Eur J Pediatr 134 139–143 Occurrence Handle7439199

    PubMed  Google Scholar 

  8. ML Martinez-Frias E Bermejo E Rodriguez-Pinilla L Prieto JL Frias (1998) ArticleTitleEpidemiological analysis of outcomes of pregnancy in gestational diabetic mothers Am J Med Genet 78 140–145 Occurrence Handle10.1002/(SICI)1096-8628(19980630)78:2<140::AID-AJMG8>3.0.CO;2-S Occurrence Handle1:STN:280:DyaK1czjslKlsw%3D%3D Occurrence Handle9674904

    Article  CAS  PubMed  Google Scholar 

  9. E Gilbert-Barness (1997) Potter’s Pathology of the Fetus and the Infant, 4th ed Mosby-Year Book St. Louis 808–822

    Google Scholar 

  10. UJ Eriksson LA Borg H Forsberg J Styrud (1991) ArticleTitleDiabetic embryopathy. Studies with animal and in vitro models Diabetes 40 IssueIDSuppl 2 94–98

    Google Scholar 

  11. ZJ Hagay Y Weiss I Zusman et al. (1995) ArticleTitlePrevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos Am J Obstet Gynecol 173 1036–1041 Occurrence Handle10.1016/0002-9378(95)91323-8 Occurrence Handle1:CAS:528:DyaK28XktVKj Occurrence Handle7485290

    Article  CAS  PubMed  Google Scholar 

  12. F Facchinetti VL Dawson TM Dawson (1998) ArticleTitleFree radicals as mediators of neuronal injury Cell Mol Neurobiol 18 667–682 Occurrence Handle10.1023/A:1020221919154 Occurrence Handle1:CAS:528:DyaK1MXjtl2hug%3D%3D Occurrence Handle9876873

    Article  CAS  PubMed  Google Scholar 

  13. F Mercuri L Quagliaro A Ceriello (2000) ArticleTitleOxidative stress evaluation in diabetes Diabetes Technol Ther 2 589–600 Occurrence Handle10.1089/15209150050502014 Occurrence Handle1:CAS:528:DC%2BD3MXhsVykt7c%3D Occurrence Handle11469623

    Article  CAS  PubMed  Google Scholar 

  14. E Sivan EA Reece YK Wu CJ Homko M Polansky M Borenstein (1996) ArticleTitleDietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis Am J Obstet Gynecol 175(4 Pt 1 793–799

    Google Scholar 

  15. FA Van Assche W Gepts (1971) ArticleTitleThe cytological composition of the foetal endocrine pancreas in normal and pathological conditions Diabetologia 7 434–444 Occurrence Handle1:STN:280:CS2C2M7jtlQ%3D Occurrence Handle4111432

    CAS  PubMed  Google Scholar 

  16. F Fallucca A Sabbatini N Di Biase E Borrello A Napoli E Sciullo (2000) ArticleTitleFetal pancreatic function in infants of diabetic and rhesus-isoimmunized women Obstet Gynecol 95 195–198 Occurrence Handle10.1016/S0029-7844(99)00552-9 Occurrence Handle1:STN:280:DC%2BD3c7jslSntg%3D%3D Occurrence Handle10674579

    Article  CAS  PubMed  Google Scholar 

  17. FA Van Assche L Aerts K Holemans L Vercruysse (1994) ArticleTitleThe endocrine pancreas in nonimmune hydrops fetalis Am J Obstet Gynecol 171 236–238

    Google Scholar 

  18. NW Kooy SJ Lewis JA Royall YZ Ye DR Kelly JS Beckman (1997) ArticleTitleExtensive tyrosine nitration in human myocardial inflammation: evidence for the presence of peroxynitrite Crit Care Med 25 812–819 Occurrence Handle10.1097/00003246-199705000-00017 Occurrence Handle1:STN:280:ByiA3s7is10%3D Occurrence Handle9187601

    Article  CAS  PubMed  Google Scholar 

  19. TM Wizemann CR Gardner JD Laskin et al. (1994) ArticleTitleProduction of nitric oxide and peroxynitrite in the lung during acute endotoxemia J Leukoc Biol 56 759–768

    Google Scholar 

  20. H Ischiropoulos AB al-Mehdi AB Fisher (1995) ArticleTitleReactive species in ischemic rat lung injury: contribution of peroxynitrite Am J Physiol 269(2 Pt 1 L158–L164

    Google Scholar 

  21. NW Kooy JA Royall YZ Ye DR Kelly JS Beckman (1995) ArticleTitleEvidence for in vivo peroxynitrite production in human acute lung injury Am J Respir Crit Care Med 151 1250–1254 Occurrence Handle1:STN:280:ByqB3M7jsVI%3D Occurrence Handle7697261

    CAS  PubMed  Google Scholar 

  22. MJ Miller JH Thompson XJ Zhang et al. (1995) ArticleTitleRole of inducible nitric oxide synthase expression and peroxynitrite formation in guinea pig ileitis Gastroenterology 109 1475–1483 Occurrence Handle1:CAS:528:DyaK28XjsVeg Occurrence Handle7557128

    CAS  PubMed  Google Scholar 

  23. W Kossenjans A Eis R Sahay D Brockman L Myatt (2000) ArticleTitleRole of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia Am J Physiol Heart Circ Physiol 278 H1311–H1319 Occurrence Handle1:CAS:528:DC%2BD3cXislSksrw%3D Occurrence Handle10749729

    CAS  PubMed  Google Scholar 

  24. PF Good P Werner A Hsu CW Olanow DP Perl (1996) ArticleTitleEvidence of neuronal oxidative damage in Alzheimer’s disease Am J Pathol 149 21–28 Occurrence Handle1:STN:280:BymB2srlsVE%3D Occurrence Handle8686745

    CAS  PubMed  Google Scholar 

  25. R Jaffe (1992) The pancreas JT Stocker LP Dehner (Eds) Pediatric Pathology JB Lippincott Philadelphia

    Google Scholar 

  26. S Huggle JC Hunsaker CM Coyne DL Sparks (1996) ArticleTitleOxidative stress in sudden infant death syndrome J Child Neurol 11 433–438

    Google Scholar 

  27. JV Hunt CC Smith SP Wolff (1990) ArticleTitleAutoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose Diabetes 39 1420–1424 Occurrence Handle1:CAS:528:DyaK3MXhs1WrtLc%3D Occurrence Handle2227114

    CAS  PubMed  Google Scholar 

  28. SP Wolff (1986) The Potential Role of Oxidative Stress in Diabetes and Its Complications: Novel Implications for Theory and Therapy Churchill-Livingstone New York

    Google Scholar 

  29. A Ceriello (1997) ArticleTitleAcute hyperglycaemia and oxidative stress generation Diabetic Med 14 IssueIDSuppl 3 S45–S49 Occurrence Handle10.1002/(SICI)1096-9136(199708)14:3+<S45::AID-DIA444>3.3.CO;2-I Occurrence Handle9272613

    Article  PubMed  Google Scholar 

  30. MA Warso WE Lands (1983) ArticleTitleLipid peroxidation in relation to prostacyclin and thromboxane physiology and pathophysiology Br Med Bull 39 277–280 Occurrence Handle1:CAS:528:DyaL3sXls12mtbY%3D Occurrence Handle6414574

    CAS  PubMed  Google Scholar 

  31. RP Mason B Kalyanaraman BE Tainer TE Eling (1980) ArticleTitleA carbon-centered free radical intermediate in the prostaglandin synthetase oxidation of arachidonic acid. Spin trapping and oxygen uptake studies J Biol Chem 255 5019–5022 Occurrence Handle1:CAS:528:DyaL3cXksVSns7o%3D Occurrence Handle6246094

    CAS  PubMed  Google Scholar 

  32. E Pinter EA Reece CZ Leranth et al. (1986) ArticleTitleArachidonic acid prevents hyperglycemia-associated yolk sac damage and embryopathy Am J Obstet Gynecol 155 691–702 Occurrence Handle1:CAS:528:DyaL28XmtFyrtL8%3D Occurrence Handle3094372

    CAS  PubMed  Google Scholar 

  33. P Odetti G Angelini D Dapino et al. (1998) ArticleTitleEarly glycoxidation damage in brains from Down’s syndrome Biochem Biophys Res Commun 243 849–851

    Google Scholar 

  34. S Tan F Zhou VG Nielsen Z Wang CL Gladson DA Parks (1999) ArticleTitleIncreased injury following intermittent fetal hypoxia-reoxygenation is associated with increased free radical production in fetal rabbit brain J Neuropathol Exp Neurol 58 972–981

    Google Scholar 

  35. JA Golden (1998) ArticleTitleHoloprosencephaly: a defect in brain patterning J Neuropathol Exp Neurol 57 991–999

    Google Scholar 

  36. K Jellinger H Gross E Kaltenback W Grisold (1981) ArticleTitleHoloprosencephaly and agenesis of the corpus callosum: frequency of associated malformations Acta Neuropathol (Berl) 55 1–10 Occurrence Handle1:STN:280:BiyD2cvivVY%3D

    CAS  Google Scholar 

  37. M Tamaru Y Yoneda K Ogita J Shimizu T Matsutani Y Nagata (1992) ArticleTitleExcitatory amino acid receptors in brains of rats with methylazoxymethanol-induced microencephaly Neurosci Res 14 13–25 Occurrence Handle1:CAS:528:DyaK38Xlt1Cnsrc%3D Occurrence Handle1324453

    CAS  PubMed  Google Scholar 

  38. M Zoli EM Pich M Cimino et al. (1990) ArticleTitleMorphometrical and microdensitometrical studies on peptide- and tyrosine hydroxylase-like immunoreactivities in the forebrain of rats prenatally exposed to methylazoxymethanol acetate Brain Res Dev Brain Res 51 45–61 Occurrence Handle10.1016/0165-3806(90)90257-Y Occurrence Handle1:CAS:528:DyaK3cXhtlChsr0%3D Occurrence Handle1967563

    Article  CAS  PubMed  Google Scholar 

  39. J Busciglio BA Yankner (1995) ArticleTitleApoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro Nature 378(6559 776–779 Occurrence Handle10.1038/378776a0

    Article  Google Scholar 

  40. A Furuta DL Price CA Pardo et al. (1995) ArticleTitleLocalization of superoxide dismutases in Alzheimer’s disease and Down’s syndrome neocortex and hippocampus Am J Pathol 146 357–367 Occurrence Handle1:STN:280:ByqC28%2FhtlA%3D Occurrence Handle7856748

    CAS  PubMed  Google Scholar 

  41. JJ Mitchell M Paiva MB Heaton (1999) ArticleTitleThe antioxidants vitamin E and beta-carotene protect against ethanol-induced neurotoxicity in embryonic rat hippocampal cultures Alcohol 17 163–168 Occurrence Handle10.1016/S0741-8329(98)00051-2 Occurrence Handle1:CAS:528:DyaK1MXhtlygsL4%3D Occurrence Handle10064385

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eliezer Masliah.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hockett, P., Emery, S., Hansen, L. et al. Evidence of Oxidative Stress in the Brains of Fetuses with CNS Anomalies and Islet Cell Hyperplasia. Pediatr. Dev. Pathol. 7, 370–379 (2004). https://doi.org/10.1007/s10024-001-0130-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10024-001-0130-2

Navigation