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dc.contributor.advisorNapper, Ruthen_NZ
dc.contributor.advisorDuxson, Marilynen_NZ
dc.contributor.authorLi, Yuhongen_NZ
dc.date.available2011-01-25T00:22:45Z
dc.date.copyright2005en_NZ
dc.identifierhttp://adt.otago.ac.nz/public/adt-NZDU20070502.100319en_NZ
dc.identifier.citationLi, Y. (2005). Effect of alcohol exposure in early gestation on brain development (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/493en
dc.identifier.urihttp://hdl.handle.net/10523/493
dc.description.abstractFetal alcohol spectrum disorders (FASD), caused by maternal alcohol consumption during pregnancy, has been extensively studied in the human. Animal studies show that alcohol exposure during very early development may result in severe brain damage, often incompatible with a postnatal life. However, for surviving offspring it is unknown whether they suffer long term brain damage. The final assembly of the mature brain results from a controlled balance between proliferation of glial and neuronal precursors and programmed cell death. The overall aim of the current study was to use a physiologically relevant mouse model to assess the acute and long-term effects of binge alcohol exposure on the early embryo, to simulate human pregnancy at the third week of gestation when pregnancy may be undetected. A number of paradigms were used to assess the acute dose-response effect, the blood alcohol concentration (BAC) profile and the extent of cell death following alcohol exposure on gestational day (G) 7.5. The exposure paradigms were single binge IG6.5, IG4.5, IP4.5, or an extended binge IG4.5+, IG3.0+. Two control groups were Con6.5 and Con4.5+. Acute cell death was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), activated caspase-3 staining, and transmission electron microscopy. Cell proliferation was investigated using S-phase immuno-labeling, bromodeoxyuridine (BrdU) birthdating and immuno-detection (BrdU/anti-BrdU). The long-term effects were investigated at G18.5 and postnatal day (PN) 60. Unbiased stereological methods were used to assess the effect of ethanol exposure at G7.5 on neocortical volume, cell number and density of neurons, glial cells, and capillary cells at PN60. The first principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute apoptotic cell death in the ectoderm of the mouse embryo. Cell death was dependent on both peak BAC and the duration of elevated BAC. Significant increased cell death (TUNEL labeling) was observed in groups IG6.5 (9.43 ± 2.08%) and IG4.5+ (8.97 ± 2.12%) compared with control groups Con6.5 (2.14 ± 0.09%) and Con4.5+ (2.81 ± 0.36%). There was no significant increased cell death in ethanol exposed groups IG4.5 (3.43 ± 0.45%), IP4.5 (3.68 ± 0.67%), or IG3.0+ (1.72 ± 0.24%). TEM analysis revealed that cell death exhibited characteristics of the apoptotic pathway. The second principal finding of the present study was that binge ethanol exposure during gastrulation resulted in acute arrested proliferation in the ectoderm of the mouse embryo. The S-phase proliferation was significantly decreased within the whole ectoderm in the ethanol exposed group IG6.5 (45.58 ± 2.34%) compared with control group Con6.5 (62.08 ± 3.11%). The third principal finding of the present study was that binge ethanol exposure during gastrulation induced the long term effect of laminate disorganization in the neocortex. The incidence of abnormal lamination was 87.5% in IG6.5 compared with 16.7% in IG3.0+ and 14.3% in Con6.5. Although ethanol exposure increased embryonic reabsorption, decreased litter size, and increased abnormal offspring, neocortical volume, and the total number of neurons, glial cells, and capillary cells was not affected. The total number (10⁶) of neurons, glial cells, and endothelial cells respectively was 12.221 ± 0.436, 4.865 ± 0.167, and 2.874 ± 0.234 in IG6.5; 11.987 ± 0.416, 4.942 ± 0.133, and 2.922 ± 0.130 in IG3.0+; and 11.806 ± 0.368, 5.166 ± 0.267, and 3.284 ± 0.217 in controls, at PN60. These results provide important information pertinent to fetal outcome for those women who drink heavily in early pregnancy. The results also demonstrate the importance of the pattern of ethanol exposure and blood alcohol concentration in determining the magnitude of ethanol's teratogenic impact. Ethanol exposure on G7.5 that resulted in a high transient BAC, induced disorganized neocortical lamination, indicative of a permanent structural change. This disruption may result in altered neocortical function and requires further investigation.en_NZ
dc.format.mimetypeapplication/pdf
dc.languageenen_NZ
dc.publisherUniversity of Otagoen_NZ
dc.rightshttp://www.otago.ac.nz/administration/policies/otago003228.htmlen_NZ
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.rights.urihttp://www.otago.ac.nz/administration/policies/otago003228.html
dc.subjectfetal alcohol syndromeen_NZ
dc.subjectfetusen_NZ
dc.subjectchemicalsen_NZ
dc.subjectbrainen_NZ
dc.subjectgrowthen_NZ
dc.subjectpregnancyen_NZ
dc.subjectdrugsen_NZ
dc.subjecteffecten_NZ
dc.titleEffect of alcohol exposure in early gestation on brain developmenten_NZ
dc.typeThesisen_NZ
thesis.degree.disciplineDepartment of Anatomy & Structural Biologyen_NZ
thesis.degree.nameDoctor of Philosophyen_NZ
thesis.degree.grantorUniversity of Otagoen_NZ
thesis.degree.levelDoctoral Thesesen_NZ
otago.interloanyesen_NZ
otago.openaccessOpen
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