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20151201150139.0 |
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100428s2010 txu sbm 000 0 eng d |
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|a (OCoLC)ocn609883960
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|a (OCoLC)609883960
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|a (TxCM)http://hdl.handle.net/1969.1/ETD-TAMU-3274
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| 040 |
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|a TXA
|c TXA
|d UtOrBLW
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| 049 |
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|a TXAM
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|a 2007
|a Dissertation
|a 1969.1/ETD-TAMU-3274
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| 100 |
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|a Hill, Denise Suzanne.
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|a Investigations into arsenate-induced neural tube defects in a mouse model /
|c by Denise Suzanne Hill.
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| 264 |
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|a [College Station, Tex.] :
|b [Texas A&M University],
|c [2010]
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|a 1 online resource.
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|a text
|b txt
|2 rdacontent
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|a computer
|b c
|2 rdamedia
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|a online resource
|b cr
|2 rdacarrier
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| 500 |
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|a "Major Subject: Toxicology"
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|a Title from author supplied metadata (automated record created 2010-03-12 12:08:51).
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| 502 |
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|b Doctor of Philosophy
|c Texas A&M University
|d 2007
|o http://hdl.handle.net/1969.1/ETD-TAMU-3274
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|a Includes bibliographical references.
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|a Text (Dissertation)
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|a Neural tube defects (NTDs) are malformations affecting about 2.6/1000 births worldwide, and 1/1000 in the United States. Their etiology remains unknown, and is likely due to interaction of genetic susceptibility factors with environmental exposure. Of the many environmental agents considered to potentially contribute to NTD risk, arsenic is one that is surrounded in controversy. We have developed a model system utilizing maternal intraperitoneal (I.P.) exposure on E7.5 and E8.5 to As 9.6 mg/kg (as sodium arsenate) in a normal inbred mouse strain, LM/Bc/Fnn, that is sensitive to arsenate-induced exencephaly. We investigated arsenate induced gene expression changes using DNA microarrays of embryonic anterior neural tube tissue, as well as monitoring of metabolic function in conjunction with the administration of select compounds to rescue the normal phenotype. Finally, to address questions concerning the importance of route of administration and potential maternal toxicity, a teratology study was performed using three arsenate doses administered orally. Regarding the gene expression study, we identified several candidate genes and ontology groups that may be responsible for arsenate's teratogenicity. Genes include: engrailed 1 (En-1), platelet derived growth factor receptor alpha (Pdgfra) and ephrinA7 (EphA7). Gene ontology groups identified include oxidative phosphorylation, redox response, and regulation of I-kappaB kinase/NF-kappaB cascade. Acute arsenate exposure induced disruption of mitochondrial function and dependent glucose homeostasis: subsequent hyperglycemia was teratogenic. Maternal treatment with insulin or n-acetyl cysteine, an antioxidant and precursor of glutathione synthesis, proved highly successful in rescuing both the normal phenotype, and to differing degree, the maternal hyperglycemia. Maternal oral arsenate administration also resulted in exencephaly, with exposed embryos exhibiting a positive linear trend with arsenate dosage. There were also linear trends in the relationships between arsenate dose and anomalies involving several components of the axial skeleton: the vertebrae and calvarium. There was no evidence of maternal toxicity as shown by lack of differences in maternal body weight gain, liver, and kidney weights. In conclusion, maternal arsenate exposure (regardless of exposure route) was teratogenic in our model, primarily causing NTDs. Responsible mechanisms may involve disruption of redox and glucose homeostasis as well as expression of established NTD candidate genes.
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| 500 |
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|a Electronic resource.
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|a Major toxicology.
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|a arsenic
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|a environmental
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|a teratogen
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|a NTD
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|a arsenate
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| 653 |
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|a neural tube defect
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| 700 |
1 |
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|a Donnelly, K. C.,
|e thesis advisor.
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1 |
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|a Finnell, Richard H.,
|e thesis advisor.
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| 856 |
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|u http://hdl.handle.net/1969.1/ETD-TAMU-3274
|z Link to OAK Trust copy
|t 0
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| 948 |
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|a cataloged
|b h
|c 2010/4/28
|d c
|e jgreene
|f 12:48:45 pm
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| 994 |
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|a C0
|b TXA
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| 999 |
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|a MARS
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| 999 |
f |
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|s 1aae7827-5dbb-322d-baa8-fa281f39cf42
|i 336ebd51-446d-3e34-a4ff-410dc3381110
|t 0
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| 952 |
f |
f |
|a Texas A&M University
|b College Station
|c Electronic Resources
|s www_evans
|d Available Online
|t 0
|e 2007 Dissertation 1969.1/ETD-TAMU-3274
|h Other scheme
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| 998 |
f |
f |
|a 2007 Dissertation 1969.1/ETD-TAMU-3274
|t 0
|l Available Online
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