Investigations into arsenate-induced neural tube defects in a mouse model

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 pote...

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Main Author: Hill, Denise Suzanne
Other Authors: Donnelly, Kirby C.
Format: Others
Language:en_US
Published: 2010
Subjects:
NTD
Online Access:http://hdl.handle.net/1969.1/ETD-TAMU-3274
http://hdl.handle.net/1969.1/ETD-TAMU-3274
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spelling ndltd-tamu.edu-oai-repository.tamu.edu-1969.1-ETD-TAMU-32742013-01-08T10:40:15ZInvestigations into arsenate-induced neural tube defects in a mouse modelHill, Denise SuzannearsenicteratogenarsenateNTDenvironmentalneural tube defectNeural 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 (Pdgfrα) 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.Donnelly, Kirby C.Finnell, Richard H.2010-01-15T00:02:32Z2010-01-16T01:30:38Z2010-01-15T00:02:32Z2010-01-16T01:30:38Z2007-122009-05-15BookThesisElectronic Dissertationtextelectronicapplication/pdfborn digitalhttp://hdl.handle.net/1969.1/ETD-TAMU-3274http://hdl.handle.net/1969.1/ETD-TAMU-3274en_US
collection NDLTD
language en_US
format Others
sources NDLTD
topic arsenic
teratogen
arsenate
NTD
environmental
neural tube defect
spellingShingle arsenic
teratogen
arsenate
NTD
environmental
neural tube defect
Hill, Denise Suzanne
Investigations into arsenate-induced neural tube defects in a mouse model
description 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 (Pdgfrα) 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.
author2 Donnelly, Kirby C.
author_facet Donnelly, Kirby C.
Hill, Denise Suzanne
author Hill, Denise Suzanne
author_sort Hill, Denise Suzanne
title Investigations into arsenate-induced neural tube defects in a mouse model
title_short Investigations into arsenate-induced neural tube defects in a mouse model
title_full Investigations into arsenate-induced neural tube defects in a mouse model
title_fullStr Investigations into arsenate-induced neural tube defects in a mouse model
title_full_unstemmed Investigations into arsenate-induced neural tube defects in a mouse model
title_sort investigations into arsenate-induced neural tube defects in a mouse model
publishDate 2010
url http://hdl.handle.net/1969.1/ETD-TAMU-3274
http://hdl.handle.net/1969.1/ETD-TAMU-3274
work_keys_str_mv AT hilldenisesuzanne investigationsintoarsenateinducedneuraltubedefectsinamousemodel
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