Arsenic: Metabolism, cytotoxicity and toxicogenetic alterations in the developing lung

Persistent Link:
http://hdl.handle.net/10150/280443
Title:
Arsenic: Metabolism, cytotoxicity and toxicogenetic alterations in the developing lung
Author:
Petrick, Jay Scott
Issue Date:
2003
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Environmental arsenic exposure is associated with human cancers of the skin, lung, kidney, and bladder. Mechanisms of arsenic toxicity and carcinogenicity, however, remain poorly studied and merit further investigation. The present studies address the effects of arsenic metabolism on toxicity, under the hypothesis that arsenic metabolism results in both detoxication and bioactivation. Inorganic arsenic and methylated metabolites were tested for toxicity in cultured cells, demonstrating that both detoxication and bioactivation occurs with metabolism, dependent upon methylation and valence state. Monomethylated MMAIII , the most toxic metabolite in cultured cells was also a potent inhibitor of pyruvate dehydrogenase and was more lethal than arsenite in hamsters, illustrating its role as an arsenic bioactivation product. The lung is an established target of arsenic exposure. Arsenic also crosses placenta during pregnancy, reaching the developing fetus. Given this evidence, the present studies investigate the ability of arsenic to target the developing lung following in utero exposure to low doses of arsenic during fetal development. Fetal rats were exposed to 500 mug/L arsenic via maternal drinking water, from conception to embryonic day eighteen. In order to assess toxicogenetic alterations in the developing lung, subtractive hybridization was used to create a cDNA library of arsenic-induced differential gene expression. This library consisted of 326 clones that were subsequently spotted on a cDNA microarray, including those involved in lung development and in formation of the extracellular matrix. In order to model effects of arsenic on gene expression in the developing lung, microarrays were conducted utilizing cultured lung cells dosed with four sub-cytotoxic doses of arsenic for up to fourteen days. These arrays showed that arsenic modulates a decreasing number of genes over the time course and that genes are primarily upregulated following short exposures. Selected array and subtracted library gene expression was also evaluated by quantitative real time PCR and western immunoblotting. Additional microarrays were conducted with 500 ppb arsenic treated fetal lung tissue using a commercial cDNA microarray, revealing perturbations in cellular proliferation and angiogenesis genes in vivo. Collectively, these studies indicate that lung development can be perturbed by gestational arsenic exposure.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Toxicology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
Lantz, R. Clark

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleArsenic: Metabolism, cytotoxicity and toxicogenetic alterations in the developing lungen_US
dc.creatorPetrick, Jay Scotten_US
dc.contributor.authorPetrick, Jay Scotten_US
dc.date.issued2003en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractEnvironmental arsenic exposure is associated with human cancers of the skin, lung, kidney, and bladder. Mechanisms of arsenic toxicity and carcinogenicity, however, remain poorly studied and merit further investigation. The present studies address the effects of arsenic metabolism on toxicity, under the hypothesis that arsenic metabolism results in both detoxication and bioactivation. Inorganic arsenic and methylated metabolites were tested for toxicity in cultured cells, demonstrating that both detoxication and bioactivation occurs with metabolism, dependent upon methylation and valence state. Monomethylated MMAIII , the most toxic metabolite in cultured cells was also a potent inhibitor of pyruvate dehydrogenase and was more lethal than arsenite in hamsters, illustrating its role as an arsenic bioactivation product. The lung is an established target of arsenic exposure. Arsenic also crosses placenta during pregnancy, reaching the developing fetus. Given this evidence, the present studies investigate the ability of arsenic to target the developing lung following in utero exposure to low doses of arsenic during fetal development. Fetal rats were exposed to 500 mug/L arsenic via maternal drinking water, from conception to embryonic day eighteen. In order to assess toxicogenetic alterations in the developing lung, subtractive hybridization was used to create a cDNA library of arsenic-induced differential gene expression. This library consisted of 326 clones that were subsequently spotted on a cDNA microarray, including those involved in lung development and in formation of the extracellular matrix. In order to model effects of arsenic on gene expression in the developing lung, microarrays were conducted utilizing cultured lung cells dosed with four sub-cytotoxic doses of arsenic for up to fourteen days. These arrays showed that arsenic modulates a decreasing number of genes over the time course and that genes are primarily upregulated following short exposures. Selected array and subtracted library gene expression was also evaluated by quantitative real time PCR and western immunoblotting. Additional microarrays were conducted with 500 ppb arsenic treated fetal lung tissue using a commercial cDNA microarray, revealing perturbations in cellular proliferation and angiogenesis genes in vivo. Collectively, these studies indicate that lung development can be perturbed by gestational arsenic exposure.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Toxicology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorLantz, R. Clarken_US
dc.identifier.proquest3108943en_US
dc.identifier.bibrecord.b44830300en_US
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