Oxidative DNA Damage and DNA Binding Induced by 2, 2-Bis (Bromomethyl)-1, 3-Propanediol: Possible Mode of Action Implicated in its Carcinogenicity

Persistent Link:
http://hdl.handle.net/10150/223375
Title:
Oxidative DNA Damage and DNA Binding Induced by 2, 2-Bis (Bromomethyl)-1, 3-Propanediol: Possible Mode of Action Implicated in its Carcinogenicity
Author:
Kong, Weixi
Issue Date:
2012
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:
The studies in this dissertation research were conducted to investigate the possible mode of action by which a brominated flame retardant, 2, 2-Bis (bromomethyl)-1, 3-propanediol (BMP) causes genotoxicity. Binding of BMP to DNA and BMP induced DNA strand breaks were investigated in SV-40 immortalized human uroepithelial cells (UROtsa) as an in vitro model for the bladder (a tissue that developed cancer after two year exposure to BMP in rodents). Results showed binding of [¹⁴C]-BMP equivalents to DNA increased with increased exposure time and concentration of [¹⁴C]-BMP. Comet analysis indicated BMP significantly increased the extent of DNA strand breaks at 1 and 3 h of incubation. However, strand breaks were repaired by 6 h of incubation. The DNA damaging effects of BMP at 1 h was concentration dependent. Compared with the parent compound, BMP-glucuronide (the predominant metabolite of BMP) bound less to DNA and produced less DNA strand breaks in UROtsa cells. Evidences that the BMP induced strand breaks were the result of an oxidative stress include: a concentration and time dependent increase in ROS generation; increased expression of Nrf2 and HSP70; complete attenuation of BMP induced DNA strand breaks by the antioxidant, NAC; and the presence of the oxidized base 8-OHguanine. UROtsa cells appear to be target cells for BMP because, as compared to rat hepatocytes (non-target cells), these cells lack the ability to detoxify BMP via glucuronidation and also because they are deficient in glutathione, a major intracellular antioxidant molecule. Both of these genotoxic events, DNA binding and oxidative DNA damage may, in part, contribute to BMP carcinogenicity observed in rodents. The relevance of current results to humans is remained to be established.
Type:
text; Electronic Dissertation
Keywords:
mechanism; mode of action; Medical Pharmacology; brominated flame retardant; genotoxicity
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Medical Pharmacology
Degree Grantor:
University of Arizona
Advisor:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleOxidative DNA Damage and DNA Binding Induced by 2, 2-Bis (Bromomethyl)-1, 3-Propanediol: Possible Mode of Action Implicated in its Carcinogenicityen_US
dc.creatorKong, Weixien_US
dc.contributor.authorKong, Weixien_US
dc.date.issued2012-
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.abstractThe studies in this dissertation research were conducted to investigate the possible mode of action by which a brominated flame retardant, 2, 2-Bis (bromomethyl)-1, 3-propanediol (BMP) causes genotoxicity. Binding of BMP to DNA and BMP induced DNA strand breaks were investigated in SV-40 immortalized human uroepithelial cells (UROtsa) as an in vitro model for the bladder (a tissue that developed cancer after two year exposure to BMP in rodents). Results showed binding of [¹⁴C]-BMP equivalents to DNA increased with increased exposure time and concentration of [¹⁴C]-BMP. Comet analysis indicated BMP significantly increased the extent of DNA strand breaks at 1 and 3 h of incubation. However, strand breaks were repaired by 6 h of incubation. The DNA damaging effects of BMP at 1 h was concentration dependent. Compared with the parent compound, BMP-glucuronide (the predominant metabolite of BMP) bound less to DNA and produced less DNA strand breaks in UROtsa cells. Evidences that the BMP induced strand breaks were the result of an oxidative stress include: a concentration and time dependent increase in ROS generation; increased expression of Nrf2 and HSP70; complete attenuation of BMP induced DNA strand breaks by the antioxidant, NAC; and the presence of the oxidized base 8-OHguanine. UROtsa cells appear to be target cells for BMP because, as compared to rat hepatocytes (non-target cells), these cells lack the ability to detoxify BMP via glucuronidation and also because they are deficient in glutathione, a major intracellular antioxidant molecule. Both of these genotoxic events, DNA binding and oxidative DNA damage may, in part, contribute to BMP carcinogenicity observed in rodents. The relevance of current results to humans is remained to be established.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectmechanismen_US
dc.subjectmode of actionen_US
dc.subjectMedical Pharmacologyen_US
dc.subjectbrominated flame retardanten_US
dc.subjectgenotoxicityen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSipes, I. Glennen_US
dc.contributor.committeememberDavis, Thomas P.en_US
dc.contributor.committeememberCherrington, Nathanen_US
dc.contributor.committeememberBaker, Amandaen_US
dc.contributor.committeememberStamer, W. Danielen_US
dc.contributor.committeememberSipes, I. Glennen_US
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