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Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines. / Ume-Kulsoom Shah

Swansea University Author: Ume-Kulsoom Shah

Abstract

ro-carcinogens e.g. B[a]P and PhIP require metabolic activation to exert genotoxicity. Both B[a]P and PhIP are known to cause different types of cancers, however, very little is known about the dose response of these two chemicals at low concentrations. This study was conducted to determine the effe...

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Published: 2014
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa43055
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2018-08-29T15:15:30.1027734</datestamp><bib-version>v2</bib-version><id>43055</id><entry>2018-08-02</entry><title>Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.</title><swanseaauthors><author><sid>6c7ed2055a3cf57122b5be39d3a43359</sid><ORCID>NULL</ORCID><firstname>Ume-Kulsoom</firstname><surname>Shah</surname><name>Ume-Kulsoom Shah</name><active>true</active><ethesisStudent>true</ethesisStudent></author></swanseaauthors><date>2018-08-02</date><abstract>ro-carcinogens e.g. B[a]P and PhIP require metabolic activation to exert genotoxicity. Both B[a]P and PhIP are known to cause different types of cancers, however, very little is known about the dose response of these two chemicals at low concentrations. This study was conducted to determine the effect of low doses of B[a]P and PhIP and their exposure time on cell lines with varying levels of metabolic activity.Micronucleus and HPRT assays were conducted to determine the effect of low doses of B[a]P on micronuclei induction and mutation frequency following 4 or 24 h exposure. MCL-5 and HepG2 cell lines showed higher induction of micronuclei irrespective of B[a]P dose and exposure time. Micronuclei induction was least in AHH-1 while TK-6 cells showed no micronuclei induction. HPRT assay also showed higher mutation frequency in MCL-5 as compared to AHH-1 at both time exposures. Analysis of mutation spectra of MCL-5 and AHH-1 HPRT mutants revealed that the type of mutations observed in B[a]P treated cells were different to those observed in untreated control B[a]P-induced mutations were predominantly G -&gt;T transversions. Real time PCR assays revealed higher induction of CYP1A1 and CY1A2 enzymes in response to B[a]P in MCL-5 and HepG2 cell lines.Studies on PhIP showed significantly higher cytotoxicity, genotoxicity and mutation frequency in the MCL-5 and HepG2 cell lines than AHH-1 cells. Micronucleus assays (24h) revealed 1.56 and 1.9-.fold increase in micronuclei induction in MCL-5 and HepG2, respectively as compared to control. A similar trend was observed in 4h PhIP exposure study, where MCL-5 and HepG2 had 1.83 and 1.92-.fold increase respectively. These findings are in line with the metabolic potential of the cell lines. Real-time PCR assays showed that over all, expression of CYP1A1 and CY1A2 was higher in HepG2 than MCL-5 following PhIP exposure for 24h. PhIP was observed to induce a significantly higher mutation frequency in MCL-5 cell lines than untreated control. Mutation type also varied among PhIP treated and untreated control of MCL-5. PhIP treated MCL-5 cells showed predominantly G -&gt;T transversions.These studies showed that cells with higher metabolic activity are relatively more capable of activating B[a]P and PhIP and therefore show higher genotoxicity in response to dose and exposure of these pro-carcinogens. Considering the results of this study, potential risk of B[a]P and PhIP induced cancers has been discussed</abstract><type>E-Thesis</type><journal/><journalNumber></journalNumber><paginationStart/><paginationEnd/><publisher/><placeOfPublication/><isbnPrint/><issnPrint/><issnElectronic/><keywords>Genotoxicity, mutation</keywords><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2014</publishedYear><publishedDate>2014-12-31</publishedDate><doi/><url/><notes/><college>COLLEGE NANME</college><department>Swansea University Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><apcterm/><lastEdited>2018-08-29T15:15:30.1027734</lastEdited><Created>2018-08-02T16:24:31.1786128</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Ume-Kulsoom</firstname><surname>Shah</surname><orcid>NULL</orcid><order>1</order></author></authors><documents><document><filename>0043055-02082018162543.pdf</filename><originalFilename>10821447.pdf</originalFilename><uploaded>2018-08-02T16:25:43.1100000</uploaded><type>Output</type><contentLength>23113907</contentLength><contentType>application/pdf</contentType><version>E-Thesis</version><cronfaStatus>true</cronfaStatus><embargoDate>2018-08-02T16:25:43.1100000</embargoDate><copyrightCorrect>false</copyrightCorrect></document></documents><OutputDurs/></rfc1807>
spelling 2018-08-29T15:15:30.1027734 v2 43055 2018-08-02 Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines. 6c7ed2055a3cf57122b5be39d3a43359 NULL Ume-Kulsoom Shah Ume-Kulsoom Shah true true 2018-08-02 ro-carcinogens e.g. B[a]P and PhIP require metabolic activation to exert genotoxicity. Both B[a]P and PhIP are known to cause different types of cancers, however, very little is known about the dose response of these two chemicals at low concentrations. This study was conducted to determine the effect of low doses of B[a]P and PhIP and their exposure time on cell lines with varying levels of metabolic activity.Micronucleus and HPRT assays were conducted to determine the effect of low doses of B[a]P on micronuclei induction and mutation frequency following 4 or 24 h exposure. MCL-5 and HepG2 cell lines showed higher induction of micronuclei irrespective of B[a]P dose and exposure time. Micronuclei induction was least in AHH-1 while TK-6 cells showed no micronuclei induction. HPRT assay also showed higher mutation frequency in MCL-5 as compared to AHH-1 at both time exposures. Analysis of mutation spectra of MCL-5 and AHH-1 HPRT mutants revealed that the type of mutations observed in B[a]P treated cells were different to those observed in untreated control B[a]P-induced mutations were predominantly G ->T transversions. Real time PCR assays revealed higher induction of CYP1A1 and CY1A2 enzymes in response to B[a]P in MCL-5 and HepG2 cell lines.Studies on PhIP showed significantly higher cytotoxicity, genotoxicity and mutation frequency in the MCL-5 and HepG2 cell lines than AHH-1 cells. Micronucleus assays (24h) revealed 1.56 and 1.9-.fold increase in micronuclei induction in MCL-5 and HepG2, respectively as compared to control. A similar trend was observed in 4h PhIP exposure study, where MCL-5 and HepG2 had 1.83 and 1.92-.fold increase respectively. These findings are in line with the metabolic potential of the cell lines. Real-time PCR assays showed that over all, expression of CYP1A1 and CY1A2 was higher in HepG2 than MCL-5 following PhIP exposure for 24h. PhIP was observed to induce a significantly higher mutation frequency in MCL-5 cell lines than untreated control. Mutation type also varied among PhIP treated and untreated control of MCL-5. PhIP treated MCL-5 cells showed predominantly G ->T transversions.These studies showed that cells with higher metabolic activity are relatively more capable of activating B[a]P and PhIP and therefore show higher genotoxicity in response to dose and exposure of these pro-carcinogens. Considering the results of this study, potential risk of B[a]P and PhIP induced cancers has been discussed E-Thesis Genotoxicity, mutation 31 12 2014 2014-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-29T15:15:30.1027734 2018-08-02T16:24:31.1786128 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ume-Kulsoom Shah NULL 1 0043055-02082018162543.pdf 10821447.pdf 2018-08-02T16:25:43.1100000 Output 23113907 application/pdf E-Thesis true 2018-08-02T16:25:43.1100000 false
title Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
spellingShingle Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
Ume-Kulsoom Shah
title_short Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
title_full Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
title_fullStr Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
title_full_unstemmed Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
title_sort Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines.
author_id_str_mv 6c7ed2055a3cf57122b5be39d3a43359
author_id_fullname_str_mv 6c7ed2055a3cf57122b5be39d3a43359_***_Ume-Kulsoom Shah
author Ume-Kulsoom Shah
author2 Ume-Kulsoom Shah
format E-Thesis
publishDate 2014
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description ro-carcinogens e.g. B[a]P and PhIP require metabolic activation to exert genotoxicity. Both B[a]P and PhIP are known to cause different types of cancers, however, very little is known about the dose response of these two chemicals at low concentrations. This study was conducted to determine the effect of low doses of B[a]P and PhIP and their exposure time on cell lines with varying levels of metabolic activity.Micronucleus and HPRT assays were conducted to determine the effect of low doses of B[a]P on micronuclei induction and mutation frequency following 4 or 24 h exposure. MCL-5 and HepG2 cell lines showed higher induction of micronuclei irrespective of B[a]P dose and exposure time. Micronuclei induction was least in AHH-1 while TK-6 cells showed no micronuclei induction. HPRT assay also showed higher mutation frequency in MCL-5 as compared to AHH-1 at both time exposures. Analysis of mutation spectra of MCL-5 and AHH-1 HPRT mutants revealed that the type of mutations observed in B[a]P treated cells were different to those observed in untreated control B[a]P-induced mutations were predominantly G ->T transversions. Real time PCR assays revealed higher induction of CYP1A1 and CY1A2 enzymes in response to B[a]P in MCL-5 and HepG2 cell lines.Studies on PhIP showed significantly higher cytotoxicity, genotoxicity and mutation frequency in the MCL-5 and HepG2 cell lines than AHH-1 cells. Micronucleus assays (24h) revealed 1.56 and 1.9-.fold increase in micronuclei induction in MCL-5 and HepG2, respectively as compared to control. A similar trend was observed in 4h PhIP exposure study, where MCL-5 and HepG2 had 1.83 and 1.92-.fold increase respectively. These findings are in line with the metabolic potential of the cell lines. Real-time PCR assays showed that over all, expression of CYP1A1 and CY1A2 was higher in HepG2 than MCL-5 following PhIP exposure for 24h. PhIP was observed to induce a significantly higher mutation frequency in MCL-5 cell lines than untreated control. Mutation type also varied among PhIP treated and untreated control of MCL-5. PhIP treated MCL-5 cells showed predominantly G ->T transversions.These studies showed that cells with higher metabolic activity are relatively more capable of activating B[a]P and PhIP and therefore show higher genotoxicity in response to dose and exposure of these pro-carcinogens. Considering the results of this study, potential risk of B[a]P and PhIP induced cancers has been discussed
published_date 2014-12-31T03:54:10Z
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