Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells
- Autores
- Chiappini, Florencia Ana; Pontillo, Carolina Andrea; Randi, Andrea Silvana; Alvarez, Laura; Kleiman, Diana Leonor
- Año de publicación
- 2013
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. We have previously shown that chronic HCB exposure triggers apoptosis in rat thyroid follicular cells. This study was carried out to investigate the molecular mechanism by which the pesticide causes apoptosis in FRTL-5 rat thyroid cells exposed to HCB (0.005, 0.05, 0.5, and 5μM) for 2, 6, 8, 24, and 48 h. HCB treatment lowered cell viability and induced apoptotic cell death in a dose- and time-dependent manner, as demonstrated by morphological nuclear changes and the increase of DNA fragmentation. The pesticide increased activation of caspases- 3, -8, and full-length caspase-10 processing. HCB induced mitochondrial membrane depolarization, release of cytochrome c and apoptosis-inducing factor (AIF), from the mitochondria to the cytosol, and AIF nuclear translocation. Cell death was accompanied by an increase in reactive oxygen species (ROS) generation. Blocking of ROS production, with a radical scavenger (Trolox), resulted in inhibition of AIF nuclear translocation and returned cells survival to control levels, demonstrating that ROS are critical mediators of HCB-induced apoptosis. The pesticide increased ERK1/2, JNK, and p38 phosphorylation in a timeand dose-dependent manner. However, when FRTL-5 cells were treated with specific MAPK inhibitors, only blockade of MEK1/2 with PD98059 prevented cell loss of viability, as well as caspase-3 activation. In addition, we demonstrated that HCB-induced production of ROS has a critical role in ERK1/2 activation. These results demonstrate for the first time that HCB induces apoptosis in FRTL-5 cells, by ROS-mediated ERK1/2 activation, through caspase-dependent and -independent pathways.
Fil: Chiappini, Florencia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;
Fil: Pontillo, Carolina Andrea. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;
Fil: Randi, Andrea Silvana. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;
Fil: Alvarez, Laura. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;
Fil: Kleiman, Diana Leonor. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina; - Materia
-
HEXACHLOROBENZENE
ERK1/2
APOPTOSIS
REACTIVE OXYGEN SPECIES - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/1824
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CONICET Digital (CONICET) |
spelling |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cellsChiappini, Florencia AnaPontillo, Carolina AndreaRandi, Andrea SilvanaAlvarez, LauraKleiman, Diana LeonorHEXACHLOROBENZENEERK1/2APOPTOSISREACTIVE OXYGEN SPECIEShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. We have previously shown that chronic HCB exposure triggers apoptosis in rat thyroid follicular cells. This study was carried out to investigate the molecular mechanism by which the pesticide causes apoptosis in FRTL-5 rat thyroid cells exposed to HCB (0.005, 0.05, 0.5, and 5μM) for 2, 6, 8, 24, and 48 h. HCB treatment lowered cell viability and induced apoptotic cell death in a dose- and time-dependent manner, as demonstrated by morphological nuclear changes and the increase of DNA fragmentation. The pesticide increased activation of caspases- 3, -8, and full-length caspase-10 processing. HCB induced mitochondrial membrane depolarization, release of cytochrome c and apoptosis-inducing factor (AIF), from the mitochondria to the cytosol, and AIF nuclear translocation. Cell death was accompanied by an increase in reactive oxygen species (ROS) generation. Blocking of ROS production, with a radical scavenger (Trolox), resulted in inhibition of AIF nuclear translocation and returned cells survival to control levels, demonstrating that ROS are critical mediators of HCB-induced apoptosis. The pesticide increased ERK1/2, JNK, and p38 phosphorylation in a timeand dose-dependent manner. However, when FRTL-5 cells were treated with specific MAPK inhibitors, only blockade of MEK1/2 with PD98059 prevented cell loss of viability, as well as caspase-3 activation. In addition, we demonstrated that HCB-induced production of ROS has a critical role in ERK1/2 activation. These results demonstrate for the first time that HCB induces apoptosis in FRTL-5 cells, by ROS-mediated ERK1/2 activation, through caspase-dependent and -independent pathways.Fil: Chiappini, Florencia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;Fil: Pontillo, Carolina Andrea. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;Fil: Randi, Andrea Silvana. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;Fil: Alvarez, Laura. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;Fil: Kleiman, Diana Leonor. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina;Oxford University Press2013-05-24info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/1824Chiappini, Florencia Ana; Pontillo, Carolina Andrea; Randi, Andrea Silvana; Alvarez, Laura; Kleiman, Diana Leonor; Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells; Oxford University Press; Toxicological Sciences; 134; 2; 24-5-2013; 276-2901096-6080enginfo:eu-repo/semantics/altIdentifier/url/http://toxsci.oxfordjournals.org/content/134/2/276.full.pdf+htmlinfo:eu-repo/semantics/altIdentifier/doi/doi:10.1093/toxsci/kft117info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:58Zoai:ri.conicet.gov.ar:11336/1824instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:34:58.287CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
title |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
spellingShingle |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells Chiappini, Florencia Ana HEXACHLOROBENZENE ERK1/2 APOPTOSIS REACTIVE OXYGEN SPECIES |
title_short |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
title_full |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
title_fullStr |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
title_full_unstemmed |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
title_sort |
Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells |
dc.creator.none.fl_str_mv |
Chiappini, Florencia Ana Pontillo, Carolina Andrea Randi, Andrea Silvana Alvarez, Laura Kleiman, Diana Leonor |
author |
Chiappini, Florencia Ana |
author_facet |
Chiappini, Florencia Ana Pontillo, Carolina Andrea Randi, Andrea Silvana Alvarez, Laura Kleiman, Diana Leonor |
author_role |
author |
author2 |
Pontillo, Carolina Andrea Randi, Andrea Silvana Alvarez, Laura Kleiman, Diana Leonor |
author2_role |
author author author author |
dc.subject.none.fl_str_mv |
HEXACHLOROBENZENE ERK1/2 APOPTOSIS REACTIVE OXYGEN SPECIES |
topic |
HEXACHLOROBENZENE ERK1/2 APOPTOSIS REACTIVE OXYGEN SPECIES |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. We have previously shown that chronic HCB exposure triggers apoptosis in rat thyroid follicular cells. This study was carried out to investigate the molecular mechanism by which the pesticide causes apoptosis in FRTL-5 rat thyroid cells exposed to HCB (0.005, 0.05, 0.5, and 5μM) for 2, 6, 8, 24, and 48 h. HCB treatment lowered cell viability and induced apoptotic cell death in a dose- and time-dependent manner, as demonstrated by morphological nuclear changes and the increase of DNA fragmentation. The pesticide increased activation of caspases- 3, -8, and full-length caspase-10 processing. HCB induced mitochondrial membrane depolarization, release of cytochrome c and apoptosis-inducing factor (AIF), from the mitochondria to the cytosol, and AIF nuclear translocation. Cell death was accompanied by an increase in reactive oxygen species (ROS) generation. Blocking of ROS production, with a radical scavenger (Trolox), resulted in inhibition of AIF nuclear translocation and returned cells survival to control levels, demonstrating that ROS are critical mediators of HCB-induced apoptosis. The pesticide increased ERK1/2, JNK, and p38 phosphorylation in a timeand dose-dependent manner. However, when FRTL-5 cells were treated with specific MAPK inhibitors, only blockade of MEK1/2 with PD98059 prevented cell loss of viability, as well as caspase-3 activation. In addition, we demonstrated that HCB-induced production of ROS has a critical role in ERK1/2 activation. These results demonstrate for the first time that HCB induces apoptosis in FRTL-5 cells, by ROS-mediated ERK1/2 activation, through caspase-dependent and -independent pathways. Fil: Chiappini, Florencia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina; Fil: Pontillo, Carolina Andrea. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina; Fil: Randi, Andrea Silvana. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina; Fil: Alvarez, Laura. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina; Fil: Kleiman, Diana Leonor. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina; |
description |
Hexachlorobenzene (HCB) is an organochlorine pesticide widely distributed in the environment. We have previously shown that chronic HCB exposure triggers apoptosis in rat thyroid follicular cells. This study was carried out to investigate the molecular mechanism by which the pesticide causes apoptosis in FRTL-5 rat thyroid cells exposed to HCB (0.005, 0.05, 0.5, and 5μM) for 2, 6, 8, 24, and 48 h. HCB treatment lowered cell viability and induced apoptotic cell death in a dose- and time-dependent manner, as demonstrated by morphological nuclear changes and the increase of DNA fragmentation. The pesticide increased activation of caspases- 3, -8, and full-length caspase-10 processing. HCB induced mitochondrial membrane depolarization, release of cytochrome c and apoptosis-inducing factor (AIF), from the mitochondria to the cytosol, and AIF nuclear translocation. Cell death was accompanied by an increase in reactive oxygen species (ROS) generation. Blocking of ROS production, with a radical scavenger (Trolox), resulted in inhibition of AIF nuclear translocation and returned cells survival to control levels, demonstrating that ROS are critical mediators of HCB-induced apoptosis. The pesticide increased ERK1/2, JNK, and p38 phosphorylation in a timeand dose-dependent manner. However, when FRTL-5 cells were treated with specific MAPK inhibitors, only blockade of MEK1/2 with PD98059 prevented cell loss of viability, as well as caspase-3 activation. In addition, we demonstrated that HCB-induced production of ROS has a critical role in ERK1/2 activation. These results demonstrate for the first time that HCB induces apoptosis in FRTL-5 cells, by ROS-mediated ERK1/2 activation, through caspase-dependent and -independent pathways. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013-05-24 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/1824 Chiappini, Florencia Ana; Pontillo, Carolina Andrea; Randi, Andrea Silvana; Alvarez, Laura; Kleiman, Diana Leonor; Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells; Oxford University Press; Toxicological Sciences; 134; 2; 24-5-2013; 276-290 1096-6080 |
url |
http://hdl.handle.net/11336/1824 |
identifier_str_mv |
Chiappini, Florencia Ana; Pontillo, Carolina Andrea; Randi, Andrea Silvana; Alvarez, Laura; Kleiman, Diana Leonor; Reactive oxygen species and extracellular signal-regulated kinase 1/2 mediate hexachlorobenzene-induced cell death in FRTL-5 rat throyd cells; Oxford University Press; Toxicological Sciences; 134; 2; 24-5-2013; 276-290 1096-6080 |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://toxsci.oxfordjournals.org/content/134/2/276.full.pdf+html info:eu-repo/semantics/altIdentifier/doi/doi:10.1093/toxsci/kft117 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613085258579968 |
score |
13.070432 |