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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/1824

id CONICETDig_df0f212320e14fdcb2059ab047031a7d
oai_identifier_str oai:ri.conicet.gov.ar:11336/1824
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str 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
_version_ 1844613085258579968
score 13.070432