Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.toxlet.2020.04.009 http://hdl.handle.net/11449/200384 |
Resumo: | This study unveiled the early cellular and molecular events induced by 1,2-dimethylhydrazine (DMH) in the colon and liver and their implications on pre- and neoplastic lesion burden in a late timepoint. Male Wistar rats received four DMH injections (40 mg/kg body weight) for 2 weeks and were sacrificed 24 h (short-term study) or 22 (medium-term study) weeks after the last DMH administration. In the short-term study, DMH led to increased leukocyte (comet assay) and colon (H2AX) genotoxicity, enhanced proliferation (Ki-67) and apoptosis (caspase-3) indexes in both liver and colon. Furthermore, the expression of mRNA (Cat, Gsta1, Gsta2, Gpx1, Gstm1, Sod1, Sod2 and Sod3) and the activity of antioxidant agents were diminished in the colon and liver of DMH-induced rats, eliciting an environment of oxidative stress featuring elevated lipid hydroperoxide levels. Apoptosis effectors were upregulated in the liver (Bax, Casp3 and Fas), and developmental genes were downregulated in both colon and liver (Foxa1, Foxa2, Smad2 and Smad4). In the medium-term study, DMH led to a high number of preneoplastic colonic aberrant crypt foci and tumors (adenomas and invasive adenocarcinomas) but few preneoplastic hepatic glutathione S-transferase (GST-P)-positive foci. Our novel gene expression data highlights overlooked mechanisms in the liver (main metabolizing organ) and colon (main target organ) on toxicity and carcinogenesis induced by repeated doses of DMH, as both organs should be considered in further interventions on the initiation stage of colon carcinogenesis. |
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Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development1,2-DimethylhydrazineAberrant crypt fociAntioxidant defenseColon tumorsGene expressionGST-P positive preneoplastic fociMucin depleted fociThis study unveiled the early cellular and molecular events induced by 1,2-dimethylhydrazine (DMH) in the colon and liver and their implications on pre- and neoplastic lesion burden in a late timepoint. Male Wistar rats received four DMH injections (40 mg/kg body weight) for 2 weeks and were sacrificed 24 h (short-term study) or 22 (medium-term study) weeks after the last DMH administration. In the short-term study, DMH led to increased leukocyte (comet assay) and colon (H2AX) genotoxicity, enhanced proliferation (Ki-67) and apoptosis (caspase-3) indexes in both liver and colon. Furthermore, the expression of mRNA (Cat, Gsta1, Gsta2, Gpx1, Gstm1, Sod1, Sod2 and Sod3) and the activity of antioxidant agents were diminished in the colon and liver of DMH-induced rats, eliciting an environment of oxidative stress featuring elevated lipid hydroperoxide levels. Apoptosis effectors were upregulated in the liver (Bax, Casp3 and Fas), and developmental genes were downregulated in both colon and liver (Foxa1, Foxa2, Smad2 and Smad4). In the medium-term study, DMH led to a high number of preneoplastic colonic aberrant crypt foci and tumors (adenomas and invasive adenocarcinomas) but few preneoplastic hepatic glutathione S-transferase (GST-P)-positive foci. Our novel gene expression data highlights overlooked mechanisms in the liver (main metabolizing organ) and colon (main target organ) on toxicity and carcinogenesis induced by repeated doses of DMH, as both organs should be considered in further interventions on the initiation stage of colon carcinogenesis.Department of Pathology Botucatu Medical School São Paulo State University (UNESP)Department of Structural and Functional Biology Institute of Biosciences of Botucatu São Paulo State University (UNESP)Department of Pathology Botucatu Medical School São Paulo State University (UNESP)Department of Structural and Functional Biology Institute of Biosciences of Botucatu São Paulo State University (UNESP)Universidade Estadual Paulista (Unesp)Ramos Caetano, Brunno Felipe [UNESP]Baptista Tablas, Mariana [UNESP]Ribeiro Romualdo, Guilherme [UNESP]Marchesan Rodrigues, Maria Aparecida [UNESP]Barbisan, Luís Fernando [UNESP]2020-12-12T02:05:14Z2020-12-12T02:05:14Z2020-09-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article67-79http://dx.doi.org/10.1016/j.toxlet.2020.04.009Toxicology Letters, v. 329, p. 67-79.1879-31690378-4274http://hdl.handle.net/11449/20038410.1016/j.toxlet.2020.04.0092-s2.0-85084372102Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengToxicology Lettersinfo:eu-repo/semantics/openAccess2021-10-23T12:39:39Zoai:repositorio.unesp.br:11449/200384Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462021-10-23T12:39:39Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
title |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
spellingShingle |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development Ramos Caetano, Brunno Felipe [UNESP] 1,2-Dimethylhydrazine Aberrant crypt foci Antioxidant defense Colon tumors Gene expression GST-P positive preneoplastic foci Mucin depleted foci |
title_short |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
title_full |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
title_fullStr |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
title_full_unstemmed |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
title_sort |
Early molecular events associated with liver and colon sub-acute responses to 1,2-dimethylhydrazine: Potential implications on preneoplastic and neoplastic lesion development |
author |
Ramos Caetano, Brunno Felipe [UNESP] |
author_facet |
Ramos Caetano, Brunno Felipe [UNESP] Baptista Tablas, Mariana [UNESP] Ribeiro Romualdo, Guilherme [UNESP] Marchesan Rodrigues, Maria Aparecida [UNESP] Barbisan, Luís Fernando [UNESP] |
author_role |
author |
author2 |
Baptista Tablas, Mariana [UNESP] Ribeiro Romualdo, Guilherme [UNESP] Marchesan Rodrigues, Maria Aparecida [UNESP] Barbisan, Luís Fernando [UNESP] |
author2_role |
author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Ramos Caetano, Brunno Felipe [UNESP] Baptista Tablas, Mariana [UNESP] Ribeiro Romualdo, Guilherme [UNESP] Marchesan Rodrigues, Maria Aparecida [UNESP] Barbisan, Luís Fernando [UNESP] |
dc.subject.por.fl_str_mv |
1,2-Dimethylhydrazine Aberrant crypt foci Antioxidant defense Colon tumors Gene expression GST-P positive preneoplastic foci Mucin depleted foci |
topic |
1,2-Dimethylhydrazine Aberrant crypt foci Antioxidant defense Colon tumors Gene expression GST-P positive preneoplastic foci Mucin depleted foci |
description |
This study unveiled the early cellular and molecular events induced by 1,2-dimethylhydrazine (DMH) in the colon and liver and their implications on pre- and neoplastic lesion burden in a late timepoint. Male Wistar rats received four DMH injections (40 mg/kg body weight) for 2 weeks and were sacrificed 24 h (short-term study) or 22 (medium-term study) weeks after the last DMH administration. In the short-term study, DMH led to increased leukocyte (comet assay) and colon (H2AX) genotoxicity, enhanced proliferation (Ki-67) and apoptosis (caspase-3) indexes in both liver and colon. Furthermore, the expression of mRNA (Cat, Gsta1, Gsta2, Gpx1, Gstm1, Sod1, Sod2 and Sod3) and the activity of antioxidant agents were diminished in the colon and liver of DMH-induced rats, eliciting an environment of oxidative stress featuring elevated lipid hydroperoxide levels. Apoptosis effectors were upregulated in the liver (Bax, Casp3 and Fas), and developmental genes were downregulated in both colon and liver (Foxa1, Foxa2, Smad2 and Smad4). In the medium-term study, DMH led to a high number of preneoplastic colonic aberrant crypt foci and tumors (adenomas and invasive adenocarcinomas) but few preneoplastic hepatic glutathione S-transferase (GST-P)-positive foci. Our novel gene expression data highlights overlooked mechanisms in the liver (main metabolizing organ) and colon (main target organ) on toxicity and carcinogenesis induced by repeated doses of DMH, as both organs should be considered in further interventions on the initiation stage of colon carcinogenesis. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-12T02:05:14Z 2020-12-12T02:05:14Z 2020-09-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.toxlet.2020.04.009 Toxicology Letters, v. 329, p. 67-79. 1879-3169 0378-4274 http://hdl.handle.net/11449/200384 10.1016/j.toxlet.2020.04.009 2-s2.0-85084372102 |
url |
http://dx.doi.org/10.1016/j.toxlet.2020.04.009 http://hdl.handle.net/11449/200384 |
identifier_str_mv |
Toxicology Letters, v. 329, p. 67-79. 1879-3169 0378-4274 10.1016/j.toxlet.2020.04.009 2-s2.0-85084372102 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Toxicology Letters |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
67-79 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1797789834014621696 |