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1.
J Hazard Mater ; 385: 121521, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31699484

RESUMO

Trichloroethylene (TCE), a widely used chlorinated solvent, is a common environmental pollutant. Current evidence shows that TCE could induce heart defects during embryonic development, but the underlining mechanism(s) remain unclear. Since activation of the aryl hydrocarbon receptor (AHR) could induce oxidative stress, we hypothesized that AHR-mediated oxidative stress may play a role in the cardiac developmental toxicity of TCE. In this study, we found that the reactive oxygen species (ROS) scavenger, N-Acetyl-L-cysteine (NAC), and AHR inhibitors, CH223191 (CH) and StemRegenin 1, significantly counteracted the TCE-induced heart malformations in zebrafish embryos. Moreover, both CH and NAC suppressed TCE-induced ROS and 8-OHdG (8-hydroxy-2' -deoxyguanosine). TCE did not affect ahr2 and cyp1a expression, but increased cyp1b1 expression, which was restored by CH supplementation. CH also attenuated the TCE-induced mRNA expression changes of Nrf2 signalling genes (nrf2b, gstp2, sod2, ho1, nqo1) and cardiac differentiation genes (gata4, hand2, c-fos, sox9b). In addition, the TCE enhanced SOD activity was attenuated by CH. Morpholino knockdown confirmed that AHR mediated the TCE-induced ROS and 8-OHdG generation in the heart of zebrafish embryos. In conclusion, our results suggest that AHR mediates TCE-induced oxidative stress, leading to DNA damage and heart malformations in zebrafish embryos.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Cardiopatias Congênitas/embriologia , Receptores de Hidrocarboneto Arílico/metabolismo , Tricloroetileno/toxicidade , Proteínas de Peixe-Zebra/metabolismo , Acetilcisteína/farmacologia , Animais , Compostos Azo/farmacologia , Cardiotoxicidade/embriologia , Dano ao DNA/efeitos dos fármacos , Coração/embriologia , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Purinas/farmacologia , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores
2.
Zebrafish ; 16(4): 379-387, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31145051

RESUMO

Envenomation by the Venezuelan bushmaster snake (Lachesis muta muta) (Serpentes: Viperidae) is characterized by local and cardiac alterations. This study investigates the in vivo cardiac dysfunction, tissue destruction, and cellular processes triggered by Lachesis muta muta snake crude venom and a C-type lectin (CTL)-like toxin named Mutacytin-1 (MC-1). The 28 kDa MC-1 was obtained by molecular exclusion, ion exchange, and C-18 (checking pureness) reverse-phase chromatographies. N-terminal sequencing of the first eight amino acids (NNCPQ LLM) revealed 100% identity with Mutina (CTL-like) isolated from Lachesis stenophrys, which is a Ca2+-dependent-type galactoside-binding lectin from Bothrops jararaca and CTL BpLec from Bothrops pauloensis. The cardiotoxicity in zebrafish of MC-1 was evaluated by means of specific phenotypic expressions and larvae behavior at 5, 15, 30, 40 and 60 min post-treatment. The L. muta muta venom and MC-1 also produced heart rate/rhythm alterations, circulation modifications, and the presence of thrombus and apoptotic phenomenon with pericardial damages. Acridine orange (100 µg/mL) was used to visualize apoptosis cellular process in control and treated whole embryos. The cardiotoxic alterations happened in more than 90% of all larvae under the action of L. muta muta venom and MC-1. The findings have demonstrated the potential cardiotoxicity by L. muta muta venom, suggesting the possibility of cardiovascular damages to patients after bushmaster envenoming.


Assuntos
Cardiotoxicidade/embriologia , Cardiotoxinas/farmacologia , Crotalinae , Lectinas Tipo C , Proteínas de Répteis/química , Venenos de Serpentes/química , Peixe-Zebra/embriologia , Animais , Cardiotoxinas/química , Crotalinae/embriologia , Embrião não Mamífero/efeitos dos fármacos , Lectinas Tipo C/química , Proteínas de Répteis/farmacologia
3.
Environ Toxicol Chem ; 34(2): 420-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25477153

RESUMO

The cardiac toxicity of zebrafish embryos in response to the lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well characterized. Dioxin contamination levels in nature are usually lower, however, and sublethal TCDD toxicity is less investigated. The present study found that the nonlethal doses of TCDD for 72-h-postfertilization (hpf) zebrafish embryos were 25 pg/mL and lower. For the present study, sublethal TCDD concentrations of 10 pg/mL and 25 pg/mL were selected, and their toxicity was then characterized. The results showed that embryos still exhibited acute and subchronic cardiac toxicity at these 2 dosages. The stroke volume and cardiac output of these embryos significantly declined early until 8 d postexposure. Embryos' heart size became smaller, and the hearts contained fewer cardiomyocytes per heart, with decreased cardiomyocyte proliferation. Apoptosis was not detected either in the TCDD-treated or the control hearts. Real-time polymerase chain reaction (PCR) revealed that the transcription of a battery of cell-cycle-related genes was suppressed within the sublethal TCDD-treated heart. In contrast, embryonic jaw development seemed not to be affected. The present study suggests that dioxin contamination, even at lower levels, might lead to cardiac toxicity in fish embryos. Such cardiac toxicity presents as disrupted normal heart function, originating from the anti-proliferative effect of sublethal TCDD on cardiomyocytes.


Assuntos
Cardiotoxicidade/embriologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Dibenzodioxinas Policloradas/toxicidade , Peixe-Zebra/embriologia , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/embriologia , Contagem de Células , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Arcada Osseodentária/efeitos dos fármacos , Arcada Osseodentária/embriologia , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
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