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[This corrects the article DOI: 10.1186/s41021-020-0146-3.].
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Owing to the use of ethyl tert-butyl ether (ETBE) as a fuel additive, the possible adverse effects of ETBE exposure have become a public concern. Our previous study showed that ETBE-induced toxicity in aldehyde dehydrogenase 2 (Aldh2) gene knockout (KO) mice was caused by its primary metabolite acetaldehyde, which was toxic. However, it is unclear whether tert-butyl alcohol (TBA), another main metabolite of ETBE, plays a role in ETBE-induced toxicity. To investigate this relationship, we analyzed the changes of TBA concentrations in tissues after ETBE exposure, and then evaluated the toxicity after direct TBA treatment in both KO and wild-type (WT) mice. An exposure to 500 ppm ETBE via inhalation resulted in the formation of its three metabolites, TBA, 2-methyl-1,2-propanediol and ethanol, whose concentrations in the liver, brain, fat and testis of male KO mice were significantly higher than the corresponding concentrations observed in male WT mice. Direct treatment to TBA (20 mg/mL of drinking water) caused significant changes in relative organ weights and histopathology, and increased levels of genetic damages in both types of mice. These toxic effects were also seen in KO mice exposed to a lower concentration of TBA (5 mg/mL), which was associated with increased oxidative stress in serum (reduced glutathione and reduced glutathione/oxidized glutathione ratio decreased). Our findings indicate that ALDH2 is involved in the metabolism of ETBE and TBA, and ALDH2 deficiency could greatly increase the sensitivity to TBA-induced toxicity.
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Aldeído-Desidrogenase Mitocondrial/deficiência , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Deficiências Nutricionais/fisiopatologia , Camundongos Knockout/genética , terc-Butil Álcool/toxicidade , Animais , Variação Genética , Genótipo , Exposição por Inalação , Masculino , Camundongos , Modelos Animais , Testes de ToxicidadeRESUMO
BACKGOUND: A variety of in vivo and in vitro studies to assess the genotoxicity of titanium dioxide nanoparticles (TiO2 NPs) have been reported, but the results are inconsistent. Recently, we reported that TiO2 NPs exhibit no genotoxic effects in the liver and erythrocytes during a relatively brief period following intravenous injection into mice. However, there is no information about long-term genotoxicity due to TiO2 NP accumulation in tissues. In this study, we investigated the long-term mutagenic effects of TiO2 NPs and the localization of residual TiO2 NPs in mouse liver after multiple intravenous injections. RESULTS: Male gpt delta C57BL/6 J mice were administered with various doses of TiO2 NPs weekly for 4 consecutive weeks. The long-term mutagenic effects on the liver were analyzed using gpt and Spi- mutation assays 90 days after the final injection. We also quantified the amount of titanium in the liver using inductively coupled plasma mass spectrometry and observed the localization of TiO2 NPs in the liver using transmission electron microscopy. Although TiO2 NPs were found in the liver cells, the gpt and Spi- mutation frequencies in the liver were not significantly increased by the TiO2 NP administration. CONCLUSIONS: These results clearly show that TiO2 NPs have no mutagenic effects on the liver, even though the particles remain in the liver long-term.
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We investigated the effects of enteral nutrition formula on non-steroidal anti-inflammatory drug (NSAID)-induced gastric lesions in mice. Male ICR mice aged 7-9 weeks old were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition (25 or 50 mL/kg each). Indomethacin (IND) was orally administered at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of the mice given enteral nutrition showed a significant, dose-dependent decrease compared to the purified water-treated group, and no significant difference was seen between the two enteral nutrition-treated groups. Comparable time courses of plasma IND concentrations suggest that enteral nutrition does not inhibit gastrointestinal absorption of IND. Our findings indicate that administering enteral nutrition could inhibit the onset of NSAID-induced gastric ulcers.
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Nutrição Enteral , Alimentos Formulados , Indometacina/toxicidade , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Úlcera Gástrica/patologiaRESUMO
Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen.
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Butilidroxibutilnitrosamina/toxicidade , Carcinógenos/toxicidade , Toluidinas/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Animais , Testes de Carcinogenicidade , Carcinógenos/administração & dosagem , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo Real , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
Previous experiments showed that high concentrations of ethyl tertiary butyl ether (ETBE) exposure (500-5,000 ppm) significantly resulted in DNA damages in aldehyde dehydrogenase 2 (Aldh2) knockout (KO) mice. This study was aimed to verify the genotoxic effects in three genetic types, Aldh2 KO, heterogeneous (HT), and wild type (WT), of mice exposed to lower concentrations of ETBE (50-500 ppm) by inhalation. Histopathology assessments in the livers, measurements of genotoxic biomarkers in blood and livers, and urinary 8-hydroxydeoxyguanosion (8-OH-dG) for the oxidative DNA damage of whole body were performed. Significant histopathological changes and DNA strand breaks both in hepatocytes and leukocytes were found in HT and KO male mice exposed to ≥200 ppm ETBE, but not in 50 ppm ETBE. 8-OH-dG levels either in liver or urine were higher in the HT and KO male mice exposed to ≥200 ppm ETBE. The pathological and genetic effects of ETBE were almost at the same extents for HT and KO mice. Thus, 50 ppm could be the no observed adverse effect level for ETBE in HT and KO male mice, which was far lower than the 500 ppm in WT mice. These results suggested that decrease and deficiency of ALDH2 activity would significantly increase the sensitivity to ETBE-induced genotoxicity as well as hepatotoxic effects after exposure even to low concentrations of ETBE. Environ. Mol. Mutagen. 60: 145-153, 2019. © 2018 Wiley Periodicals, Inc.
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Aldeído-Desidrogenase Mitocondrial/genética , Dano ao DNA/efeitos dos fármacos , Etil-Éteres/toxicidade , 8-Hidroxi-2'-Desoxiguanosina , Animais , Dano ao DNA/genética , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Desoxiguanosina/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Exposição por Inalação , Fígado/efeitos dos fármacos , Camundongos , Camundongos KnockoutRESUMO
1,2-Dichloropropane (1,2-DCP) is used as an industrial solvent, insecticide fumigant and household dry cleaning product. Carcinogenicity caused by long-term exposure to 1,2-DCP is well established. However, the possible liver damage and related toxic mechanisms associated with acute inhalation exposure to 1,2-DCP are rarely reported. In this study, we investigated the effects of individual and combined exposure to 1,2-DCP and dichloromethane (DCM) on mice liver. The results showed that 1,2-DCP significantly caused liver necrosis, possibly due to 1,2-DCP-induced inhibition of the mitochondrial respiratory chain complex I-IV activities, resulting in mitochondrial dysfunction and extreme ATP consumption. Moreover, 1,2-DCP also decreased mitochondrial defense ability by inhibiting the mitochondrial glutathione S-transferase 1 (MGST1) activity, further aggravating liver damage. Additionally, we found that DCM co-exposure potentially enhanced 1,2-DCP toxicity. Our findings suggest that inhibition of mitochondrial function and MGST1 activity play critical roles in modulating 1,2-DCP-induced liver damage. Furthermore, our results contribute to study the new mechanism of mitochondria-dominated signaling pathways underlying liver injury induced by 1,2-DCP and DCM.
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Exposição por Inalação/efeitos adversos , Fígado/efeitos dos fármacos , Cloreto de Metileno/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Propano/análogos & derivados , Animais , Sinergismo Farmacológico , Glutationa Transferase/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Mitocôndrias Hepáticas/enzimologia , Propano/toxicidade , Testes de Toxicidade AgudaRESUMO
1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1,2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1,2-DCP. In this study, we examined the genotoxicity of 1,2-DCP using phosphorylated histone H2AX (γ-H2AX), a sensitive DNA damage marker. 1,2-DCP showed dose- (1-10mM: 4h) and time-dependent (1-24h: 5mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1). Additionally, γ-H2AX generation was observed in the livers of mice inhalationally exposed to 1,2-DCP at concentrations of 100, 200, and 400 ppm. During an in vitro mechanistic investigation, we found that γ-H2AX generation by 1,2-DCP was clearly attenuated in the presence of disulfiram and 4-methylpyrazole, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, we showed that 1,2-DCP increased the levels of intracellular reactive oxygen species (ROS), with the increase significantly inhibited by CYP2E1 inhibitors. These results suggested that ROS produced via the cytochrome P450 2E1 metabolic process of 1,2-DCP was a major causal factor for γ-H2AX generation by treatment with 1,2-DCP.
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Citocromo P-450 CYP2E1/metabolismo , Histonas/biossíntese , Mutagênicos/toxicidade , Propano/análogos & derivados , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Dano ao DNA , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Exposição por Inalação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Propano/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Fatores de TempoRESUMO
Titanium dioxide (TiO2) nanoparticles are increasingly manufactured in large amounts for use in industrial applications such as cosmetics, pigments, foods, and as photo-catalysts. Many in vitro studies have examined the genotoxicity of TiO2 nanomaterials; some of these studies suggest that TiO2 nanoparticles (NPs) are genotoxic. Several in vivo studies have also been reported recently, but the results are inconsistent. In this study, we investigated, using several genotoxicity endpoints, the effects of dispersed TiO2 suspensions following multiple intravenous injections in mice. Male gpt Delta C57BL/6J mice were administered TiO2 NPs at doses of 2, 10 or 50mg/kg body weight per week for 4 consecutive weeks. Genotoxic effects were then analyzed by the Pig-a gene mutation assay and the micronucleus assay on peripheral blood, and by the alkaline comet, gpt mutation, and Spi(-) mutation assays on the liver. We also assessed the localization of TiO2 NPs in the liver, by transmission electron microscopy. Administration of TiO2 NPs did not significantly increase any of the following endpoints: frequency of Pig-a mutants (erythrocytes); frequency of micronuclei (reticulocytes); level of DNA damage (liver); frequencies of gpt and Spi(-) mutants (liver). Most TiO2 NPs in the liver were found in the sinuses and inside Kupffer cells, although some were occasionally observed in liver parenchymal cells. These results indicate that TiO2 NPs do not have genotoxic effects on mouse liver or bone marrow.
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Dano ao DNA/genética , DNA/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Testes para Micronúcleos , Titânio/toxicidade , Animais , Dano ao DNA/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
ALDH2 is involved in the metabolism of styrene, a widely used industrial material, but no data are available regarding the influence of this enzyme on the metabolic fate as well as toxic effects of this chemical. In this study, we recruited 329 workers occupationally exposed to styrene and 152 unexposed controls. DNA strand breaks, DNA-base oxidation in leukocytes and urinary 8-hydroxydeoxyguanosine (8-OH-dG) were assayed as biomarkers to measure genotoxic effects. Meanwhile, we examined the genetic polymorphisms, including ALDH2, EXPH1, GSTM1, GSTT1 and CYP2E1, and also analyzed the levels of styrene exposure through detecting urinary styrene metabolites and styrene concentration in air. In terms of DNA damage, the three genotoxic biomarkers were significantly increased in exposed workers as compared with controls. And the styrene-exposed workers with inactive ALDH2 *2 allele were subjected to genotoxicity in a higher degree than those with ALDH2 *1/*1 genotype. Also, lower levels of urinary styrene metabolites (MA + PGA) were observed in styrene-exposed workers carrying ALDH2 *2 allele, suggesting slower metabolism of styrene. The polymorphisms of other enzymes showed less effect. These results suggested that styrene metabolism and styrene-induced genotoxicity could be particularly modified by ALDH2 polymorphisms. The important role of ALDH2 indicated that the accumulation of styrene glycoaldehyde, a possible genotoxic intermediate of styrene, could account for the genotoxicity observed, and should be taken as an increased risk of cancer.
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Aldeído-Desidrogenase Mitocondrial/metabolismo , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/enzimologia , Estireno/intoxicação , Adulto , Aldeído-Desidrogenase Mitocondrial/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Testes de Mutagenicidade , Doenças Profissionais/genética , Doenças Profissionais/patologia , Exposição Ocupacional , Polimorfismo Genético , Estireno/farmacocinéticaAssuntos
Neoplasias dos Ductos Biliares/induzido quimicamente , Colangiocarcinoma/induzido quimicamente , Indústrias , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Saúde Ocupacional , Impressão , Solventes/efeitos adversos , Animais , Cricetinae , Citocromo P-450 CYP2E1 , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/embriologia , Masculino , Cloreto de Metileno/efeitos adversos , Cloreto de Metileno/metabolismo , Camundongos , Propano/efeitos adversos , Propano/análogos & derivados , Propano/metabolismo , Ratos , Solventes/metabolismo , Compostos Orgânicos Voláteis/efeitos adversos , Compostos Orgânicos Voláteis/metabolismoRESUMO
1,2-Dichloropropane (1,2-DCP), a solvent, which is the main component of the cleaner used in the offset printing companies in Japan, is suspected to be the causative agent of bile duct cancer, which has been recently reported at high incidence in those offset printing workplaces. While there are some reports about the acute toxicity of 1,2-DCP, no information about its metabolism related to toxicity in animals is available. As part of our efforts toward clarifying the role of 1,2-DCP in the development of cancer, we studied the metabolic pathways and the hepatotoxic effect of 1,2-DCP in mice with or without cytochrome P450 2E1 (CYP2E1) activity. In an in vitro reaction system containing liver homogenate, 1,2-DCP was only metabolized by liver tissue of wild-type mice but not by that of cyp2e1-null mice. Furthermore, the kinetics of the solvent in mice revealed a great difference between the two genotypes; 1,2-DCP administration resulted in dose-dependent hepatic damage, as shown biochemically and pathologically, but this effect was only observed in wild-type mice. The nuclear factor κB p52 pathway was involved in the liver response to 1,2-DCP. Our results clearly indicate that the oxidative metabolism of 1,2-DCP in mice is exclusively catalyzed by CYP2E1, and this step is indispensable for the manifestation of the hepatotoxic effect of the solvent.
Assuntos
Carcinógenos Ambientais/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Citocromo P-450 CYP2E1/metabolismo , Fígado/metabolismo , Propano/análogos & derivados , Solventes/metabolismo , Ativação Metabólica , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Animais não Endogâmicos , Carcinógenos Ambientais/administração & dosagem , Carcinógenos Ambientais/análise , Carcinógenos Ambientais/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/genética , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Inseticidas/administração & dosagem , Inseticidas/sangue , Inseticidas/metabolismo , Inseticidas/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Subunidade p52 de NF-kappa B/metabolismo , Oxirredução , Propano/administração & dosagem , Propano/sangue , Propano/metabolismo , Propano/toxicidade , Solventes/administração & dosagem , Solventes/análise , Solventes/toxicidade , ToxicocinéticaRESUMO
OBJECTIVE: Occurrence of cholangiocarcinoma was recently reported at a high incidence rate among the employees working for an offset printing company in Osaka, Japan. 1,2-Dichloropropane (1,2-DCP) and dichloromethane (DCM) are suspected to be the causes of the cancer, as they had been used as ink cleaners in large amounts. However, it is not clear whether these chlorinated organic solvents played a role in the occurrence of cholangiocarcinoma or why the incidence rate is so high among the workers in this industry. To provide possible evidence for this severe occupational problem, we investigated the genotoxic effects of 1,2-DCP and DCM. METHODS: Male B6C3F1 and gpt Delta C57BL/6J mice were exposed by inhalation to the individual solvents or both solvents at multiple concentrations including the levels that were possibly present in the workplaces. The genotoxicity was analyzed by Pig-a gene mutation and micronuclei assays in peripheral blood and gpt mutation and comet assays in the livers of mice after repeated inhalation of 1,2-DCP or/and DCM. RESULTS: The Pig-a mutant frequencies and micronuclei incidences were not significantly increased by exposure of either 1,2-DCP or/and DCM at any concentration, suggesting there was no genotoxic potential in bone marrow for both solvents. In the liver, DNA damage, as measured by the comet assay, was dose dependently increased by 1,2-DCP but not by DCM. The gpt mutant frequency was 2.6-fold that of the controls in the co-exposure group. CONCLUSIONS: These results indicate that 1,2-DCP showed stronger genotoxicity in the liver and that the genotoxic effects were greatly enhanced by simultaneous exposure to DCM.
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Cloreto de Metileno/toxicidade , Mutagênicos/toxicidade , Propano/análogos & derivados , Solventes/toxicidade , Animais , Medula Óssea/efeitos dos fármacos , Dano ao DNA , Exposição por Inalação , Fígado/efeitos dos fármacos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Propano/toxicidadeRESUMO
No data are available regarding aldehyde dehydrogenase 2 (ALDH2) polymorphisms related to the reproductive toxicity possibly caused by ethyl tertiary butyl ether (ETBE). In this study, two inhalation experiments were performed in Aldh2 knockout (KO), heterogeneous (HT) and wild type (WT) C57BL/6 male mice exposed to ETBE, and the data about general toxicity, testicular histopathology, sperm head numbers, sperm motility and sperm DNA damage were collected. The results showed that the 13-week exposure to 0, 500, 1,750 and 5,000 ppm ETBE significantly decreased sperm motility and increased levels of sperm DNA strand breaks and 8-hydroxy-deoxyguanosine in both WT and KO mice, the effects were found in 1,750 and 5,000 ppm groups of WT mice, and all of the three exposed groups of KO mice compared to the corresponding control; furthermore, ETBE also caused decrease in the relative weights of testes and epididymides, the slight atrophy of seminiferous tubules of testis and reduction in sperm numbers of KO mice exposed to ≥500 ppm. In the experiment of exposure to lower concentrations of ETBE (0, 50, 200 and 500 ppm) for 9 weeks, the remarkable effects of ETBE on sperm head numbers, sperm motility and sperm DNA damage were further observed in KO and HT mice exposed to 200 ppm ETBE, but not in WT mice. Our findings suggested that only exposure to high concentrations of ETBE might result in reproductive toxicity in mice with normal active ALDH2, while low active and inactive ALDH2 enzyme significantly enhanced the ETBE-induced reproductive toxicity in mice, even exposed to low concentrations of ETBE, mainly due to the accumulation of acetaldehyde as a primary metabolite of ETBE.
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Aldeído Desidrogenase/metabolismo , Etil-Éteres/toxicidade , Fertilidade/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Aldeído Desidrogenase/deficiência , Aldeído Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial , Animais , Biomarcadores/metabolismo , Biotransformação , Ensaio Cometa , Dano ao DNA , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Relação Dose-Resposta a Droga , Etil-Éteres/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho do Órgão/efeitos dos fármacos , Medição de Risco , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia , Fatores de TempoRESUMO
Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1-6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females.
Assuntos
Aldeído Desidrogenase/metabolismo , Etil-Éteres/toxicidade , Acetaldeído/sangue , Administração por Inalação , Aldeído Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial , Animais , Ensaio Cometa , Dano ao DNA , Etil-Éteres/sangue , Etil-Éteres/farmacocinética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes para Micronúcleos , Propilenoglicóis/sangue , Fatores Sexuais , Testes de Toxicidade Subcrônica , terc-Butil Álcool/sangueRESUMO
Ethyl tertiary butyl ether (ETBE) is used as an additive to gasoline to reduce carbon monoxide emissions in some developed countries. So far, ETBE was not found with positive results in many genotoxic assays. This study is undertaken to investigate the modifying effects of deficiency of aldehyde dehydrogenase 2 (ALDH2) on the toxicity of ETBE in the livers of mice. Eight-week-old wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice of both sexes were exposed to 0, 500, 1,750, and 5,000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Histopathology assessments and measurements of genetic effects in the livers were performed. Significantly increased accidences of centrilobular hypertrophy were observed in the livers of WT and KO mice of both sexes in 5,000 ppm group; there was a sex difference in centrilobular hypertrophy between male and female KO mice, with more severe damage in the males. In addition, DNA strand breaks, 8-hydroxyguanine DNA-glycosylase (hOGG1)-modified oxidative base modification, and 8-hydroxydeoxyguanosine as genetic damage endpoints were significantly increased in three exposure groups in KO male mice, while these genotoxic effects were only found in 5,000 ppm group of KO female mice. In WT mice, significant DNA damage was seen in 5,000 ppm group of male mice, but not in females. Thus, sex differences in DNA damage were found not only in KO mice, but also in WT mice. These results suggest that ALDH2 polymorphisms and sex should be taken into considerations in predicting human health effects of ETBE exposure.
Assuntos
Aldeído Desidrogenase/deficiência , Etil-Éteres/toxicidade , Fígado/efeitos dos fármacos , Mutagênicos/toxicidade , Aldeído Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial , Animais , Crescimento Celular/efeitos dos fármacos , Quebras de DNA , Dano ao DNA , DNA Glicosilases/metabolismo , Etil-Éteres/classificação , Feminino , Predisposição Genética para Doença , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes de Mutagenicidade , Mutagênicos/classificação , Fatores Sexuais , Especificidade da EspécieRESUMO
To clarify the genotoxicity of ethyl tertiary butyl ether (ETBE), a gasoline additive, male and female C57BL/6 mice of Aldh2+/+ and Aldh2-/- genotypes, aged 8 wk, were exposed to 0, 500, 1,750, or 5,000 ppm ETBE for 6 h/day, 5 d per week for 13 wk. DNA damage in leukocytes was measured by the alkaline comet assay and expressed quantitatively as Tail Intensity (TI). For male mice, TI was significantly higher in all three groups exposed to ETBE than in those without exposure within Aldh2-/- mice, whereas within Aldh2+/+ mice, TI increased only in those exposed to 5,000 ppm of ETBE as compared with mice without exposure. For female mice, a significant increase in TI values was observed in the group exposed to 5,000 ppm of ETBE as compared with those without exposure within Aldh2-/- mice; TI in Aldh2-/- mice exposed to 1,750 and 5,000 ppm was significantly higher than in Aldh2+/+ mice without exposure. TI did not significantly increase in any of the groups exposed to ETBE within female Aldh2+/+ mice. Based on the results we suggest that Aldh2-/- mice are more sensitive to DNA damage caused by ETBE than Aldh2+/+ mice and that males seem more susceptible to this effect than females.
Assuntos
Aldeído Desidrogenase , Dano ao DNA/genética , Etil-Éteres/toxicidade , Exposição por Inalação/efeitos adversos , Leucócitos , Aldeído-Desidrogenase Mitocondrial , Análise de Variância , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Knockout , Fatores Sexuais , Estatística como AssuntoRESUMO
Exposure to polychlorobiphenyls (PCBs) has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCBs. We determined whether prenatal exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), a di-ortho-substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats were given PCB 153 (0, 1, or 4 mg/kg/d) orally from gestational day (GD) 10 to 16, and somatic parameters and thyroid functions in offspring were examined. We found no dose-dependent changes in body weight, body length, tail length, or weight of liver, kidney, testis, seminal vesicle, prostate, ovary, relative organ weight, anogenital distance (AGD), or AGD index in offspring at 1, 3 or 9 wk of age. We observed no compound-related changes in the plasma concentrations of thyroxine (T(4)), tri-iodothyronine (T(3)) or thyroid-stimulating hormone (TSH), although there was a significant difference in T(3) only in 1-wk-old males. In addition, thyroid glands from PCB 153 groups had normal T(4) responses to exogenous TSH in vivo. These findings suggest that low doses of PCB 153 given prenatally (GD 10-16, 1-4 mg/kg/d) might have little effect on postnatal somatic growth or thyroid development of male and female rat offspring under the experimental conditions of the present study.
Assuntos
Crescimento e Desenvolvimento/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Glândula Tireoide/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Monitoramento Ambiental , Feminino , Rim/patologia , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Próstata/patologia , Ratos , Ratos Sprague-Dawley , Glândulas Seminais/patologia , Testículo/patologia , Testes de Função Tireóidea , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl), a non-coplanar PCB and the congener most widely distributed in the environment, was orally administered to pregnant Sprague-Dawley (Crj: CD (SD) IGS) rats from gestation day 10 through 16 at doses of 0 (control), 16 and 64 mg/kg body weight. Female pups were sacrificed at 1, 3, 6, and 9 wk, and at 1 yr of age to evaluate the differences in brain neurotransmitters and their metabolites between PCB153-exposed and control groups. Brain levels of norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), acetylcholine (ACh), and choline (Ch) in discrete brain regions or in whole brain were measured. At 1 to 3 wk after birth, brain levels of DA, DOPAC, HVA, 5HT and 5HIAA in PCB-exposed groups were higher than those of the control group. At 9 wk after birth, DA turnover was reduced in half of the four brain areas examined (forebrain and hindbrain), and 5HIAA levels were increased in all brain areas in the PCB-treated group compared to those of the control group. At 1 yr after birth, the levels of DA, DOPAC, and HVA in the hippocampus, hypothalamus, and medulla oblongata were lower in the PCB-exposed groups than in the control group. Prenatal exposure to PCB153 stimulated the turnover of 5HT neurons in the brain of female offspring at early stages (1 to 9 wk) of development. On the other hand, the turnover of DA neurons in the PCB-exposed groups was reduced in late stages (9 wk to 1 yr) of development compared with that of the control group. The brain neurotransmitters of dams treated with PCB were assayed at 3 wk after delivery (15 wk old), and decreases in DA, DOPAC, and HVA were observed. PCB153 reduced the activity of DA neurons in the brain of dams. These results are discussed in relation to health effects observed in humans exposed to PCBs.
Assuntos
Química Encefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Bifenilos Policlorados/administração & dosagem , Bifenilos Policlorados/efeitos adversos , Transmissão Sináptica/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Feminino , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Exposure to polychlorobiphenyl (PCB) mixtures at an early stage of development has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCB. The present study was undertaken to determine whether prenatal exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), a di-ortho-substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats (Crj: CD (SD) IGS) were given PCB 153 (0, 16, or 64 mg/kg/day) orally from gestational day (GD) 10 through GD 16, and developmental parameters in the male and female offspring were examined. We found no dose-dependent changes in body weight, body length (nose-anus length), tail length, or the weights of kidneys, testes, ovaries and uterus in offspring at 1 or 3 weeks of age. Liver weights were increased in the PCB 153-treated groups, although we observed a significant difference only in males. Anogenital distance was unaffected in the PCB 153-treated groups. We observed a significant dose-dependent decrease in the plasma concentrations of thyroxine and tri-iodothyronine, whereas those of thyroid-stimulating hormone were not significantly changed. In addition, there were no dose-dependent changes in plasma concentrations of growth hormone and insulin-like growth factor-I in any dose group. These findings suggest that prenatal exposure to PCB 153 (GD 10-16, 16-64 mg/kg/day) may alter the thyroid status in rat offspring to some extent without affecting somatic growth or its related hormonal parameters.