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1.
Toxicol Appl Pharmacol ; 388: 114872, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881176

RESUMO

Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.


Assuntos
Acetamidas/toxicidade , Carcinógenos/toxicidade , Contaminação de Alimentos , Neoplasias Hepáticas/genética , Modelos Biológicos , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , Imunidade/genética , Antígeno Ki-67/análise , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , RNA-Seq , Ratos , Ratos Wistar , Medição de Risco/métodos , Testes de Toxicidade Crônica/métodos , Regulação para Cima/efeitos dos fármacos
2.
Toxicol Mech Methods ; 18(1): 17-23, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-20020887

RESUMO

ABSTRACT Chlorpyrifos (CPF) is a widely used organophosphate insecticide. In addition to its known properties of cholinesterase inhibition, the production of reactive oxygen species (ROS) has been suggested as a possible toxic mechanism. To investigate CPF-generated ROS, rat neuronal PC12 cells were exposed to CPF concentrations of 0 to 5000 mug/mL in Krebs buffered media (KRH), KRH + 4% bovine serum albumin (BSA), and KRH + 25 muM of the antioxidant Trolox for 0 to 5 h. Paraquat served as a positive control for ROS. The fluorescent probe 2,7-dichlorodihydro-fluorescein and the MTS assay were used to measure ROS and cytotoxicity, respectively. Examinations into CPF-albumin binding were also conducted. CPF was not strongly cytotoxic to PC12 cells, causing only mild cytotoxicity at 5000 mug/ml. In KRH media, CPF-generated ROS was observed at 4 and 5 h at 500 and 1000 mug/mL, and at 1 to 5 h at 5000 mug/mL CPF. In KRH + 4% BSA, ROS was seen only at 5 h in 5000 mug/mL CPF. Trolox significantly reduced CPF- and paraquat-induced ROS. Calculated CPF-albumin binding at 1, 10, and 100 mug/mL CPF in 4% BSA was 96%, 75%, and 15%. These data show CPF at >/=500 mug/mL induced ROS in PC12 cells, but the addition of the antioxidant Trolox and 4% BSA dramatically reduced ROS levels.

3.
Toxicol Sci ; 97(1): 120-7, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17329239

RESUMO

Doses of xenobiotics at or near LD50 may result in substantial hypothermia in mice. Hypothermia has previously been associated with an increase in micronuclei (MN) formation. The present series of investigations examined the potential for phenol to induce hypothermia in mice and its correlation to previously reported MN induction. In order to examine the potential etiology of phenol-induced MN, evaluation of kinetochore status of MN was also carried out. Phenol-induced hypothermia was assessed in CD1 mice following a single ip dose of phenol ranging from 0-500 mg/kg. Phenol at 300 mg/kg or above caused significant and prolonged hypothermia in male and female mice (up to 7 degrees C decrease). In the micronucleus test, single ip doses of phenol to CD1 mice at 0, 30, 100, or 300 mg/kg produced a significant and prolonged hypothermia and a significant increase in MN only at 300 mg/kg; no marked effect on either body temperature or MN was observed at lower doses. A statistically significant increase in kinetochore-positive MN was observed at the 300-mg/kg dose; however, the response was considerably less than that observed for a known spindle poison. Hence, the induction of MN by phenol occurred only at a dose that produced substantial and prolonged physiologic hypothermia, but interruption of the cell spindle apparatus appeared to play only a minor role in MN formation. These data are suggestive of a threshold mechanism for the induction of MN by phenol treatment in mice.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Hipotermia/induzido quimicamente , Cinetocoros/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Mutagênicos/toxicidade , Fenol/toxicidade , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Relação Dose-Resposta a Droga , Feminino , Hipotermia/genética , Hipotermia/fisiopatologia , Cinetocoros/metabolismo , Masculino , Camundongos , Testes para Micronúcleos
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