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1.
Mol Neurobiol ; 55(7): 6201-6214, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29270919

RESUMO

This study was conducted to investigate the mechanism of action and extent of selective dopaminergic neurodegeneration caused by exposure to trichloroethylene (TCE) leading to the endogenous formation of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-ß-carboline (TaClo) in rodents. Beginning at 3 months of age, male C57BL/6 mice received oral TCE dissolved in vehicle for 8 months. Dopaminergic neuronal loss was assessed by nigral tyrosine hydroxylase (TH) immunoreactivity. Selective dopaminergic neurodegeneration was determined based on histological analysis of non-dopaminergic neurons in the brain. Behavioral assays were evaluated using open field activity and rotarod tests. Mitochondrial complex I activity, oxidative stress markers, and microglial activation were also examined in the substantia nigra. The level of TaClo was detected using HPLC-electrospray ionization tandem mass spectrometry. Dopaminergic neurotoxicity of TaClo was determined in midbrain organotypic cultures from rat pups. Following 8 months of TCE treatment, there was a progressive and selective loss of 50% of the dopaminergic neurons in mouse substantia nigra (SN) and about 50% loss of dopamine and 72% loss of 3,4-dihydroxyphenylacetic acid in the striatum, respectively. In addition, motor deficits, mitochondrial impairment, oxidative stress, and inflammation were measured. TaClo content was quantified in the brain after TCE treatment. In organotypic cultures, TaClo rather than TCE induced dopaminergic neuronal loss, similar to MPP+. TCE exposure may stimulate the endogenous formation of TaClo, which is responsible for dopaminergic neurodegeneration. However, even prolonged administration of TCE was insufficient for producing a greater than 50% loss of nigral dopamine neurons, indicating that additional co-morbid factors would be needed for mimicking the profound loss of dopamine neurons seen in Parkinson's disease.


Assuntos
Doença de Parkinson/etiologia , Medição de Risco , Tricloroetileno/toxicidade , Administração Oral , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dopamina/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Degeneração Neural/patologia , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/patologia , Dobramento de Proteína/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Tricloroetileno/administração & dosagem , alfa-Sinucleína/metabolismo
2.
J Immunotoxicol ; 14(1): 95-102, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28366041

RESUMO

Trichloroethylene (TCE) is a widespread environmental contaminant associated with developmental immunotoxicity and neurotoxicity. Previous studies have shown that MRL+/+ mice exposed to TCE from gestation through early-life demonstrate robust increases in inflammatory markers in peripheral CD4+ T-cells, as well as glutathione depletion and increased oxidative stress in cerebellum-associated with alterations in behavior. Since increased oxidative stress is associated with neuroinflammation, we hypothesized that neuroinflammatory markers could be altered relative to unexposed mice. MRL+/+ mice were given 0.5 mg/ml of TCE in vehicle or vehicle (water with 1% Alkamuls EL-620) from conception through early adulthood via drinking water to dams and then directly to post-weaning offspring. Animals were euthanized at 49 days of age and levels of pro- and anti-inflammatory cytokines, density of T-cell staining, and micro-glial morphology were evaluated in brains to begin to ascertain a neuroinflammatory profile. Levels of IL-6 were decreased in female animals and while not statistically significant, and levels of IL-10 were higher in brains of exposed male and female animals. Supportive of this observation, although not statistically significant, the number of ameboid microglia was higher in exposed relative to unexposed animals. This overall profile suggests the emergence of an anti-inflammatory/neuroprotective phenotype in exposed animals, possibly as a compensatory response to neuroinflammation that is known to be induced by developmental exposure to TCE.


Assuntos
Encéfalo/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Inflamação Neurogênica/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Tricloroetileno/administração & dosagem , Animais , Biomarcadores/metabolismo , Encéfalo/imunologia , Células Cultivadas , Poluição Ambiental/efeitos adversos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Estresse Oxidativo , Gravidez
3.
Chem Res Toxicol ; 29(10): 1773-1777, 2016 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-27618143

RESUMO

Trichloroethylene (TCE), a common environmental contaminant, causes hepatocellular carcinoma in mice but not in rats. To understand the mechanisms of the species-specific hepatocarcinogenecity of TCE, we examined the methylation status of DNA in the liver of rats exposed to TCE at 0 or 1000 mg/kg b.w. for 5 days using MeDIP-chip, bisulfite sequencing, COBRA, and LC-MS/MS. The related mRNA expression levels were measured by qPCR. Although no global DNA methylation change was detected, 806 genes were hypermethylated and 186 genes were hypomethylated. The genes with hypermethylated DNA were enriched in endocytosis, MAPK, and cAMP signaling pathways. We further confirmed the hypermethylation of Uhrf2 DNA and the hypomethylation of Hadhb DNA, which were negatively correlated with their mRNA expression levels. The transcriptional levels of Jun, Ihh, and Tet2 were significantly downregulated, whereas Cdkn1a was overexpressed. No mRNA expression change was found for Mki67, Myc, Uhrf1, and Dnmt1. In conclusion, TCE-induced DNA methylation changes in rats appear to suppress instead of promote hepatocarcinogenesis, which might play a role in the species-specific hepatocarcinogenecity of TCE.


Assuntos
Metilação de DNA/efeitos dos fármacos , DNA/química , DNA/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Tricloroetileno/toxicidade , Animais , DNA/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Tricloroetileno/administração & dosagem
4.
Toxicol Lett ; 260: 1-7, 2016 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-27553676

RESUMO

CD4+ T cells in female MRL+/+ mice exposed to solvent and water pollutant trichloroethylene (TCE) skew toward effector/memory CD4+ T cells, and demonstrate seemingly non-monotonic alterations in IFN-γ production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naïve CD4+ T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5mg/ml in drinking water). A time-dependent effect of TCE exposure on both Ifng gene expression and IFN-γ protein production was observed in effector/memory CD4+ T cells, with an increase after 22 weeks of exposure and a decrease after 40 weeks of exposure. No such effect of TCE was observed in naïve CD4+ T cells. A cumulative increase in DNA methylation in the CpG sites of the promoter of the Ifng gene was observed in effector/memory, but not naïve, CD4+ T cells over time. Also unique to the Ifng promoter was an increase in methylation variance in effector/memory compared to naïve CD4+ T cells. Taken together, the CpG sites of the Ifng promoter in effector/memory CD4+ T cells were especially sensitive to the effects of TCE exposure, which may help explain the regulatory effect of the chemical on this gene.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Interferon gama/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Solventes/toxicidade , Tricloroetileno/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Ilhas de CpG/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Éxons/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hormese , Memória Imunológica/efeitos dos fármacos , Interferon gama/agonistas , Interferon gama/antagonistas & inibidores , Interferon gama/genética , Íntrons/efeitos dos fármacos , Camundongos Endogâmicos MRL lpr , Reprodutibilidade dos Testes , Solventes/administração & dosagem , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Fatores de Tempo , Tricloroetileno/administração & dosagem , Poluentes Químicos da Água/administração & dosagem
5.
HLA ; 88(4): 164-71, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27558172

RESUMO

Human leukocyte antigen HLA-B*13:01 is identified currently as a marker of individual susceptibility to drug-induced hypersensitivity reaction, such as dapsone-induced hypersensitivity reactions (DIHRs) and trichloroethylene-induced dermatitis. Therefore, screening for the HLA-B*13:01 allele can assist clinics in identifying patients at risk of developing DIHRs. By combining the allele-specific primers with TaqMan probes, we established a single tube, triplex real-time PCR to detect HLA-B*13:01. The reliability of this assay was validated by the comparison of genotyping results with those by sequence-based typing (SBT). With this assay, the distribution of HLA-B*13:01 in a total of 350 blood samples from four ethnic groups: Han, Tibetan, Uighur, and Buyei were determined. A 100% concordance was observed between the results with the established real-time PCR and SBT in 100 samples. The detection limit of this assay was 0.016 ng genomic DNA. The prevalence of HLA-B*13:01 carriers were 11%, 8%, 1%, and 2% in the Buyei (n = 100), Northern Han (n = 100), Tibetan (n = 100), and Uighur (n = 50) populations, respectively. The multiplex real-time PCR assay provided a fast and reliable method for accurate detection of HLA-B*13:01 allele prior to dapsone administration in clinical practice and onset of the reaction after exposure to trichloroethylene.


Assuntos
Hipersensibilidade a Drogas/diagnóstico , Frequência do Gene , Antígeno HLA-B13/genética , Teste de Histocompatibilidade/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase Multiplex/normas , Alelos , Sequência de Bases , China , Primers do DNA/síntese química , Primers do DNA/metabolismo , Sondas de DNA/síntese química , Sondas de DNA/metabolismo , Dapsona/administração & dosagem , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/etnologia , Hipersensibilidade a Drogas/imunologia , Etnicidade , Éxons , Antígeno HLA-B13/classificação , Antígeno HLA-B13/imunologia , Voluntários Saudáveis , Humanos , Íntrons , Limite de Detecção , Análise de Sequência de DNA , Tricloroetileno/administração & dosagem
6.
Toxicol Sci ; 147(2): 339-49, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26136231

RESUMO

Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor-mediated toxicodynamic effects.


Assuntos
PPAR alfa/metabolismo , Tricloroetileno/toxicidade , Animais , Esquema de Medicação , Feminino , Rim/química , Rim/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Toxicocinética , Ácido Tricloroacético/análise , Ácido Tricloroacético/metabolismo , Tricloroetileno/administração & dosagem , Tricloroetileno/farmacocinética
7.
PLoS One ; 9(12): e116179, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25549359

RESUMO

Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.


Assuntos
Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Tricloroetileno/administração & dosagem , Administração Oral , Animais , Células Cultivadas , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tricloroetileno/farmacologia
8.
Mutagenesis ; 29(3): 209-14, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24618993

RESUMO

The in vivo genotoxic potential of trichloroethylene (TCE) was evaluated by examining the incidence of micronucleated polychromatic erythrocytes (MN-PCEs) in the bone marrow. Groups of male CD rats were exposed by inhalation to targeted concentrations of 0 (negative control), 50, 500, 2500 or 5000 ppm for 6 consecutive hours on a single day. The exposure concentrations were selected to overlap those employed by a published study that reported a 2- to 3-fold increase in the frequency of micronuclei in male rats following a single inhalation exposure to 5, 500 and 5000 ppm TCE for 6h but not following repeated exposure to similar concentrations. In addition, any treatment-related findings were assessed in the context of potential TCE-induced hypothermia. Clinical signs consistent with marked TCE-induced sedation were observed in rats exposed to 5000 ppm and subsequently three rats died prior to the end of the 6h exposure period. No remarkable changes in body temperature were observed in surviving animals monitored with transponders before and after exposures. There were no statistically significant increases in the frequencies of MN-PCEs in groups treated with the test material as compared to the negative controls. The positive control animals showed a significant increase in the frequency of MN-PCEs and a decrease in the relative proportion of PCEs among erythrocytes as compared to the negative control animals. There were no statistically significant differences in the per cent PCEs in groups treated with the test material. As no increase in the incidence of micronuclei was observed in any of the TCE exposure groups, kinetochore analyses were not performed. Under the experimental conditions used, TCE was considered to be negative in the rat bone marrow micronucleus test.


Assuntos
Mutagênicos/toxicidade , Tricloroetileno/toxicidade , Aneugênicos/administração & dosagem , Aneugênicos/toxicidade , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Exposição por Inalação , Masculino , Testes para Micronúcleos/métodos , Mutagênicos/administração & dosagem , Ratos , Tricloroetileno/administração & dosagem
10.
Cardiovasc Toxicol ; 13(1): 77-84, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22855351

RESUMO

Trichloroethylene (TCE) is an organic solvent and common environmental contaminant. TCE exposure is associated with heart defects in humans and animal models. Primary metabolism of TCE in adult rodent models is by specific hepatic cytochrome P450 enzymes (Lash et al. in Environ Health Perspect 108:177-200, 2000). As association of TCE exposure with cardiac defects is in exposed embryos prior to normal liver development, we investigated metabolism of TCE in the early embryo. Developing chick embryos were dosed in ovo with environmentally relevant doses of TCE (8 and 800 ppb) and RNA was extracted from cardiac and extra-cardiac tissue (whole embryo without heart). Real-time PCR showed upregulation of CYP2H1 transcripts in response to TCE exposure in the heart. No detectable cytochrome expression was found in extra-cardiac tissue. As seen previously, the dose response was non-monotonic and 8 ppb elicited stronger upregulation than 800 ppb. Immunostaining for CYP2C subfamily expression confirmed protein expression and showed localization in both myocardium and endothelium. TCE exposure increased protein expression in both tissues. These data demonstrate that the earliest embryonic expression of phase I detoxification enzymes is in the developing heart. Expression of these CYPs is likely to be relevant to the susceptibility of the developing heart to environmental teratogens.


Assuntos
Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Regulação Enzimológica da Expressão Gênica , Coração/efeitos dos fármacos , Coração/embriologia , Tricloroetileno/administração & dosagem , Animais , Embrião de Galinha , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Solventes/administração & dosagem
11.
Toxicology ; 304: 49-56, 2013 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-23211455

RESUMO

The industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose-response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8 mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response. As TCE is primarily metabolised by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450. Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilisation of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Formiatos/urina , Rim/efeitos dos fármacos , Solventes/toxicidade , Tricloroetileno/toxicidade , Animais , Citocromo P-450 CYP2E1/efeitos dos fármacos , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Etilenocloroidrina/análogos & derivados , Etilenocloroidrina/toxicidade , Feminino , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Fatores Sexuais , Solventes/administração & dosagem , Solventes/metabolismo , Especificidade da Espécie , Fatores de Tempo , Ácido Tricloroacético/toxicidade , Tricloroetileno/administração & dosagem , Tricloroetileno/metabolismo
13.
J Immunotoxicol ; 7(4): 350-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20925451

RESUMO

Numerous epidemiological studies have associated episodes of increased air pollution with increased incidence of respiratory disease, including pneumonia, croup, and bronchitis. Trichloroethylene (TCE) and chloroform are among 33 hazardous air pollutants identified by the U.S. Environmental Protection Agency as presenting the greatest threat to public health in the largest number of urban areas. Also, both are common indoor air pollutants. Here, we assessed the potential effects of TCE and chloroform on resistance to pulmonary bacterial infection and related alveolar macrophage (AM) function. CD-1 mice were exposed by inhalation to filtered air (control) or concentrations of TCE ranging from 5 to 200 ppm, or concentrations of chloroform ranging from 100 to 2000 ppm. Immediately following exposure, mice were challenged with an aerosol of Streptococcus zooepidemicus and monitored for clearance of bacteria from the lung and mortality. In separate experiments, exposed mice were injected intratracheally with viable bacteria and phagocytic function was evaluated in macrophages obtained from lung washes 30 min later. The NOEL for enhanced mortality to infection was 25 ppm for TCE and 500 ppm for chloroform. Relative to the air controls, differences in clearance of bacteria from the lung were noted in mice exposed to TCE (NOEL = 50 ppm) and to chloroform (NOEL 100 ppm), and differences in AM phagocytic index were noted for TCE (NOEL = 100 ppm) and for chloroform (NOEL < 100 ppm). The data support the utility of the S. zooepidemicus infectivity model in assessing potential increased risk of respiratory infection and suggest that delayed clearance of bacteria from the lung or decreased phagocytosis are viable alternatives to mortality as an endpoint. Collectively, these endpoints are among the most sensitive health effects reported for TCE.


Assuntos
Clorofórmio/administração & dosagem , Pulmão/efeitos dos fármacos , Infecções Estreptocócicas/imunologia , Streptococcus equi/imunologia , Tricloroetileno/administração & dosagem , Poluentes Atmosféricos/efeitos adversos , Animais , Clorofórmio/efeitos adversos , Humanos , Imunidade Ativa/efeitos dos fármacos , Exposição por Inalação , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos , Modelos Animais , Fagocitose/efeitos dos fármacos , Streptococcus equi/patogenicidade , Tricloroetileno/efeitos adversos
14.
Toxicol Appl Pharmacol ; 241(1): 36-60, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19660485

RESUMO

We have developed a comprehensive, Bayesian, PBPK model-based analysis of the population toxicokinetics of trichloroethylene (TCE) and its metabolites in mice, rats, and humans, considering a wider range of physiological, chemical, in vitro, and in vivo data than any previously published analysis of TCE. The toxicokinetics of the "population average," its population variability, and their uncertainties are characterized in an approach that strives to be maximally transparent and objective. Estimates of experimental variability and uncertainty were also included in this analysis. The experimental database was expanded to include virtually all available in vivo toxicokinetic data, which permitted, in rats and humans, the specification of separate datasets for model calibration and evaluation. The total combination of these approaches and PBPK analysis provides substantial support for the model predictions. In addition, we feel confident that the approach employed also yields an accurate characterization of the uncertainty in metabolic pathways for which available data were sparse or relatively indirect, such as GSH conjugation and respiratory tract metabolism. Key conclusions from the model predictions include the following: (1) as expected, TCE is substantially metabolized, primarily by oxidation at doses below saturation; (2) GSH conjugation and subsequent bioactivation in humans appear to be 10- to 100-fold greater than previously estimated; and (3) mice had the greatest rate of respiratory tract oxidative metabolism as compared to rats and humans. In a situation such as TCE in which there is large database of studies coupled with complex toxicokinetics, the Bayesian approach provides a systematic method of simultaneously estimating model parameters and characterizing their uncertainty and variability. However, care needs to be taken in its implementation to ensure biological consistency, transparency, and objectivity.


Assuntos
Glutationa/metabolismo , Modelos Biológicos , Solventes/farmacocinética , Tricloroetileno/farmacocinética , Animais , Teorema de Bayes , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Oxirredução , Ratos , Sistema Respiratório/metabolismo , Solventes/administração & dosagem , Solventes/toxicidade , Especificidade da Espécie , Tricloroetileno/administração & dosagem , Tricloroetileno/toxicidade
15.
Drug Metab Dispos ; 37(10): 1994-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19581386

RESUMO

1,1,2-Trichloroethylene (TCE), a volatile organic contaminant (VOC) of drinking water in the Unites States, is frequently present in trace amounts. TCE is currently classified by the International Agency for Research on Cancer and the U.S. Environmental Protection Agency as a probable human carcinogen, because it produces tumors in some organs of certain strains of mice or rats in chronic, high-dose bioassays. Previous studies (Toxicol Appl Pharmacol 60:509-526, 1981; Regul Toxicol Pharmacol 8:447-466, 1988) used physiological modeling principles to reason that the liver should remove virtually all of a well metabolized VOC, such as TCE, as long as concentrations in the portal blood were not high enough to saturate metabolism. To test this hypothesis, groups of unanesthetized male Sprague-Dawley rats received intravenous injections of 0.1, 1.0, or 2.5 mg TCE/kg as an aqueous emulsion. Other rats were gavaged with 0.0001, 0.001, 0.01, 0.1, 1, 2.5, 5, or 10 mg TCE/kg b.wt. Serial microblood samples were taken via an indwelling carotid artery cannula, to generate blood TCE versus time profiles. Headspace solid-phase microextraction gas chromatography with negative chemical ionization mass spectrometry (limit of quantitation = 25 pg/ml) was used to quantify TCE. TCE was undetectable in rats given 0.0001 mg/kg, but it exhibited linear kinetics from 0.1 to 5.0 mg/kg. Bioavailability was consistent over this dosage range, ranging from 12.5 to 16.4%. The presence of these limited amounts of TCE in the arterial blood disprove the aforementioned hypothesis, yet demonstrate that first-pass hepatic and pulmonary elimination in the rat afford its extrahepatic organs protection from potential adverse effects by the majority of the low levels of TCE absorbed from drinking water.


Assuntos
Tricloroetileno/farmacologia , Animais , Disponibilidade Biológica , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Camundongos , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Microextração em Fase Sólida , Distribuição Tecidual , Tricloroetileno/administração & dosagem , Tricloroetileno/sangue , Estados Unidos
16.
Toxicol Appl Pharmacol ; 237(2): 188-95, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19332086

RESUMO

Even though reactive oxygen and nitrogen species (RONS) are implicated as mediators of autoimmune diseases (ADs), little is known about contribution of protein oxidation (carbonylation and nitration) in the pathogenesis of such diseases. The focus of this study was, therefore, to establish a link between protein oxidation and induction and/or exacerbation of autoimmunity. To achieve this, female MRL +/+ mice were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 6 or 12 weeks (10 mmol/kg, i.p., every 4(th) day). TCE treatment resulted in significantly increased formation of nitrotyrosine (NT) and induction of iNOS in the serum at both 6 and 12 weeks of treatment, but the response was greater at 12 weeks. Likewise, TCE treatment led to greater NT formation, and iNOS protein and mRNA expression in the livers and kidneys. Moreover, TCE treatment also caused significant increases ( approximately 3 fold) in serum protein carbonyls (a marker of protein oxidation) at both 6 and 12 weeks. Significantly increased protein carbonyls were also observed in the livers and kidneys (2.1 and 1.3 fold, respectively) at 6 weeks, and to a greater extent at 12 weeks (3.5 and 2.1 fold, respectively) following TCE treatment. The increases in TCE-induced protein oxidation (carbonylation and nitration) were associated with significant increases in Th1 specific cytokine (IL-2, IFN-gamma) release into splenocyte cultures. These results suggest an association between protein oxidation and induction/exacerbation of autoimmune response. The results present a potential mechanism by which oxidatively modified proteins could contribute to TCE-induced autoimmune response and necessitates further investigations for clearly establishing the role of protein oxidation in the pathogenesis of ADs.


Assuntos
Doenças Autoimunes/induzido quimicamente , Carbonilação Proteica/efeitos dos fármacos , Tricloroetileno/toxicidade , Animais , Células Cultivadas , Citocinas/metabolismo , Esquema de Medicação , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Baço/citologia , Tricloroetileno/administração & dosagem , Tirosina/análogos & derivados , Tirosina/metabolismo
17.
Chem Res Toxicol ; 22(4): 626-32, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19254012

RESUMO

Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell activation in autoimmune-prone MRL+/+ mice. MRL+/+ mice are usually thought of as a model of systemic lupus rather than an organ-specific disease such as autoimmune hepatitis. Consequently, the present study examined gene expression and metabolites to delineate the liver events that skewed the autoimmune response toward that organ in TCE-treated mice. Female MRL+/+ mice were treated with 0.5 mg/mL TCE in their drinking water. The results showed that TCE-induced autoimmune hepatitis could be detected in as little as 26 weeks. TCE exposure also generated a time-dependent increase in the number of antibodies specific for liver proteins. The gene expression correlated with the metabolite analysis to show that TCE upregulated the methionine/homocysteine pathway in the liver after 26 weeks of exposure. The results also showed that TCE exposure altered the expression of selective hepatic genes associated with immunity and inflammation. On the basis of these results, future mechanistic studies will focus on how alterations in genes associated with immunity and inflammation, in conjunction with protein alterations in the liver, promote liver immunogenicity in TCE-treated MRL+/+ mice.


Assuntos
Doenças Autoimunes/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Poluentes Ambientais/toxicidade , Fígado/metabolismo , Tricloroetileno/toxicidade , Administração Oral , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos T CD4-Positivos/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Poluentes Ambientais/administração & dosagem , Feminino , Regulação da Expressão Gênica , Hepatite Autoimune/imunologia , Hepatite Autoimune/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/efeitos dos fármacos , Análise de Componente Principal , Tricloroetileno/administração & dosagem
18.
Biomed Chromatogr ; 22(9): 977-84, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18506680

RESUMO

Trichloroethylene (TCE) is a small halogenated compound that has been used extensively as a metal degreaser and a solvent for the past 100 years. As a result of its widespread use, TCE can be found in the groundwater of about one-third of the hazardous waste sites on the United States Environmental Protection Agency's National Priorities List. Human exposure to TCE in the environmental media is of concern because TCE has been found to be carcinogenic in laboratory animals. This paper describes the development and validation of a HS-SPME-GC/MS method for determination of TCE in rat plasma. The effects of different parameters such as sample volume, extraction and desorption conditions, fiber positions and salt addition were investigated and optimized. The method is rapid, simple, sensitive and requires a very small sample volume. The lower limit of quantitation was 0.25 ng/mL and correlation coefficient (r(2)) values for the linear range of 0.25-100 ng/mL were 0.996 or greater. The precision and accuracy for intra-day and inter-day were better than 8.0%. This validated method was successfully applied to study the toxicokinetic behavior of TCE following low levels of oral administration.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Microextração em Fase Sólida/métodos , Tricloroetileno/sangue , Administração Oral , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Tricloroetileno/administração & dosagem
19.
Histol Histopathol ; 22(9): 977-88, 2007 09.
Artigo em Inglês | MEDLINE | ID: mdl-17523075

RESUMO

We have investigated the toxic effects of trichloroethylene (TCE) on the epididymis and epididymal sperm in mice. Mice were exposed to TCE (1000 ppm) by inhalation for 6 h/day for 5 days/week for 1 to 4 weeks. Segments of the epididymis (caput, corpus and cauda) were examined by light and electron microscopy. At the light microscopic level, degeneration and sloughing of epithelial cells were evident as early as 1 week after TCE exposure, and were most pronounced after 4 weeks. Such epithelial damage was observed in the caput, corpus and cauda regions of the epididymis. Ultrastructural observations revealed vesiculation in the cytoplasm, disintegration of basolateral cell membranes, and sloughing of epithelial cells. Sperm were found in situ in the cytoplasm of degenerated epididymal cells. Additionally, a large number of sperm in the epididymal lumen exhibited abnormalities including malformation of head and tail components. Our results demonstrated that exposure to TCE by inhalation causes damage to the epididymal epithelium and sperm.


Assuntos
Epididimo/citologia , Células Epiteliais/efeitos dos fármacos , Solventes/toxicidade , Espermatozoides/efeitos dos fármacos , Tricloroetileno/toxicidade , Administração por Inalação , Animais , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos , Solventes/administração & dosagem , Espermatozoides/patologia , Espermatozoides/ultraestrutura , Fatores de Tempo , Tricloroetileno/administração & dosagem
20.
Birth Defects Res B Dev Reprod Toxicol ; 77(5): 405-12, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17066414

RESUMO

The potential for trichloroethylene (TCE) and perchloroethylene (PERC) to induce developmental toxicity was investigated in Crl:CD (SD) rats whole-body exposed to target concentrations of 0, 50, 150 or 600 ppm TCE or 0, 75, 250 or 600 ppm PERC for six hours/day, seven days/week on gestation day (GD) 6-20 and 6-19, respectively. Actual chamber concentrations were essentially identical to target with the exception of the low PERC exposure level, which was 65 ppm. The highest exposure levels exceeded the limit concentration (2 mg/L) specified in the applicable test guidelines. Maternal necropsies were performed the day following the last exposure. Dams exposed to 600 ppm TCE exhibited maternal toxicity, as evidenced by decreased body weight gain (22% less than control) during GD 6-9. There were no maternal effects at 50 or 150 ppm TCE and no indications of developmental toxicity (including heart defects or other terata) at any exposure level tested. Therefore, the TCE NOEC for maternal toxicity was 150 ppm, whereas the embryo/fetal NOEC was 600 ppm. Maternal responses to PERC were limited to slight, but statistically significant reductions in body weight gain and feed consumption during the first 3 days of exposure to 600 ppm, resulting in a maternal NOEC of 250 ppm. Developmental effects at 600 ppm consisted of reduced gravid uterus, placental and fetal body weights, and decreased ossification of thoracic vertebral centra. Developmental effects at 250 ppm were of minimal toxicological significance, being limited to minor decreases in fetal and placental weight. There were no developmental effects at 65 ppm.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Exposição por Inalação , Tetracloroetileno/toxicidade , Tricloroetileno/toxicidade , Anormalidades Induzidas por Medicamentos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Feto/anormalidades , Feto/efeitos dos fármacos , Feto/embriologia , Exposição Materna , Gravidez , Ratos , Ratos Sprague-Dawley , Tetracloroetileno/administração & dosagem , Tricloroetileno/administração & dosagem , Aumento de Peso/efeitos dos fármacos
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