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1.
Artigo em Chinês | MEDLINE | ID: mdl-34488279

RESUMO

Occupational exposure to trichloroethylene can induce a series of immune diseases which include systemic rash, multiple system and organ damage, which are defined as occupational medicamentosa-like dermatitis due to trichloroethylene (OMLDT) . This article reviews the research progress of the role of T cell immunity, humoral immunity and complement system in the immunological pathogenesis of OMLDT to provide theoretical basis for the diagnosis and treatment of OMLDT.


Assuntos
Dermatite Ocupacional , Exposição Ocupacional , Tricloroetileno , Proteínas do Sistema Complemento , Dermatite Ocupacional/etiologia , Humanos , Tricloroetileno/toxicidade
2.
Artigo em Inglês | MEDLINE | ID: mdl-34360388

RESUMO

Pesticide adjuvants (PAs) denote the general term for auxiliaries in pesticide preparations except for the active components. Toluene, chloroform, and trichloroethylene are the three most commonly used PAs as organic solvents. The residues of the three chemicals in the process of production and application of pesticides may endanger the ecosystem. In the present study, the mutagenicity of toluene, chloroform, and trichloroethylene as well the mixture of the three chemicals was tested by the Salmonella typhimurium reverse mutation test (Ames test) with TA97, TA98, TA100, and TA102 strains in the system with and without rat liver microsomal preparations (S9). The four tester strains have been used for more than 40 years to detect mutagenic compounds in chemicals, cosmetics, and environmental samples. The mutagenicity was detected on tester strains in the separated experiment from the three chemicals. The addition of S9 decreased the mutation ratios of toluene to four strains, except for the TA100 strain, but increased the mutation ratios of chloroform to four strains except for the TA98 strain. Trichloroethylene caused positive mutagenicity to become negative on the TA102 strain. In the mixed experiment, positive effects were detected only on the TA102 strain in the absence of S9. The addition of S9 increased the mutagenicity except for the TA102 strain. The mixture of toluene, chloroform, and trichloroethylene showed antagonism in mutagenicity to tester strains, except for the TA102 strain without S9. However, the mixture showed a synergistic effect to tester strains after adding S9 except for the TA98 strain.


Assuntos
Praguicidas , Tricloroetileno , Animais , Clorofórmio/toxicidade , Ecossistema , Testes de Mutagenicidade , Mutagênicos , Ratos , Tolueno/toxicidade , Tricloroetileno/toxicidade
3.
Artigo em Chinês | MEDLINE | ID: mdl-34074090

RESUMO

Trichloroethylene (TCE) is a commonly used organic solvent in industry and it was classified as a Group I carcinogen by IARC, with immunotoxicity, hepatotoxicity, kidney toxicity and neurotoxicity. Increasing evidence suggests that TCE-induced autoimmune diseases and cancer are involved in epigenetic modifications. This paper summarized the mechanism of DNA methylation, histone modification and microRNA in toxicity of TCE according to the newly published articles, so as to provide new ideas for further revealing the mechanism of TCE exposure affecting health.


Assuntos
Neoplasias , Tricloroetileno , Metilação de DNA , Epigênese Genética , Humanos , Solventes , Tricloroetileno/toxicidade
4.
Toxicol Appl Pharmacol ; 424: 115597, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051218

RESUMO

Trichloroethene (TCE), a widely used industrial solvent, is associated with the development of autoimmune diseases (ADs), including systemic lupus erythematosus and autoimmune hepatitis. Increasing evidence support a linkage between altered gut microbiome composition and the onset of ADs. However, it is not clear how gut microbiome contributes to TCE-mediated autoimmunity, and initial triggers for microbiome-host interactions leading to systemic autoimmune responses remain unknown. To achieve this, female MRL+/+ mice were treated with 0.5 mg/ml TCE for 52 weeks and fecal samples were subjected to 16S rRNA sequencing to determine the microbiome composition. TCE exposure resulted in distinct bacterial community revealed by ß-diversity analysis. Notably, we observed reduction in Lactobacillaceae, Rikenellaceae and Bifidobacteriaceae families, and enrichment of Akkermansiaceae and Lachnospiraceae families after TCE exposure. We also observed significantly increased colonic oxidative stress and inflammatory markers (CD14 and IL-1ß), and decreased tight junction proteins (ZO-2, occludin and claudin-3). These changes were associated with increases in serum antinuclear and anti-smooth muscle antibodies and cytokines (IL-6 and IL-12), together with increased PD1 + CD4+ T cells in TCE-exposed spleen and liver tissues. Importantly, fecal microbiota transplantation (FMT) using feces from TCE-treated mice to antibiotics-treated mice induced increased anti-dsDNA antibodies and hepatic CD4+ T cell infiltration in the recipient mice. Our studies thus delineate how imbalance in gut microbiome and mucosal redox status together with gut inflammatory response and permeability changes could be the key factors in contributing to TCE-mediated ADs. Furthermore, FMT studies provide a solid support to a causal role of microbiome in TCE-mediated autoimmunity.


Assuntos
Autoimunidade/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Tricloroetileno/toxicidade , Animais , Esquema de Medicação , Feminino , Microbioma Gastrointestinal/fisiologia , Inflamação , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Estresse Oxidativo , Baço/efeitos dos fármacos
5.
Toxicology ; 457: 152804, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33930529

RESUMO

Trichloroethene (TCE) exposure is associated with the induction of autoimmune diseases (ADs). Although oxidative stress plays a major role in TCE-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Dysregulation of redox-sensitive nuclear factor (erythroid-derived 2)-like2 (Nrf2), resulting in uncontrolled antioxidant and cytoprotective genes, and pro-inflammatory MAPK signaling pathways could be critical in TCE-mediated disease progression. This study was, therefore, focused on establishing status and contribution of Nrf2 and MAPK signaling in TCE-mediated inflammatory and autoimmune responses, especially during disease progression. To achieve these objectives, time-response studies were conducted by treating female MRL+/+ mice with TCE (0.5 mg/mL, a dose relevant to human exposure) for 24, 36 and 52 wks. TCE exposure led to reduction in Nrf2 expression, but increased phos-NF-κB (p65) and iNOS along with increased phosphorylation of MAPKs (p38, ERK and JNK) and downstream pro-inflammatory cytokines IL-12, TNF-α and RANTES in the livers in a time-dependent manner. These changes were also associated with time-dependent increases in liver protein carbonyls and induction of serum anti-dsDNA antibodies (marker of systemic lupus erythematosus disease), further supporting the role of oxidative stress and Nrf2/MAPK signaling in TCE-mediated autoimmune response progression. The mechanistic role of MAPK in TCE-mediated autoimmunity was further established by treating MRL+/+ mice with sulforaphane (SFN; 8 mg/kg, i.p., every other day) along with TCE (10 mmol/kg, i.p., every 4th day) for 6 wks using an established protocol, and by in vitro treatment of T cells with dichloroacetyl chloride (a TCE metabolite) with/without p38 MAPK inhibitor. SFN treatment attenuated the TCE-mediated phosphorylation of p38 MAPK. More importantly, treatment with SFN or p38 inhibitor led to suppression of downstream pro-inflammatory cytokines IL-12 and TNF-α. These findings thus support the contribution of Nrf2 and MAPK signaling pathways and help in delineating novel potential therapeutic targets against TCE-mediated autoimmunity.


Assuntos
Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/metabolismo , Progressão da Doença , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Tricloroetileno/toxicidade , Animais , Doenças Autoimunes/imunologia , Feminino , Humanos , Células Jurkat , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Transgênicos , Oxirredução/efeitos dos fármacos , Solventes/toxicidade
6.
Artigo em Chinês | MEDLINE | ID: mdl-33535331

RESUMO

Objective: To observe the expressions of complement 3 (C3) and endothelial cell injury-associated proteins before and after cathepsin L (CTSL) blockade in renal injury of trichloroethylene (TCE) -sensitized mice. Methods: In June 2018, 41 SPF female BALB/c mice were divided respectively into blank control group (n=5) , vehicle control group (n=5) , TCE group (n=15) and TCE+CTSLi group (n=16) to establish trichloroethylene-sensitized mice model by pretreating the mice with intraperitoneal injection of CTSL inhibitor (CTSLi) and using TCE for the first and last challenge. According to the skin sensitization score, the mice were divided into positive group and negative group. 72 hours after the last challenge, the renal function indexes of the mice were detected, the pathological changes of mice kidneys were observed, and the glomerular C3 and endothelial cell damage-related proteins [vascular cell adhesion molecule 1 (VCAM-1) , tight junction protein 5 (Claudin-5) and Syndecan-1] expression levels were detected. Results: The sensitization rates of mice in TCE group and TCE+CTSLi group were 53.3% (8/15) and 50.0% (8/16) , respectively, and there was no significant difference between the two groups (P>0.05) . Compared with vehicle control group and the corresponding TCE negative group, the serum creatinine (CRE) and blood urea nitrogen (BUN) levels of mice in the TCE positive group was increased, while the TCE positive group were higher than the TCE+CTSLi positive group (P<0.05) . Pathological examination showed obvious vacuolar degeneration and cellular edema in the mice kidney of the TCE positive group. In the TCE+CTSLi positive group, the above pathological damage was significantly improved. Immunohistochemical results showed that the expression of glomerular C3 fragment and VCAM-1 in TCE positive group were significantly higher than that of the vehicle control and TCE negative group (P<0.05) , while TCE+CTSLi positive group was significantly lower than that of TCE positive group (P<0.05) . Western blot test results showed that the relative expression levels of Claudin-5 and Syndecan-1 protein in the mice glomeruli of TCE positive group were significantly lower than those in the vehicle control group and TCE negative group (P<0.05) . Compared with the TCE positive group, the Claudin-5 protein was increased in the kidney of the TCE+CTSLi positive group, but the difference was not statistically significant (P>0.05) , while the Syndecan-1 protein was significantly increased in the TCE+CTSLi positive group (P<0.05) . Conclusion: CTSL may mediate the glomerular structural damage by cutting complement C3, activating the complement system, damaging endothelial cell structural protein Syndecan-1 and overexpressing adhesion molecule VCAM-1 in TCE-sensitized mice. Inhibiting the expression of CTSL may be an effective way to protect the glomerular integrity of structure and function in pharmacology.


Assuntos
Tricloroetileno , Animais , Catepsina L , Complemento C3 , Células Endoteliais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Tricloroetileno/toxicidade
7.
Toxicology ; 452: 152697, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524428

RESUMO

Trichloroethylene (TCE), a prevalent environmental contaminant, has been shown to induce cardiac malformations. Resveratrol (RSV) is a natural polyphenolic compound exhibiting protective effects on heart development. To investigate if RSV could protect against TCE-induced heart defects, we exposed zebrafish embryos to TCE (10 ppb) in the presence or absence of RSV (1 µg/mL). Our results showed that RSV significantly attenuated TCE-induced heart defects in zebrafish embryos. The TCE-induced ROS (reactive oxygen species) generation, 8-OHdG (8-hydroxy-2`-deoxyguanosine) formation and cell proliferation were significantly counteracted by RSV. Moreover, RSV attenuated the TCE-induced changes in mRNA expression or activity of genes involved in AHR and Nrf2 signal pathways. We further showed that RSV might inhibit TCE-enhanced cell proliferation by rescuing the downregulation of the p53/p21 axis. In conclusion, our data demonstrates that RSV protects against the cardiac developmental toxicity of TCE by inhibiting AHR activity, oxidative stress and cell proliferation.


Assuntos
Cardiotônicos/farmacologia , Desenvolvimento Embrionário/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/embriologia , Resveratrol/farmacologia , Tricloroetileno/toxicidade , Animais , Desenvolvimento Embrionário/fisiologia , Solventes/toxicidade , Peixe-Zebra
8.
Toxicol Appl Pharmacol ; 412: 115390, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387578

RESUMO

The kidneys are metabolically active organs with importance in several physiological tasks such as the secretion of soluble wastes into the urine and synthesizing glucose and oxidizing fatty acids for energy in fasting (non-fed) conditions. Once damaged, the metabolic capability of the kidneys becomes altered. Here, we define metabolic tasks in a computational modeling framework to capture kidney function in an update to the iRno network reconstruction of rat metabolism using literature-based evidence. To demonstrate the utility of iRno for predicting kidney function, we exposed primary rat renal proximal tubule epithelial cells to four compounds with varying levels of nephrotoxicity (acetaminophen, gentamicin, 2,3,7,8-tetrachlorodibenzodioxin, and trichloroethylene) for six and twenty-four hours, and collected transcriptomics and metabolomics data to measure the metabolic effects of compound exposure. For the transcriptomics data, we observed changes in fatty acid metabolism and amino acid metabolism, as well as changes in existing markers of kidney function such as Clu (clusterin). The iRno metabolic network reconstruction was used to predict alterations in these same pathways after integrating transcriptomics data and was able to distinguish between select compound-specific effects on the proximal tubule epithelial cells. Genome-scale metabolic network reconstructions with coupled omics data can be used to predict changes in metabolism as a step towards identifying novel metabolic biomarkers of kidney function and dysfunction.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Nefropatias/induzido quimicamente , Túbulos Renais Proximais/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Acetaminofen/toxicidade , Animais , Células Cultivadas , Bases de Dados Genéticas , Metabolismo Energético/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Gentamicinas/toxicidade , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Metaboloma/genética , Metabolômica , Dibenzodioxinas Policloradas/toxicidade , Ratos Sprague-Dawley , Tricloroetileno/toxicidade
9.
Ecotoxicol Environ Saf ; 208: 111453, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33068984

RESUMO

Trichloroethylene (TCE), an important volatile organic solvent, causes a series of toxic damage to human. Conventional genetic mechanisms cannot fully explain its toxicity and carcinogenicity, indicative of the possible involvement of epigenetic mechanisms. Our study was intended to investigate the epigenetic toxicity and underlying mechanisms of TCE. Data showed that 0.3 mM TCE treatment for 24 h increased the growth of L-02 cells transiently. In contrast, subacute exposure to TCE inhibited cell growth and induced the genomic DNA hypomethylation and histone hyperacetylation. Further studies have revealed the TCE-induced DNA hypomethylation in the promoter regions of tumor-related genes, N-Ras, c-Jun, c-Myc, c-Fos and IGF-II, promoting their protein levels in a time-dependent manner. These results reveal there is a negative relationship existing between DNA hypomethylation and protein expression in tumor-related gene after TCE exposure under specific epigenetic microenvironment, serving as early biomarkers for TCE-associated diseases.


Assuntos
Epigênese Genética/fisiologia , Solventes/toxicidade , Tricloroetileno/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Metilação de DNA/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Histonas/metabolismo , Humanos , Neoplasias , Microambiente Tumoral/efeitos dos fármacos
10.
Ecotoxicol Environ Saf ; 208: 111439, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33039874

RESUMO

Trichloroethylene (TCE) induced occupational medicamentosa-like dermatitis (OMLDT) in patients is accompanied, typically, by renal damage. But the role of C5b-9 and IL-1ß in TCE-sensitized mouse renal tubular damage is unclear. This study aimed to investigate whether TCE-sensitized mouse renal tubular epithelial cell damage was induced by NLRP3 inflammasome and whether NLRP3 inflammasome was activated by sublytic C5b-9. In total, 52 specific pathogen-free BALB/c female mice, 6- to 8-week-old, were used for establishing the TCE-sensitized mouse model. Renal tubular epithelial cells were isolated and used for determining the sublytic level of C5b-9. Kidney histological examination, serum neutrophil gelatinase associated lipocalin (NGAL) level were used for kidney damage evaluation. Renal protein levels of C5b-9, NLRP3, ASC, Caspase-1, IL-1ß, and IL-18 were measured. The renal lesions, serum NGAL level, renal NLRP3, ASC, Caspase-1 and IL-1ß protein levels all increased significantly in TCE sensitized positive group. However, pretreatment with recombinant protein sCD59-Cys inhibited the expression of C5b-9, NLRP3 inflammasome, IL-1ß, IL-18, and attenuated renal tubular epithelial cell damage. The sublytic C5b-9 activated NLRP3 inflammasome and aggravated renal tubular epithelial cell damage. Pretreatment with recombinant protein sCD59-Cys blocked the expression of the NLRP3 inflammasome by inhibiting the expression of C5b-9, and alleviating renal tubular epithelial cell damage.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Solventes/toxicidade , Tricloroetileno/toxicidade , Animais , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Rim/metabolismo , Nefropatias/metabolismo , Lipocalina-2 , Camundongos , Camundongos Endogâmicos BALB C
11.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 38(10): 731-735, 2020 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-33142373

RESUMO

Objective: To investigate the changes in liver function and peripheral regulatory lymphocytes before and after treatment in patients with occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT) . Methods: In December 2019, 16 patients with OMDT (8 patients with erythema multiforme and 8 with erythema multiforme major) who were admitted from February 2017 to February 2019 were enrolled as subjects. Liver function parameters and percentages of peripheral regulatory lymphocytes were measured before and after treatment, and the changes in liver function and peripheral regulatory T and B lymphocytes and their correlation were analyzed. Results: Before treatment, compared with the healthy control group, the experimental group had significantly higher levels of alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , total bilirubin (TBIL) , direct bilirubin (DBIL) and gamma-glutamyl transpeptidase (GGT) and significantly lower levels of total protein (TP) , albumin (ALB) and cholinesterase (CHE) (P<0.05) . Compared with the healthy control group, the experimental group had significantly lower percentages of lymphocytes, CD4(+) T cells, CD4(+)CD25(+) Tregs, CD19(+)CD24(+)CD27(+) Bregs and CD4(+)/CD8(+) ratio, as well as a significantly higher percentage of CD8(+) T cells (P<0.05) . Before treatment, the levels of ALT, AST, GGT and DBIL were negatively correlated with the percentages of CD4(+)CD25(+) Tregs, CD19(+)CD24(+)CD27(+) Bregs, CD4(+) T cells and CD4(+)/CD8(+) ratio (r=-0.386 to -0.809, P<0.05) and was positively correlated with the percentage of CD8(+) T cells (except DBIL) (r=0.503-0.568, P<0.05) . The levels of TP and ALB were positively correlated with the percentages of CD4(+)CD25(+) Tregs, CD19(+)CD24(+)CD27(+)Bregs and CD4(+) T cells (r= 0.351-0.784, P<0.05) , ALB was negatively correlated with the percentage of CD8(+) T cells (r=-0.315, P<0.05) . CHE was positively correlated with the percentages of CD4(+)CD25(+) Tregs, CD19(+)CD24(+)CD27(+)Bregs and CD4(+)/CD8(+) ratio (r=0.390-0.527, P<0.05) . Conclusion: Immune dysfunction is observed in patients with OMDT, which may be caused by the imbalance of regulatory lymphocytes. And liver injury may be associated with the increase of CD8(+) T cells and the reductions of percentages of CD4(+) T cells, CD4(+)CD25(+) Tregs, CD19(+)CD24(+)CD27(+)Bregs and CD4(+)/CD8(+) ratio.


Assuntos
Linfócitos B Reguladores , Dermatite Ocupacional , Tricloroetileno , Linfócitos T CD8-Positivos , Humanos , Linfócitos T Reguladores , Tricloroetileno/toxicidade
12.
Toxicol Appl Pharmacol ; 408: 115258, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007382

RESUMO

Previous studies in MRL+/+ mice suggest involvement of oxidative stress (OS) in trichloroethene (TCE)-mediated autoimmunity. However, molecular mechanisms underlying the autoimmunity remain to be fully elucidated. Even though toll-like receptors (TLRs) and Nuclear factor (erythroid-derived 2)-like2 (Nrf2) pathways are implicated in autoimmune diseases (ADs), interplay of OS, TLR and Nrf2 in TCE-mediated autoimmune response remains unexplored. This study was, therefore, undertaken to clearly establish a link among OS, TLR4 and Nrf2 pathways in TCE-induced autoimmunity. Groups of female MRL+/+ mice were treated with TCE, sulforaphane (SFN, an antioxidant) or TCE + SFN (TCE, 10 mmol/kg, i.p., every 4th day; SFN, 8 mg/kg, i.p., every other day) for 6 weeks. TCE exposure led to greater formation of serum 4-hydroxynonenal (HNE)-protein adducts, HNE-specific circulating immune complexes (CICs) and protein carbonyls which were associated with significant increases in serum antinuclear antibodies (ANAs). Moreover, incubation of splenocytes from TCE-treated mice with HNE-modified proteins resulted in enhanced splenocyte proliferation and cytokine release evidenced by increased expression of cyclin D3, Cyclin-dependent kinase 6 (CDK6) and phospho-pRb as well as increased release of IL-6, TNF-α and INF-γ. More importantly, TCE exposure resulted in increased expression of TLR4, MyD88, IRAK4, NF-kB and reduced expression of Nrf2 and HO-1 in the spleen. Remarkably, SFN supplementation not only attenuated TCE-induced OS, upregulation in TLR4 and NF-kB signaling and downregulation of Nrf2, but also ANA levels. These results, in addition to providing further support to a role of OS, also suggest that an interplay among OS, TLR4 and Nrf2 pathways contributes to TCE-mediated autoimmune response. Attenuation of TCE-mediated autoimmunity by SFN provides an avenue for preventive and/or therapeutic strategies for ADs involving OS.


Assuntos
Autoimunidade/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Estresse Oxidativo/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Tricloroetileno/toxicidade , Animais , Feminino , Camundongos , NF-kappa B/imunologia , Baço/citologia , Baço/imunologia
13.
Environ Res ; 191: 109972, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32758551

RESUMO

Occupational trichloroethylene (TCE) exposure can cause hypersensitivity syndrome (TCE-HS). The human leukocyte antigen (HLA)-B*13:01 is reportedly an important allele involved in TCE-HS onset. However, the threshold exposure level causing TCE-HS in relation to HLA-B*13:01 remains unknown. We conducted a case-control study comprising 37 TCE-HS patients and 97 age- and sex-matched TCE-tolerant controls from the Han Chinese population. Urine and blood of patients were collected on the first day of hospitalization, and those of controls were collected at the end of their shifts. Urinary trichloroacetic acid (TCA) was measured as an exposure marker, and end-of-shift levels in the patients were estimated using the biological half-life of 83.7 h. HLA-B genotype was identified using DNA from blood. Crude odds ratios (ORs) for TCE-HS in the groups with urinary TCA concentration >15 mg/L to ≤50 mg/L and of >50 mg/L were 21.9 [95% confidence interval (CI) 4.2-114.1] and 27.6 (6.1-125.8), respectively, when the group with urinary TCA ≤15 mg/L was used as a reference. The frequency of HLA-B*13:01, the most common allele in the patients, was 62.2% (23/37), which was significantly higher than 17.5% (17/97) in the TCE-tolerant controls, with a crude OR of 8.4 (3.1-22.6). The mutually-adjusted ORs for urinary TCA >15 to ≤50 mg/L, >50 mg/L, and for HLA-B*13:01 were 33.4 (4.1-270.8), 34.0 (5.3-217.1), and 11.0 (2.4-50.7), respectively. In conclusion, reduction of TCE exposure to ≤15 mg/L is required for TCE-HS prevention because urinary TCA concentration >15 mg/L showed increased risk of TCE-HS, regardless of whether the patients had the HLA-B*13:01 allele.


Assuntos
Exposição Ocupacional , Tricloroetileno , Alelos , Estudos de Casos e Controles , Antígenos HLA-B/genética , Humanos , Exposição Ocupacional/efeitos adversos , Ácido Tricloroacético , Tricloroetileno/análise , Tricloroetileno/toxicidade
14.
Toxicol Lett ; 333: 130-139, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763311

RESUMO

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE+) mice. Renal dysfunction and pathological damage were also clearly observed in TCE+ mice. Moreover, the mRNA and protein expression of ET-1 increased significantly with local renal complement activation after TCE sensitisation, leading to cytokines release and inflammation. In addition, activation of p38MAPK and NF-κBp65 pathways were detected in kidneys of TCE+ mice, and CatLi pretreatment decreased these changes through complement activation antagonisation. Our research uncovered a novel role of local renal complement activation during immune kidney injury after TCE sensitisation through induction of ET-1 signalling and inflammation.


Assuntos
Ativação do Complemento/imunologia , Endotelina-1/metabolismo , Hipersensibilidade/metabolismo , Rim/efeitos dos fármacos , Insuficiência Renal/metabolismo , Tricloroetileno/toxicidade , Animais , Ativação do Complemento/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipersensibilidade/imunologia , Inflamação , Rim/imunologia , Rim/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/efeitos dos fármacos , NF-kappa B/imunologia , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/imunologia , Transdução de Sinais
15.
J Occup Health ; 62(1): e12142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32799435

RESUMO

OBJECTIVES: Occupational exposure to trichloroethylene (TCE) induces trichloroethylene hypersensitivity syndrome (TCEHS), which causes hypersensitivity dermatitis and hepatitis. However, whether TCE itself or its two metabolites, trichloroethanol (TCEOH) and trichloroacetic acid (TCA), are involved in TCEHS remains unclear. Therefore, in this study we explored the allergens causing TCEHS and characterized TCEHS-related liver injury in guinea pigs. METHOD: The guinea pig maximization test was performed using TCE, TCEOH, and TCA as candidate allergens. Skin inflammation was scored, and liver function and histopathological changes were evaluated by biochemical tests and hematoxylin and eosin staining, respectively. RESULTS: The sensitization rates for TCE, TCEOH, and TCA were 90.0%, 50.0%, and 0.0%, respectively. In the TCE and TCEOH experimental groups, the skin showed varying degrees of erythema with eosinophil granulocyte infiltration in the dermis. Additionally, serum alanine aminotransferase and γ-glutamyl transpeptidase levels increased significantly, and histological analysis revealed focal hepatocellular necrosis with inflammatory cell infiltration in the liver. CONCLUSIONS: TCE is the main cause of allergy and TCEOH is a secondary factor for allergy in guinea pigs. TCE and TCEOH can cause immune-mediated skin sensitization complicated by focal hepatic necrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Etilenocloroidrina/análogos & derivados , Necrose/induzido quimicamente , Dermatopatias/induzido quimicamente , Ácido Tricloroacético/toxicidade , Tricloroetileno/toxicidade , Animais , Etilenocloroidrina/toxicidade , Feminino , Cobaias , Hipersensibilidade/etiologia , Exposição Ocupacional
16.
Chemosphere ; 251: 126610, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32443250

RESUMO

Trichloroethylene (TCE), a widely used organic solvent, is a common environmental pollutant. Increasing evidence indicates that maternal TCE exposure is associated with congenital cardiac defects, but the underlining mechanisms remain largely unknown. In this study, we revealed that TCE exposure significantly induced heart defects and dysfunctions in zebrafish embryos. Heart tissues were dissected and subjected to high throughput sequencing and qPCR to identify differentially expressed miRNAs and mRNAs. The effects of miRNA were further verified by microinjection of antagomir or agomir. Reactive Oxygen Species (ROS) and cell proliferation were measured by using dichlorodihydrofluorescein diacetate (DCFH-DA) and EdU staining, respectively. Our results showed that 19 miRNAs were downregulated whereas 48 miRNAs were upregulated in the heart of zebrafish embryos. The downregulation of miR-133a and the upregulation of miR-182 were further validated. Moreover, we found that miR-133a agomir significantly alleviated the TCE-induced heart defects while miR-133a antagomir mimicked the toxic effect of TCE on heart development. Furthermore, miR-133a agomir significantly counteracted TCE-induced ROS production and excessive cell proliferation in the heart of zebrafish embryos. In conclusion, our results indicate that miR-133a mediates TCE-induced ROS generation, leading to excessive cell proliferation and heart defects.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Coração/efeitos dos fármacos , MicroRNAs/genética , Tricloroetileno/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Cardiotoxicidade , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Coração/embriologia , Cardiopatias Congênitas/genética , Regulação para Cima
17.
Ecotoxicology ; 29(6): 801-813, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445014

RESUMO

Trichloroethylene (TCE) is the most ubiquitous halogenated organic pollutant in the environment, it is one of the 129 priority control pollutants. In order to clarify the influence of TCE on microorganisms and nitrogen transformation in Mollisol is the core purpose of this study. Results showed that 10 mg kg-1 TCE is the concentration limit of ammonification in Mollisol. When the concentration of TCE reached 10 mg kg-1 and the effect lasted for over 7 days, the process of ammonia oxidation to nitric acid in Mollisol will be affected. TCE affected the process of nitrate (NO3-) transformation into nitrite (NO2-) by affecting the activity of nitrate reductase, thereby affected the denitrification process in soil. When the concentration of TCE is more than 10 mg kg-1 it reduced the ability of soil microorganisms to obtain nitrogen, thereby affecting soil nitrogen transformation. RDA (Redundancy analysis) showed that the activity of nitrate reductase and the number of nitrifying bacteria and denitrifying bacteria in soil was negatively correlated with the incubation of TCE. In addition, soil nitrate reductase, nitrite reductase, peroxidase activity, ammonifying bacteria, nitrifying bacteria and denitrifying bacteria were negatively correlated with TCE concentration. Beyond that PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) of functional gene structure depend on KEGG (Kyoto Encyclopedia of Genes and Genomes) showed that 20 mg kg-1 TCE significantly inhibited the metabolism of energy and other substances in Mollisol. Based on the above, it is found that TCE significantly affected nitrification and denitrification in Mollisol, thus the nitrogen transformation in Mollisol was affected by TCE contamination.


Assuntos
Microbiota/efeitos dos fármacos , Nitrificação/efeitos dos fármacos , Poluentes do Solo/toxicidade , Tricloroetileno/toxicidade , Biodegradação Ambiental/efeitos dos fármacos , Nitrogênio , Microbiologia do Solo
18.
Environ Sci Process Impacts ; 22(3): 824-832, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159184

RESUMO

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 µM Benfluorex, 5 µM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.


Assuntos
Tricloroetileno/toxicidade , Animais , Feminino , Coração/embriologia , Fator 4 Nuclear de Hepatócito/genética , Camundongos , Gravidez
19.
Toxicology ; 436: 152427, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32145346

RESUMO

The hypothesis that in utero exposures to low levels of trichloroethylene (TCE) may increase the risk of congenital heart defects (CHDs) in offspring remains a subject of substantial controversy within the scientific community due primarily to the reliance on an inconsistent and unreproducible experimental study in rats. To build on previous assessments that have primarily focused on epidemiological and experimental animal studies in developing conclusions, the objective of the current study is to conduct a systematic evaluation of mechanistic data related to in utero exposures to TCE and the development of CHDs. The evidence base was heterogeneous; 79 mechanistic datasets were identified, characterizing endpoints which ranged from molecular to organismal responses in seven species, involving both in vivo and in vitro study designs in mammalian and non-mammalian models. Of these, 24 datasets were considered reliable following critical appraisal using a study quality tool that employs metrics specific to the study type. Subsequent synthesis and integration demonstrated that the available mechanistic data: 1) did not support the potential for CHD hazard in humans, 2) did not support the biological plausibility of a response in humans based on organization via a putative adverse outcome pathway for valvulo-septal cardiac defects, and 3) were not suitable for serving as candidate studies in risk assessment. Findings supportive of an association were generally limited to in ovo chicken studies, in which TCE was administered in high concentration solutions via direct injection. Results of these in ovo studies were difficult to interpret for human health risk assessment given the lack of generalizability of the study models (including dose relevance, species-specific biological differences, variations in the construct of the study design, etc.). When the mechanistic data are integrated with findings from previous evaluations of human and animal evidence streams, the totality of evidence does not support CHDs as a critical effect in TCE human health risk assessment.


Assuntos
Coração Fetal/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Exposição Materna/efeitos adversos , Solventes/toxicidade , Testes de Toxicidade , Tricloroetileno/toxicidade , Animais , Determinação de Ponto Final , Feminino , Cardiopatias Congênitas/embriologia , Humanos , Gravidez , Medição de Risco
20.
Environ Sci Process Impacts ; 22(3): 472-486, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32022077

RESUMO

Trichloroethylene (TCE) is an industrial solvent and a common environmental contaminant detected in thousands of hazardous waste sites. Risk of exposure is a concern for workers in occupations that use TCE as well as for residents who live near industries that use TCE or who live near TCE-contaminated sites. Although renal, hepatic and carcinogenic effects of TCE have been documented, less is known about TCE impacts on reproductive functions despite epidemiology reports associating maternal TCE exposure with adverse pregnancy outcomes. Toxicological evidence suggests that the placenta mediates at least some of the adverse pregnancy outcomes associated with TCE exposure. Toxicology studies show that the TCE metabolite, S-(1,2-dichlorovinyl)-l-cysteine (DCVC) generates toxic effects such as mitochondrial dysfunction, apoptosis, oxidative stress, and release of prostaglandins and pro-inflammatory cytokines in placental cell lines. Each of these mechanisms of toxicity have significant implications for placental functions and, thus, ultimately the health of mother and developing child. Despite these findings there remain significant gaps in our knowledge about effects of TCE on the placenta, including effects on specific placental cell types and functions as well as sex differences in response to TCE exposure. Due to the critical role that the placenta plays in pregnancy, future research addressing some of these knowledge gaps could lead to significant gains in public health.


Assuntos
Placenta/efeitos dos fármacos , Tricloroetileno/toxicidade , Criança , Cisteína , Feminino , Humanos , Masculino , Estresse Oxidativo , Gravidez , Solventes
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