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1.
Sci Total Environ ; 715: 136805, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32041038

RESUMO

Aryl hydrocarbon receptor (AhR) plays important roles in the interferences of dioxin exposure with the occurrence and development of tumors. Neuroblastoma is a kind of malignant tumor with high mortality and its occurrence is getting higher in dioxin exposed populations. However, there is still a lack of direct evidence of influences of dioxin on neuroblastoma cell migration. SK-N-SH is a human neuroblastoma cell line which has been used to reveal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced dysregulation of certain promigratory gene. Thus, in this study, we employed SK-N-SH cells to investigate the effects of TCDD on the spontaneous movement of neuroblastoma cells, which is a short-range cell migratory behavior related to clone formation and tumor metastasis in vitro. Using unlabeled live cell imaging and high content analysis, we characterized the spontaneous movement under a full-nutrient condition in SK-N-SH cells. We found that the spontaneous movement of SK-N-SH cells was inhibited after 36- or 48-h treatment with TCDD at relative low concentrations (10-10 or 2 × 10-10 M). The TCDD-treated cells were unable to move as freely as that of control cells, resulting in less diffusive trajectories and a decreased displacement of the movement. In line with this cellular effect, the expression of pro-adhesive genes was significantly induced in time- and concentration-dependent manners after TCDD treatment. In addition, with the presence of AhR antagonist, CH223191, the effects of TCDD on the gene expression and the spontaneous cell movement were effectively reversed. Thus, we proposed that AhR-mediated up-regulation of pro-adhesive genes might be involved in the inhibitory effects of dioxin on the spontaneous movement of neuroblastoma cells. To our knowledge, this is the first piece of direct evidence about the influence of dioxin on neuroblastoma cell motility.

2.
Chem Res Toxicol ; 33(3): 731-741, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32077278

RESUMO

Traditional toxicity testing reliant on animal models is costly and low throughput, posing a significant challenge with the increasing numbers of chemicals that humans are exposed to in the environment. The purpose of this investigation was to build optimal prediction models for various human in vivo/organ-level toxicity end points (extracted from ChemIDPlus) using chemical structure and Tox21 in vitro quantitative high-throughput screening (qHTS) bioactivity assay data. Several supervised machine learning algorithms were applied to model 14 human toxicity end points pertaining to vascular, kidney, ureter and bladder, and liver organ systems. Three metrics were used to evaluate model performance: area under the receiver operating characteristic curve (AUC-ROC), balanced accuracy (BA), and Matthews correlation coefficient (MCC). The top four models, with AUC-ROC values >0.8, were derived for endocrine (0.90 ± 0.00), musculoskeletal (0.88 ± 0.02), peripheral nerve and sensation (0.85 ± 0.01), and brain and coverings (0.83 ± 0.02) toxicities, whereas the best model AUC-ROC values were >0.7 for the remaining 10 toxicities. Model performance was found to be dependent on the specific data set, model type, and feature selection method used. In addition, chemical structure and assay data showed different levels of contribution to the prediction of different toxicity end points. Although in vitro assay data, when combined with chemical structure, slightly improved the predictive accuracy for most end points (11 out of 14), a noteworthy finding was the near equal success of the structure-only models, which do not require Tox21 qHTS screening data, and the relatively poor performance of assay-only models. Thus, the top-performing structure-only models from this study could be applied for hazard screening of large sets of chemicals for potential human toxicity, whereas the largest assay contributions to models (i.e., cellular targets) could be used, along with the top-contributing structural features, to provide insight into toxicity mechanisms.

3.
Environ Int ; 134: 105193, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31775093

RESUMO

Dioxin exposure is reported to affect nervous system development and increase the risk of neurodegenerative diseases. Generally, dioxin exerts its neurotoxicity via aryl hydrocarbon receptor (AhR). Neurofilament (NF) light (NFL) protein is a biomarker for both neuronal differentiation and neurodegeneration and its expression is controlled by the mitogen-activated protein kinase (MAPK) pathway. However, the effects of dioxin on NFL expression and involved mechanisms are incompletely understood. We aimed to investigate the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on NFL expression and elucidate the underlining signaling pathways and their potential crosstalk, specifically between MAPK and AhR pathway. We employed primary cultured rat cortical neurons to evaluate the effect of TCDD exposure on NFL expression. We also used nerve growth factor (NGF)-treated PC12 cells with specific inhibitors to investigate the involvement of and potential crosstalk between the MAPK pathway and the AhR pathway in mediating the effects of TCDD on NFL expression. After TCDD exposure, NFL mRNA and protein levels were upregulated in cultured neurons. NFL protein was preferentially found in the cell body compared with neurites of the cultured neurons. In PC12 cells, TCDD enhanced both NGF-induced NFL expression and phosphorylation of ERK1/2 and p38. The addition of MAPK-pathway inhibitors (PD98059 and SB230580) partially blocked the TCDD-induced NFL upregulation. CH223191, an AhR antagonist, reversed the upregulation of NFL and phosphorylation of ERK1/2 and p38 induced by TCDD. This study demonstrated TCDD-induced upregulation of NFL in cultured neurons, with protein retained in the cell body. TCDD action was dependent on activation of AhR and MAPK, while crosstalk was found between these two signaling pathways.

4.
Toxicol Lett ; 311: 49-57, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31014974

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, is a persistent and ubiquitous environmental contaminant. Although the immunotoxic effects of TCDD have been reported, the mechanisms underlying these effects are still unclear. In this study, we have determined the toxic effects of TCDD on thymocytes and splenic T cells with in vitro cell culture systems. Magnetically isolated mouse splenic Th cells, Treg cells and the mixed spleen lymphocytes (SLC) were cultured and treated with TCDD and the differentiation of CD4 Th cells was determined by flow cytometery. Our results showed that different concentrations of TCDD caused immunotoxic effects through different toxicological mechanisms in both the purified mouse splenic Th cells and the mixed SLC. The low dose exposure to TCDD triggered regulatory effects in the immune system, while the high dose TCDD exposure resulted in severe immune toxicity. Notably, a decline of Treg subset was observed, suggesting an imbalanced immune regulation by TCDD treatment, as well as a possible decrease of TCDD's indirect effects on bystander immune cells. Our CD4 Th subset co-culture experiments showed that TCDD-induced pathobiology depended on immune cell balance, suggesting that cytokine-induced microenvironments further modulated toxic effects associated with TCDD exposure.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Baço/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Timócitos/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Microambiente Celular , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timócitos/imunologia , Timócitos/metabolismo
5.
Environ Pollut ; 246: 141-147, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30537652

RESUMO

Dechlorane 602 (Dec 602), a chlorinated flame retardant, has been widely detected in different environmental matrices and biota. However, toxicity data for Dec 602 seldom have been reported. A metabolomics study based on ultra-high performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry was employed to study the urine and sera metabolic profiles of mice administered with Dec 602 (0, 0.001, 0.1, and 10 mg/kg body weight per day) for 7 days. A significant difference in metabolic profiling was observed between the Dec 602 treated group and the control group by multivariate analysis, which directly reflected the metabolic perturbations caused by Dec 602. The metabolomics analyses of urine from Dec 602-exposed animals exhibited an increase in the levels of thymidine and tryptophan as well as a decrease in the levels of tyrosine, 12,13-dihydroxy-9Z-octadecenoic acid, 2-hydroxyhexadecanoic acid and cuminaldehyde. The metabolomics analyses of sera showed a decrease in the levels of kynurenic acid, daidzein, adenosine, xanthurenic acid and hypoxanthine from Dec 602-exposed animals. These findings indicated Dec 602 induced disturbance in phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan metabolism, tyrosine metabolism, pyrimidine metabolism, purine metabolism, ubiquinone and other terpenoid-quinone biosynthesis; phenylalanine metabolism and aminoacyl-tRNA biosynthesis. Significant alterations of immune and neurotransmitter-related metabolites (tyrosine, tryptophan, kynurenic acid, and xanthurenic acid) suggest that the toxic effects of Dec 602 may contribute to its interactions with the immune and neuronal systems. This study demonstrated that the UHPLC-ESI-IT-TOF-MS-based metabolomic approach can obtain more specific insights into the potential toxic effects of Dec 602 at molecular level.


Assuntos
Cromatografia Líquida de Alta Pressão , Biomarcadores Ambientais/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Hidrocarbonetos Clorados/toxicidade , Espectrometria de Massas , Metaboloma/efeitos dos fármacos , Compostos Policíclicos/toxicidade , Animais , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica , Camundongos , Análise Multivariada
6.
Transl Oncol ; 12(3): 441-452, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30576957

RESUMO

Heterogeneous response to chemotherapy is a major issue for the treatment of cancer. For most gynecologic cancers including ovarian, cervical, and placental, the list of available small molecule therapies is relatively small compared to options for other cancers. While overall cancer mortality rates have decreased in the United States as early diagnoses and cancer therapies have become more effective, ovarian cancer still has low survival rates due to the lack of effective treatment options, drug resistance, and late diagnosis. To understand chemotherapeutic diversity in gynecologic cancers, we have screened 7914 approved drugs and bioactive compounds in 11 gynecologic cancer cell lines to profile their chemotherapeutic sensitivity. We identified two HDAC inhibitors, mocetinostat and entinostat, as pan-gynecologic cancer suppressors with IC50 values within an order of magnitude of their human plasma concentrations. In addition, many active compounds identified, including the non-anticancer drugs and other compounds, diversely inhibited the growth of three gynecologic cancer cell groups and individual cancer cell lines. These newly identified compounds are valuable for further studies of new therapeutics development, synergistic drug combinations, and new target identification for gynecologic cancers. The results also provide a rationale for the personalized chemotherapeutic testing of anticancer drugs in treatment of gynecologic cancer.

7.
Environ Int ; 121(Pt 1): 906-915, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30347373

RESUMO

Autism spectrum disorder (ASD) has emerged as a major public health concern due to its fast-growing prevalence in recent decades. Environmental factors are thought to contribute substantially to the variance in ASD. Interest in environmental toxins as causes of ASD has arisen due to the high sensitivity of the developing human brain to toxic chemicals, particularly to dioxin and certain dioxin-like compounds (dioxins). As a group of typical persistent organic pollutants, dioxins have been found to exert adverse effects on human brain development. In this paper, we review the evidence for association of exposure to dioxins with neurodevelopmental abnormalities related to ASD based on both human epidemiological and animal studies. It has been documented that exposure to dioxins during critical developmental periods increased risk for ASD. This notion has been demonstrated in different populations exposed to high or background level of dioxins. Furthermore, the effects and mechanisms of action of dioxins relevant to the pathophysiology and pathogenesis of ASD are summarized, describing potential underlying mechanisms linking dioxin exposure with ASD onset. Further studies focusing on effects of prenatal/perinatal exposure to individual dioxin congeners or to mixtures of dioxins on ASD-associated behavioral and neurobiological consequences in animal models, and on the mechanisms of actions of dioxins, are needed in order to better understand how dioxin exposure might contribute to increased risk for ASD.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Dioxinas/toxicidade , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Animais , Humanos , Fatores de Risco
8.
Environ Sci Technol ; 52(15): 8065-8074, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29995397

RESUMO

Acetylcholinesterase (AChE, EC 3.1.1.7) is a classical biomarker for monitoring contamination and intoxication of organophosphate (OP) and carbamate pesticides. In addition to these classical environmental AChE inhibitors, other organic toxic substances have been found to alter AChE activity in various species. These emerging organic AChE disruptors include certain persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs), and wildly used chemicals, most of which have received considerable public health concern in recent years. It is necessary to re-evaluate the environmental significances of AChE in terms of these toxic substances. Therefore, the present review is aiming to summarize correlations of AChE activity of certain organisms with the level of the contaminants in particular habitats, disruptions of AChE activity upon treatment with the emerging disruptors in vivo and in vitro, and action mechanisms underlying the effects on AChE. Over 40 chemicals belonging to six main categories were reviewed, including 12 POPs listed in the Stockholm Convention. AChE activity in certain organisms has been found to be well correlated with the contamination level of certain persistent pesticides and PAHs in particular habitats. Moreover, it has been documented that most of the listed toxic chemicals could inhibit AChE activity in diverse species ranging from invertebrates to mammals. Besides directly inactivating AChE, the mechanisms in terms of interference with the biosynthesis have been recognized for some emerging AChE disruptors, particularly for dioxins. The collected evidence suggests that AChE could serve as a potential biomarker for a diverse spectrum of organic environmental pollutants.


Assuntos
Poluentes Ambientais , Praguicidas , Poluentes Químicos da Água , Acetilcolinesterase , Animais , Biomarcadores , Monitoramento Ambiental
9.
Environ Pollut ; 235: 965-973, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29751400

RESUMO

Dioxin-induced toxicities that affect the development of the motor system have been proposed since many years. However, cellular evidence and the molecular basis for the effects are limited. In this study, a cultured mouse myoblast cell line, C2C12, was utilized to examine the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on myogenic differentiation and expression of acetylcholinesterase (AChE), a neuromuscular transmission-related gene. The results showed that TCDD exposure at 10-10 M repressed the myotube formation of C2C12 cells by disturbing the fusion process and suppressing the expression of myosin heavy chain, a myobute structural protein, and not by induction of cytotoxicity. Furthermore, TCDD dose dependently suppressed the transcriptional expression and enzymatic activity of AChE during the myogenic differentiation, particularly in the middle stage. However, the administration of aryl hydrocarbon receptor antagonists, CH223191 and alpha-naphthoflavone, did not completely reverse the TCDD-induced downregulation of muscular AChE during myogenic differentiation. These findings suggest that low dose exposure to dioxin may result in disturbances of muscle differentiation and neuromuscular transmission.


Assuntos
Substâncias Perigosas/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Animais , Compostos Azo , Benzoflavonas , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Camundongos , Pirazóis , Receptores de Hidrocarboneto Arílico/metabolismo
10.
Environ Pollut ; 237: 508-514, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29522993

RESUMO

The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Dioxinas/toxicidade , Poluentes Ambientais/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Compostos Azo , Carcinoma Hepatocelular , Dioxinas/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Pirazóis , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
11.
J Environ Sci (China) ; 63: 260-267, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29406108

RESUMO

Dioxin can cause a series of neural toxicological effects. MicroRNAs (miRs) play important roles in regulating nervous system function and mediating cellular responses to environmental pollutants, such as dioxin. Hsa-miR-146b-5p appears to be involved in neurodegenerative diseases and brain tumors. However, little is known about effects of dioxin on the expression of hsa-miR-146b-5p. We found that the hsa-miR-146b-5p expression and its promoter activity were significantly increased in dioxin treated SK-N-SH cells, a human-derived neuroblastoma cell line. Potential roles of hsa-miR-146b-5p in mediating neural toxicological effects of dioxin may be due to the regulation of certain target genes. We further confirmed that hsa-miR-146b-5p significantly suppressed acetylcholinesterase (AChE) activity and targeted the 3'-untranslated region of the AChE T subunit, which has been down-regulated in dioxin treated SK-N-SH cells. Functional bioinformatic analysis showed that the known and predicted target genes of hsa-miR-146b-5p were involved in some brain functions or cyto-toxicities related to known dioxin effects, including synapse transmission, in which AChE may serve as a responsive gene for mediating the effect.


Assuntos
Dioxinas/toxicidade , Poluentes Ambientais/toxicidade , Acetilcolinesterase/metabolismo , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , Neuroblastoma , Testes de Toxicidade
12.
Sci Rep ; 7(1): 10103, 2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28860601

RESUMO

Emerging evidence has shown that dioxin causes dysregulation of microRNAs (miRs) in a variety of tissues or cells. However, little is known about dioxin effects on neuronal miRs expression. In the present study, 277 differentially expressed miRs were identified by miRs microarray analysis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, at 10-10 M) treated SK-N-SH neuroblastoma cells. Among them, 53 miRs exhibited changes of more than 0.4-fold. Consistent with the microarray data, we verified the induction effect of TCDD on hsa-miR-608 expression, which is a primate-specific miR associated with brain functions. Bioinformatics analysis showed involvement of hsa-miR-608 in cytoskeleton organization, in which one of the hsa-miR-608 target genes, Cell Division Cycle 42 (CDC42), might play a role. We also confirmed induction of CDC42 expression by TCDD in SK-N-SH cells. TCDD induced the expression of CDC42 mRNA in hsa-miR-608 inhibitor transfected cells more obviously than in control cells, suggesting involvement of both transcriptional and post-transcriptional mechanisms in the TCDD-induced CDC42 regulation. Furthermore, CH223191, an antagonist of the aryl hydrocarbon receptor (AhR), counteracted TCDD-induced hsa-miR-608 and CDC42 expression. These results indicated that AhR not only mediates transcriptional induction of CDC42, but also hsa-miR-608-induced post-transcriptional regulation of CDC42 in dioxin treated neuroblastoma cells.


Assuntos
Poluentes Ambientais/farmacologia , Neurônios/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacologia , Proteína cdc42 de Ligação ao GTP/genética , Linhagem Celular Tumoral , Poluentes Ambientais/toxicidade , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo
13.
J Environ Sci (China) ; 51: 165-172, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28115127

RESUMO

The health risk of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like PCBs (dl-PCBs) to human being should be assessed regularly. To evaluate the contamination levels in various food products in the Chinese market and to assess the dietary exposure of the Chinese population, 11 varieties of food groups totaling 634 samples including beef and mutton, chicken and duck, pork, fish and seafood, milk and dairy products were evaluated. The average concentrations of PCDD/Fs in all groups ranged from 0.291 to 8.468pg/g whole weight (w.w.). The average toxic equivalency concentrations were from 0.012pg TEQ/g w.w. for cereal to 0.367pg TEQ/g fat for marine oil. OCDD and 2,3,7,8-TCDF were the dominant congeners in foodstuffs. The dietary estimated mean intake for the Chinese rural and urban populations were 0.656 and 0.514pg TEQ/kg body weight/day, respectively, however, the cereal group exposure were higher to the estimate daily intake and contributed 81% for rural and 48% for urban population, followed by fish and seafood which contributed 4% and 16% to the estimate daily intake. The estimated dietary intakes were compared with the toxicological reference values and showed that both rural and urban populations were well below those values.


Assuntos
Dibenzofuranos Policlorados/análise , Dieta/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/análise , Contaminação de Alimentos/análise , Dibenzodioxinas Policloradas/análise , China , Humanos
14.
J Environ Sci (China) ; 51: 324-331, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28115145

RESUMO

Feed security is a prerequisite for safe animal food products. In this study, 13 groups of feed and feed ingredients, totaling 2067 samples, were collected in the period of 2011 to 2014 from China. The highest mean level of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) was found in fish meals and shell powders, with a concentration of 60.35ng/kg, followed by mineral origin materials. In terms of the toxicity equivalent concentration, the fish oil group showed the highest PCDD/F levels because of their bio-accumulation through the aquatic food chain, with an average concentration of 1.26ng WHO-TEQ/kg, while the lowest level was observed in compound feed for chickens and pigs, with an average value of 0.16ng WHO-TEQ/kg. OCDD and OCDF were the predominant congeners in all groups except fish oils, in which the primary congeners were 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF. For zinc chloride samples, different from other zinc-based compound samples, the main congeners were 1,2,3,4,6,7,8-HpCDF (17%), 1,2,3,4,7,8,9-HpCDF (15%), 1,2,3,4,7,8-HxCDF (12%) and OCDF (30%). Considering toxicity equivalency factors, the dominant congeners were 2,3,4,7,8-PeCDF, 1, 2,3,4,7,8-HxCDF, 2,3,7,8-TCDF and 1,2,3,7,8-PeCDD, and the contribution to the total TEQ was 29%, 16%, 14% and 12%, respectively. Overall, 2.1% (43 out of 2067) of all the analyzed samples exceeded the different individual 'European Union maximum limited levels for PCDD/Fs. This study is beneficial for the determination of the status of contamination levels of feed and feed ingredients.


Assuntos
Ração Animal/análise , Dibenzofuranos Policlorados/análise , Poluentes Ambientais/análise , Contaminação de Alimentos/análise , Dibenzodioxinas Policloradas/análise , Monitoramento Ambiental , Contaminação de Alimentos/estatística & dados numéricos
15.
J Environ Sci (China) ; 62: 92-99, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29289296

RESUMO

Several cohort studies have reported that dioxin and dioxin-like polychlorinated biphenyls might impair the nervous system and lead to neurological or neurodegenerative diseases in the elder people, but there is limited research on the involved mechanism. By using microarray analysis, we figured out the differentially expressed genes between brain samples from SD rats after low-dose (0.1µg/(kg▪bw)) dioxin exposure for six months and controls. To investigate the function changes in the course of dioxin exposure, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the differentially expressed genes. And the changes of several picked genes have been verified by real-time PCR. A total of 145 up-regulated and 64 down-regulated genes were identified. The metabolic processes, interleukin-1 secretion and production were significantly associated with the differentially expressed genes. And the genes regulated by dioxin also clustered to cholinergic synapse and long-term potentiation. Candidate biomarker genes such as egr1, gad2, gabrb3, abca1, ccr5 and pycard may be toxicological targets for dioxin. Furthermore, synaptic plasticity and neuro-immune system may be two principal affected areas by dioxin.


Assuntos
Encéfalo/fisiologia , Expressão Gênica/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Animais , Ratos , Testes de Toxicidade Crônica , Regulação para Cima
16.
Chem Biol Interact ; 259(Pt B): 282-285, 2016 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-27502150

RESUMO

PC12 is a well studied cell model for neuronal differentiation. AChE is also considered as a marker for neuronal differentiation. In this study, we detected the change of AChE activity during the NGF induced differentiation of PC 12 cells, and targeted on the ratio of the activity of AChE on the cell surface, and found that NGF mainly increased the intracellular AChE activity. Dioxin is a kind of persistent organic pollutants which have extreme impact on human health and widely distributed all over the world. Recently, AChE was reported as a target of the toxicity of dioxin. Here we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on AChE activity in the PC12 cells, and found that at the later stage of differentiation, TCDD could decrease the AChE activity. This down regulation might not related to transcriptional regulation.


Assuntos
Acetilcolinesterase/metabolismo , Fator de Crescimento Neural/farmacologia , Dibenzodioxinas Policloradas/toxicidade , Acetilcolinesterase/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células PC12 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos
17.
Chem Biol Interact ; 259(Pt B): 286-290, 2016 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-27374124

RESUMO

Acetylcholinesterase (AChE; EC 3.1.1.7) is a vital functional enzyme in cholinergic neurotransmission which can rapidly hydrolyze neurotransmitter, acetylcholine, in the central and peripheral nervous systems. Emerging evidence showed that in addition to classical environmental AChE inhibitors, e.g. organophosphate and carbamate pesticides, dioxins are a new type of xenobiotic causing impairment of AChE. Dioxin can transcriptionally or post-transcriptionally suppress AChE expression in human neuroblastoma cells or mouse immune cells via the aryl hydrocarbon receptor (AhR) pathway, respectively. Dioxins can affect gene expression through other mechanisms, such as cross-talk with other signaling cascades and epigenetic modulations. Therefore, in this review, by summarizing the known mechanisms of AChE regulation and dioxin-induced gene alteration, potential signaling cascades and epigenetic mechanisms are proposed for dioxin-mediated AChE regulation. Mitogen activated protein (MAP) kinase, 3', 5'-cyclic adenosine monophosphate (cAMP) and calcium-related singaling pathways, as well as potential epigenetic mechanisms, such as DNA methylation, and post-transcriptional regulation via microRNAs, including hsa-miR-132, hsa-miR-212 and hsa-miR-25-3p are discussed here. These proposed mechanisms may be invaluable not only to promote comprehensive understanding of the action mechanisms for dioxin, but to illustrate the molecular basis of dioxin-induced health impacts.


Assuntos
Acetilcolinesterase/metabolismo , Dioxinas/toxicidade , Neurônios/enzimologia , Transdução de Sinais/efeitos dos fármacos , Animais , Epigênese Genética/efeitos dos fármacos , Humanos , Neurônios/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo
18.
Environ Health Perspect ; 124(9): 1406-13, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27081854

RESUMO

BACKGROUND: Although the chlorinated flame retardant Dechlorane (Dec) 602 has been detected in food, human blood, and breast milk, there is limited information on potential health effects, including possible immunotoxicity. OBJECTIVES: We determined the immunotoxic potential of Dec 602 in mice by examining the expression of phenotypic markers on thymocyte and splenic lymphocyte subsets, Th1/Th2 transcription factors, and the production of cytokines and antibodies. METHODS: Adult male C57BL/6 mice were orally exposed to environmentally relevant doses of Dec 602 (1 and 10 µg/kg body weight per day) for 7 consecutive days. Thymocyte and splenic CD4 and CD8 subsets and splenocyte apoptosis were examined by flow cytometric analysis. Cytokine expression was measured at both the mRNA and the protein levels. Levels of the transcription factors Th1 (T-bet and STAT1) and Th2 (GATA3) were determined using quantitative real-time polymerase chain reaction (qPCR). Serum levels of immunoglobulins IgG1, IgG2a, IgG2b and IgE were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Splenic CD4+ and CD8+ T cell subsets were decreased compared with vehicle controls, and apoptosis was significantly increased in splenic CD4+ T cells. Expression (mRNA and protein) of Th2 cytokines [interleukin (IL)-4, IL-10, and IL-13] increased, and that of Th1 cytokines [IL-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] decreased. The Th2 transcriptional factor GATA3 increased, whereas the Th1 transcriptional factors T-bet and STAT1 decreased. As additional indicators of the Th2-Th1 imbalance, production of IgG1 was significantly increased, whereas IgG2a was reduced. CONCLUSIONS: To our knowledge, we are the first to report evidence of the effects of Dec 602 on immune function in mice, with findings indicating that Dec 602 exposure favored Th2 responses and reduced Th1 function. CITATION: Feng Y, Tian J, Xie HQ, She J, Xu SL, Xu T, Tian W, Fu H, Li S, Tao W, Wang L, Chen Y, Zhang S, Zhang W, Guo TL, Zhao B. 2016. Effects of acute low-dose exposure to the chlorinated flame retardant dechlorane 602 and Th1 and Th2 immune responses in adult male mice. Environ Health Perspect 124:1406-1413; http://dx.doi.org/10.1289/ehp.1510314.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Poluentes Ambientais/toxicidade , Retardadores de Chama/toxicidade , Hidrocarbonetos Clorados/toxicidade , Sistema Imunitário/efeitos dos fármacos , Compostos Policíclicos/toxicidade , Linfócitos T/efeitos dos fármacos , Equilíbrio Th1-Th2/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
19.
J Environ Sci (China) ; 39: 218-227, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26899660

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure in humans is associated with marked immune suppressions and increased incidence of lymphoblastic diseases. To elucidate mechanisms of impairments in humoral immune responses, we used a murine model. Following a 20-week administration of low doses of TCDD, we observed severely reduced antibody titers, dramatically decreased number of splenic Th1 and Th2 cells and an increase in CD19(+) B cells. Transcriptional profiling of CD19(+) B cells showed that markers of pre-B cells were significantly elevated, indicating delayed B cell maturation. These changes in B cells were accompanied by decreases of T helper cell numbers and reduced IgM and IgG titers. A transcriptome analysis of splenic B cells followed by Ingenuity Pathway Analysis (IPA) revealed a set of differentially expressed genes known to play roles in tumorigenesis, cell-proliferation and cell-migration. The most up-regulated transcript gene was Eph receptor A2 (EphA2), a known oncogene, and the most down-regulated transcript was ZBTB16 that codes for a negative transcriptional regulator important in epigenetic chromatin remodeling. IPA identified cAMP-responsive element modulator (CREM) and cAMP-responsive element binding protein 1 (CREB1) as top upstream regulators. Consistently, a MAPPER promoter database analysis showed that all top dysregulated genes had CREM and/or CREB1 binding sites in their promoter regions. In summary, our data showed that chronic TCDD exposure in mice caused suppressed humoral immunity accompanied with profound dysregulation of gene expression in splenic B-lymphocytes, likely through cAMP-dependent pathways. This dysregulation resulted in impairments in T-cell and B-cell differentiation and activation of the tumorigenic transcription program.


Assuntos
Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Baço/imunologia , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Peso Corporal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunidade Humoral/genética , Imunoglobulinas/metabolismo , Interleucina-6/metabolismo , Interleucinas/metabolismo , Linfoma não Hodgkin/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/citologia , Células Th1/metabolismo , Células Th2/citologia , Células Th2/metabolismo
20.
Biotechnol Bioeng ; 112(5): 947-56, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25421845

RESUMO

Since solar light energy is the source of all renewable biological energy, the direct usage of light energy by bacterial cell factory has been a very attractive concept, especially using light energy to promote anaerobic fermentation growth and even recycle low-energy carbon source when energy is the limiting factor. Proteorhodopsin(PR), a light-driven proton pump proven to couple with ATP synthesis when expressed heterogeneously, is an interesting and simple option to enable light usage in engineered strains. However, although it was reported to influence fermentation in some cases, heterogeneous proteorhodopsin expression was never shown to support growth advantage or cause metabolic shift by photophosphorylation so far. Hereby, we presented the first experimental evidence that heterogeneously expressed proteorhodopsin can provide growth advantage and cause ATP-dependent metabolism shift of acetate and lactate changes in Escherichia coli at anaerobic condition. Those discoveries suggest further application potential of PR in anaerobic fermentation where energy is a limiting factor.


Assuntos
Acetatos/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas de Bactérias/metabolismo , Escherichia coli/crescimento & desenvolvimento , Lactatos/metabolismo , Rodopsinas Microbianas/metabolismo , Anaerobiose , Proteínas de Bactérias/genética , Cupriavidus necator/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Fermentação , Expressão Gênica , Luz , Fotofosforilação , Rodopsinas Microbianas/genética
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