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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.
Sci Total Environ ; 710: 135524, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31784154

RESUMO

Polyhalogenated carbazoles (PHCZs) are emerging environmental contaminants that have caused wide concerns due to their dioxin-like toxicity and environmental persistence. It would be desirable to determine all of these chemicals using a simple analytical method. Within this study, a simple and sensitive method combining accelerated solvent extraction (ASE) with gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS/MS) was established to simultaneously analyze eleven frequently detected PHCZs in soil, including CCZ-3, CCZ-36, CCZ-1368, CCZ-2367, BCZ-3, BCZ-27, BCZ-36, BCZ-136, BCZ-1368, 1-B-36-CCZ, 18-B-36-CCZ. The calibration curves of the target analytes showed good linearity (R2 > 0.99, level = 6), and method detection limits (MDLs) ranging from 1.5 to 14.6 pg g-1. The average recoveries of the analytes in soil samples ranged from 64% to 126% with the RSD ranging from 2.0% to 10%. The developed method was successfully used for determination of these eleven PHCZs in soil samples from a tie-dye area in southwest China. Total concentrations of these eleven PHCZs ranging up to 46.3 ng g-1 dw. CCZ-36, BCZ-3, CCZ-3, 1-B-36-CCZ, 18-B-36-CCZ, and BCZ-1368 were the most abundant compounds in soil.

3.
Chem Res Toxicol ; 33(2): 614-624, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31878777

RESUMO

Dioxins, mostly through activation of aryl hydrocarbon receptor (AhR), are potent toxic substances widely distributed in the environment, while moderated suppression of AhR also exhibits anti-tumor effects. Therefore, the proper modulation of AhR activity may counteract AhR-mediated toxicities and certain diseases. In this investigation, we identified several novel AhR moderate agonists and antagonists using chemical biology approaches. The mechanisms and mode of interactions with AhR by these hits were also revealed using both experimental and computational studies. The newly identified AhR moderate agonists and antagonists were predicted to bind to AhR and modulate AhR signaling. The structure-activity relationships of moderate agonists and antagonists and their unique binding features with AhR have created a solid framework for further optimization of the next generation of AhR modulators.

4.
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.

5.
Environ Sci Technol ; 53(21): 12803-12811, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31566365

RESUMO

Field investigations have revealed the ability of the climbing perch Anabas testudineus to survive in highly contaminated water bodies. The aryl hydrocarbon receptor (AhR) pathway is vital in mediating the toxicity of aromatic hydrocarbon contaminants, and genotypic variation in the AhR can confer resistance to these contaminants. Thus, we characterized the AhR pathway in A. testudineus in order to understand the mechanism(s) underlying the resistance of this species to contaminants and to broaden current knowledge on teleost AhR. In A. testudineus, four AhRs, two AhR nuclear translocators (ARNTs), and one AhR repressor (AhRR) were found. Transient transfection assays revealed that AhR1a, AhR1b, and AhR2b were functional, whereas AhR2a was poorly activated by the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Two ARNTs (partner of AhR) and one AhRR (repressor of AhR) all were functional with each of the active AhR. As a major form, the insensitivity of AhR2a might serve as a potential mechanism for A. testudineus' reduced sensitivity to severe contamination. We explored the key residues that may account for AhR2a's insensitivity in silico and then functionally validated them in vitro. Two sites (VCS322-324, M370) in its ligand-binding domain (LBD) were proved critical for its sensitivity to TCDD. This systematic exploration of the AhR pathway showed that most members have maintained their traditional functions as expected, whereas a nonfunctionalization event has occurred for AhR2a.


Assuntos
Dibenzodioxinas Policloradas , Receptores de Hidrocarboneto Arílico , Animais , Peixes
6.
Sci Total Environ ; 690: 1170-1177, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31470480

RESUMO

In recent decades, crude recycling of electronic waste (e-waste) has caused serious pollution and threatened wild organisms in certain regions. It is therefore valuable to investigate the pollution-induced toxic effects in situ using native fish species. Unlike the death or decline observed in other species, Anabas testudineus can better adapt to severe e-waste pollution. Using it as a model, the true status of this wild organism was revealed. We collected A. testudineus from two polluted sites (st1 and st2) and conducted transcriptome analyses of the liver, gill, and kidney. Clear whole-transcriptome differences were found between polluted and clean sites and between differentially polluted sites (st1 and st2). Pathway analysis revealed that long-term e-waste pollution would cause significant hypoxia, oxidative stress, and potentially apoptosis. Accordingly, several defensive responses were elicited including 'oxidation-reduction' and the 'unfolded protein response'. Certain biological processes, including 'DNA repair' and 'endoplasmic reticulum stress response', were altered in a tissue- or burden-specific pattern suggesting transcriptome plasticity in response to distinct burdens. This study revealed the toxic impacts of e-waste pollution on wild organisms using a native fish species. Additionally, due to its highly adaptive nature, A. testudineus could be a suitable test species for such severe conditions in the wild or otherwise.


Assuntos
Resíduo Eletrônico , Perciformes/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Perfilação da Expressão Gênica , Brânquias , Rim , Fígado , Estresse Oxidativo , Transcriptoma
7.
Chem Biol Interact ; 309: 108686, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31152735

RESUMO

Acetylcholinesterase (EC3.1.1.7; AChE) is a key enzyme in the cholinergic system. Emerging evidence has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a typical persistent organic pollutant, suppressed neuronal AChE activity via dysregulation of different biosynthesis processes in human and rat neuronal cells. In the nervous system, astrocytes protect neurons from environmental pollutants. As a known target cell of TCDD, the astrocyte might be involved in TCDD effects on neuronal AChE. Therefore, in the present study, we found astrocyte-derived conditioned medium (ACM) could induce AChE activity preferentially in mature neurons in the absence of TCDD. The enzymatic activity of AChE was generally decreased in cultured cortical neurons upon direct treatment with TCDD (0.003-0.01 nM). This trend of changes in AChE activity was not significantly altered in immature neurons exposed to ACM produced in the presence of TCDD (TACM group), but reversed in mature neurons. Compared with effects of treatment with ACM plus TCDD (ACMT), a significant differential effect on AChE activity was found in the TACM group in response to TCDD treatment specifically in immature neurons, suggesting the presence of a TCDD-specific active component derived from the astrocyte. Inconsistent alterations in expression and enzymatic activities of the AChE T subunit (AChET) and the proline-rich membrane anchor (PRiMA) were found, suggesting that a mechanism of action beyond the transcriptional level might be involved. These data indicate that the astrocyte might play a protective role in TCDD-induced alterations of neuronal AChE in certain stages of differentiation.


Assuntos
Acetilcolinesterase/metabolismo , Meios de Cultivo Condicionados/química , Expressão Gênica/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacologia , Acetilcolinesterase/genética , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dibenzodioxinas Policloradas/química , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Sci Total Environ ; 687: 516-526, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31216508

RESUMO

Polyhalogenated carbazoles (PHCZs) are a class of contaminants identified with persistence and bioaccumulation property from previous studies. However, the toxic effect and mechanism of PHCZs are not fully understood. In this study, eleven PHCZs, including four chlorocarbazoles, four bromocarbazoles and two bromo/chlorocarbazoles were screened for their potential aryl hydrocarbon receptor (AhR) activity by using a dioxin responsive element-driven luciferase reporter assay. We found that nine PHCZs significantly activated AhR in a concentration-dependent manner. Their potencies of AhR activation were 1000 to 100,000 folds less than that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand. The relative AhR activation potency of the nine PHCZs followed the order 2,3,6,7-tetrachloro-9H-carbazole >2,7-dibromo-9H-carbazole >1,3,6-tribromo-9H-carbazole >1,3,6,8-tetrachloro-9H-carbazole >1,3,6,8-tetrabromo-9H-carbazole >1-bromo-3,6-dichloro-9H-carbazole >3,6-dibromo-9H-carbazole >3-bromo-9H-carbazole >1,8-dibromo-3,6-dichloro-9H-carbazole, which was partly in line with the induction of AhR-mediated CYP1A1 expression. In silico analysis indicated that the nine PHCZs could be docked into the same pocket as TCDD due to their high structural similarity. However, the shrunk size of the heterocyclic moieties in PHCZs relative to that in TCDD dramatically decreased the complex stability provided by inter-molecular interactions. Moreover, two distinguished docking poses adopted by the nine PHCZs were found, in which one was illustrated by 2367-CCZ and 27-BCZ while the other symbolized by TCDD and the left seven agonists. The differential antagonizing effects of CH223191 on PHCZ-induced AhR activity supported such pose differentiation. The present experimental and in silico data provide new direct evidence of PHCZ-AhR interaction which sheds light on AhR-associated toxicological study and risk assessment of PHCZs.

9.
Chem Biol Interact ; 308: 164-169, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100272

RESUMO

Emerging data indicate that prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could interfere with myogenic differentiation in vivo. Acetylcholinesterase (EC3.1.1.7; AChE), an enzyme critical for cholinergic neurotransmission, is abundantly expressed in neurons and mature myotubes, and we recently found that muscle AChE expression was suppressed in parallel with the inhibition of myogenic differentiation upon TCDD treatment in mouse C2C12 cells. This TCDD-induced suppression of muscle AChE was proposed to involve an aryl hydrocarbon receptor (AhR)-independent mechanism, but the precise underlying mechanism remains unclear. Considering the widely recognized role of muscular activity in AChE expression and its potential crosstalk with the AhR signaling pathway, we sought to investigate the effect of TCDD on muscle AChE expression in the presence of muscular activity. Therefore, we employed a highly contractile rat primary skeletal muscle culture system in which AChE activity and the expression of genes related to it (AChE T subunit and collagen Q (ColQ)) were increased during the myogenic differentiation process. Although TCDD treatment successfully induced the expression of genes regulated by AhR activation, the treatment exerted no notable effects on myogenic differentiation. Moreover, muscle AChE enzymatic activity and mRNA level remained unchanged following TCDD treatment, and only ColQ mRNA expression was slightly increased after 4-day treatment with TCDD (10-10 M). The compensatory role of muscle-contraction-related signaling pathways in this newly identified unresponsiveness of muscle AChE to TCDD warrants further investigation.


Assuntos
Acetilcolinesterase/metabolismo , Diferenciação Celular/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Acetilcolinesterase/genética , Animais , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Contração Muscular/efeitos dos fármacos , Mioblastos Esqueléticos/citologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
10.
Sci Total Environ ; 669: 621-630, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30893621

RESUMO

The freshwater climbing perch (Anabas testudineus) can tolerate water environments contaminated with persistent organic pollutants (POPs). The mechanisms underlying this tolerance are unknown. We used de novo transcriptomic analysis to investigate the defensive mechanisms of A. testudineus against POPs based on its genetic features and biological responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Our results revealed a specific expansion of cytochrome P450 (CYP) 3A subfamily, which may be involved in the elimination of certain POPs. In xenobiotic responses, the aryl-hydrocarbon receptor (AhR) pathway represents a critical signaling mechanism, and we characterized four AhR and two AhR nuclear translocator homologs and one AhR repressor (AhRR) gene in A. testudineus. TCDD-induced AhRR and CYP1A mRNA upregulation suggests that negative-feedback regulation of AhR signaling through AhRR helps avoid excessive xenobiotic responses. Furthermore, liver and gill transcriptomic profiles were markedly altered after TCDD exposure, with some of the altered genes being related to common defensive responses reported in other species. Based on the newly identified TCDD-altered genes, several A. testudineus-specific responses are proposed, such as enhanced fatty acid ß-oxidation. The genetic features of CYP3A subfamily and AhR pathway and the TCDD-induced defensive biological processes elucidated here enhance our understanding of A. testudineus defensive responses against POPs.


Assuntos
Transcriptoma/fisiologia , Poluentes Químicos da Água/toxicidade , Xenobióticos/toxicidade , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto , Peixes/genética , Perfilação da Expressão Gênica , Dibenzodioxinas Policloradas , RNA Mensageiro , Receptores de Hidrocarboneto Arílico , Ativação Transcricional
11.
Sci Total Environ ; 662: 639-645, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-30703721

RESUMO

Type 3 innate lymphoid cells (ILC3s) are distributed in the gut and regulate inflammation by secreting cytokines, including interferon (IFN)-γ and interleukin (IL)-17. The maintenance and function of ILC3s involve the activity of aryl hydrocarbon receptor (AhR), a potent ligand of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the most toxic dioxin congeners. Thus, TCDD exposure might affect ILC3s. To obtain in vivo evidence supporting this notion, we exposed female C57BL/6 mice orally to TCDD (low/high doses: 0.1/10 µg/kg body weight) during pregnancy and lactation periods, and after the exposure, evaluated the mothers and offspring for alterations in ILC3 differentiation and function in the colon. ILC3 frequency among colonic lamina propria lymphocytes was preferentially diminished in the offspring, and, in parallel, the median fluorescence intensity (MFI) of retinoic acid receptor-related orphan receptor (ROR)γt, which is associated with ILC3 differentiation, was also decreased in ILC3s. Conversely, the percentages of two subsets of the cells, one positive for natural cytotoxicity receptor NKp46 and the other for IL-17a, were increased in TCDD-exposed mothers and offspring. Moreover, the percentage of IFN-γ+ ILC3s was increased specifically in the mothers, but this was in conjunction with a significant decrease in the MFI of IFN-γ, which suggests that the IFN-γ+ ILC3 subset was functionally altered. In conclusion, maternal exposure to TCDD suppresses ILC3 differentiation in the offspring and influences ILC3 function in distinct manners in the mother and offspring. Our study provides new insights into the intergenerational interference of dioxins in colonic ILC3s.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Colo/imunologia , Poluentes Ambientais/efeitos adversos , Imunidade Inata/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Dibenzodioxinas Policloradas/efeitos adversos , Animais , Colo/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Teratogênios/toxicidade
12.
J Environ Sci (China) ; 76: 368-376, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528028

RESUMO

Emerging evidence showed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) could induce expression of certain reactivation-associated genes in astrocytes, however, the consequent cellular effects and molecular mechanisms are still unclear. During the process of astrocyte reactivation, migration is a critical cellular event. In the present study, we employed wound-healing assay and Transwell® motility assay to explore the effects of TCDD on cell migration in primary cultured rat cortical astrocytes. We found that upon TCDD treatments at relative low concentrations (10-10 and/or 10-9 mol/L), the ability of primary astrocytes to migrate horizontally and vertically was promoted. In line with this cellular effect, the mRNA expression of two pro-migratory genes, including cell division cycle 42 (CDC42) and matrix metalloproteinase 2 (MMP2) was induced by TCDD treatment. Dioxin exerts its toxic effects mainly through aryl hydrocarbon receptor (AhR) pathway. So the role of AhR pathway in the pro-migratory effects of TCDD was examined using an AhR antagonist, CH223191. We found that application of CH223191 significantly reversed the pro-migratory effects of TCDD. Interestingly, the basal ability of horizontal migration as well as basal levels of CDC42 and MMP2 expression were dramatically reduced suggesting a possible physiological role of AhR in maintaining the endogenous migration ability of the primary astrocytes. These findings support the notion that dioxin promotes astrocyte reactivation at molecular and cellular levels.


Assuntos
Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Astrócitos/metabolismo , Células Cultivadas , Ratos , Ratos Sprague-Dawley
13.
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
14.
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
15.
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
16.
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
17.
Environ Sci Technol ; 52(5): 2926-2933, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29437390

RESUMO

Airborne persistent toxic substances are associated with health impacts resulting from air pollution, for example, dioxins, dioxin-like polychlorinated biphenyls, and certain polycyclic aromatic hydrocarbons (PAHs), which activate aryl hydrocarbon receptors (AhR) and thereby produce adverse outcomes. Thus, a bioassay for evaluating AhR activation is required for risk assessment of ambient-air samples, and for this purpose, we developed a new and sensitive recombinant mouse hepatoma cell line, CBG2.8D, in which a novel luciferase-reporter plasmid containing two copies of a newly designed dioxin-responsive domain and a minimal promoter derived from a native gene were integrated. The minimal detection limit for 2,3,7,8-tetrachlorodibenzo- p-dioxin with this assay system was 0.1 pM. We used CBG2.8D to determine dioxin levels in 45 ambient-air samples collected in Beijing. The measured bioanalytical equivalent (BEQ) values were closely correlated with the toxic equivalent values obtained from chemical analysis. In haze ambient-air samples, the total activation of aryl hydrocarbon receptors (TAA) was considerably higher than the BEQ of dioxin-rich fractions, according to the results of the cell-based bioassay. Notably, the haze samples contained abundant amounts of PAHs, whose relative toxicity equivalent was correlated with the TAA; this finding suggests that PAHs critically contribute to the AhR-related biological impacts of haze ambient-air samples.


Assuntos
Dioxinas , Dibenzodioxinas Policloradas , Animais , Pequim , Bioensaio , Camundongos , Receptores de Hidrocarboneto Arílico
18.
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
19.
Environ Pollut ; 218: 34-38, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27552035

RESUMO

Proteomics technology is an attractive biomarker candidate discovery tool that can be applied to study large sets of biological molecules. To identify novel biomarkers and molecular targets in arsenic-induced skin lesions, we have determined the protein profile of arsenic-affected human epidermal stratum corneum by shotgun proteomics. Samples of palm and foot sole from healthy subjects were analyzed, demonstrating similar protein patterns in palm and sole. Samples were collected from the palms of subjects with arsenic keratosis (lesional and adjacent non-lesional samples) and arsenic-exposed subjects without lesions (normal). Samples from non-exposed healthy individuals served as controls. We found that three proteins in arsenic-exposed lesional epidermis were consistently distinguishably expressed from the unaffected epidermis. One of these proteins, the cadherin-like transmembrane glycoprotein, desmoglein 1 (DSG1) was suppressed. Down-regulation of DSG1 may lead to reduced cell-cell adhesion, resulting in abnormal epidermal differentiation. The expression of keratin 6c (KRT6C) and fatty acid binding protein 5 (FABP5) were significantly increased. FABP5 is an intracellular lipid chaperone that plays an essential role in fatty acid metabolism in human skin. This raises a possibility that overexpression of FABP5 may affect the proliferation or differentiation of keratinocytes by altering lipid metabolism. KRT6C is a constituent of the cytoskeleton that maintains epidermal integrity and cohesion. Abnormal expression of KRT6C may affect its structural role in the epidermis. Our findings suggest an important approach for future studies of arsenic-mediated toxicity and skin cancer, where certain proteins may represent useful biomarkers of early diagnoses in high-risk populations and hopefully new treatment targets. Further studies are required to understand the biological role of these markers in skin pathogenesis from arsenic exposure.


Assuntos
Intoxicação por Arsênico/metabolismo , Desmogleína 1/metabolismo , Epiderme/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Queratina-6/metabolismo , Ceratose/metabolismo , Adulto , Idoso , Intoxicação por Arsênico/complicações , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Desmogleína 1/genética , Regulação para Baixo , Epiderme/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Queratina-6/genética , Ceratose/etiologia , Masculino , Pessoa de Meia-Idade , Proteômica/métodos
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