RESUMEN
Polychlorinated biphenyl (PCB) is potentially harmful environmental toxicant causing cognitive decline with depressive features. PCB-induced behavioral deficits are associated with neurochemical dysfunctions, immune changes, and oxidative stress. This study investigated the neuroprotective effects of D-ribose-L-cysteine (DRLC), a neuroprotective precursor element of glutathione on PCB-induced neurobehavioral impairments. Following the initial 15 days of PCB (2 mg/kg) exposure to rats, DRLC (50 mg/kg) was given orally for an additional 15 days, from days 16 to 30. Animals were assessed for behavioral effect such as changes in locomotion, cognition, and depression. Oxidative/nitrergic stress markers; antioxidant regulatory proteins paraoxonase-1 (PON-1), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nfr2), NADPH oxidase-1 (NOX-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and neuroinflammation (NF-kß, and TNF-α); and neurochemical metabolizing enzymes (acetylcholinesterase (AChE), monoamine oxidase-A and -B (MAO-A, MAO-B)) were carried out. The PCB-induced decline in locomotion, cognitive performance, and depressive-like features were reversed by DRLC. More specifically, PCB-induced oxidative and nitrergic stress, typified by reduced levels GSH, CAT, and SOD, accompanied by elevated MDA and nitrite were attenuated by DRLC. Additionally, DRLC restored the neuroinflammatory milieu indicated by decreased NF-kß and TNF-α levels toward normal. Hyperactivities of AChE, MAO-A, MAO-B, PON-1, and NOX-1 levels as well as Nfr2, NQO1, and PON-1 due to PCB exposure were mitigated by DLRC. Our results suggest DRLC as a prospective neurotherapeutic agent against PCB-induced neurobehavioral impairments such as cognitive deficit and depressive-like feature through antioxidative and anti-nitrergic stress, anti-neuroinflammation, inhibition of brain metabolizing enzymes, and normalization of neurochemical homeostasis.
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Cisteína/análogos & derivados , Bifenilos Policlorados , Tiazolidinas , Ratas , Animales , Bifenilos Policlorados/farmacología , Acetilcolinesterasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Estudios Prospectivos , Estrés Oxidativo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Glutatión/metabolismo , Monoaminooxidasa/metabolismoRESUMEN
Some adverse effects of hydroxylated polychlorinated biphenyls (OH-PCBs) in humans are presumed to be initiated via thyroid hormone receptor (TR) binding. Due to the trial-and-error approach adopted for OH-PCB selection in previous studies, experiments designed to test the TR binding hypothesis mostly utilized inactive OH-PCBs, leading to considerable waste of time, effort and other material resources. In this paper, linear discriminant analysis (LDA) and binary logistic regression (LR) were used to develop classification models to group OH-PCBs into active and inactive TR agonists using radial distribution function (RDF) descriptors as predictor variables. The classifications made by both LDA and LR models on the training set compounds resulted in an accuracy of 84.3%, sensitivity of 72.2% and specificity of 90.9%. The areas under the ROC curves, constructed with the training set data, were found to be 0.872 and 0.880 for LDA and LR models, respectively. External validation of the models revealed that 76.5% of the test set compounds were correctly classified by both LDA and LR models. These findings suggest that the two models reported in this paper are good and reliable for classifying OH-PCB congeners into active and inactive TR agonists.
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Bifenilos Policlorados , Humanos , Bifenilos Policlorados/química , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/farmacología , Glándula Tiroides/metabolismo , Relación Estructura-Actividad Cuantitativa , Receptores de Hormona Tiroidea/metabolismo , Hormonas , HidroxilaciónRESUMEN
BACKGROUND: The prevalence of alcohol-associated liver disease (ALD), a subtype of fatty liver disease (FLD), continues to rise. ALD is a major cause of preventable death. Polychlorinated biphenyl (PCB) 126 is an environmentally relevant, dioxin-like pollutant whose negative metabolic effects have been well documented. In human and animal studies, PCB has been associated with the severity of nonalcoholic fatty liver disease (NAFLD). However, few studies have investigated whether exposures to environmental toxicants can worsen ALD. Thus, the objective of the current study was to develop an alcohol-plus-toxicant model to study how an environmental pollutant, PCB 126, impacts rodent ALD pathology. METHODS: Briefly, male C57BL/6J mice were exposed to 0.2 mg/kg PCB 126 or corn oil vehicle four days prior to ethanol feeding using the chronic-binge (10-plus-one) model. RESULTS: Concentrations of macromolecules, including hepatic lipids, carbohydrates, and protein (albumin) were impacted. Exposure to PCB 126 exacerbated hepatic steatosis and hepatomegaly in mice exposed to the chemical and fed an ethanol diet. Gene expression and the analysis of blood chemistry showed a potential net increase and retention of hepatic lipids and reductions in lipid oxidation and clearance capabilities. Depletion of glycogen and glucose was evident, which contributes to disease progression by generating systemic malnutrition. Granulocytic immune infiltrates were present but driven solely by ethanol feeding. Hepatic albumin gene expression and plasma levels were decreased by ~50% indicating a potential compromise of liver function. Finally, gene expression analyses indicated that the aryl hydrocarbon receptor and constitutive androstane receptor were activated by PCB 126 and ethanol, respectively. CONCLUSIONS: Various environmental toxicants are known to modify or enhance FLD in high-fat diet models. Findings from the present study suggest that they interact with other lifestyle factors such as alcohol consumption to reprogram intermediary metabolism resulting in exacerbated ethanol-associated systemic malnutrition in ALD.
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Contaminantes Ambientales , Hepatopatías Alcohólicas , Desnutrición , Enfermedad del Hígado Graso no Alcohólico , Bifenilos Policlorados , Humanos , Masculino , Ratones , Animales , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/farmacología , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/farmacología , Roedores , Ratones Endogámicos C57BL , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hepatopatías Alcohólicas/metabolismo , Dieta Alta en Grasa , Etanol/farmacología , Lípidos/farmacología , Desnutrición/metabolismo , Desnutrición/patologíaRESUMEN
INTRODUCTION: Hippocampal newborn neurons integrate into functional circuits where they play an important role in learning and memory. We previously showed that perinatal exposure to Aroclor 1254, a commercial mixture of polychlorinated biphenyls (PCBs) associated with alterations of cognitive function in children, disrupted the normal maturation of excitatory synapses in the dentate gyrus. We hypothesized that hippocampal immature neurons underlie some of the cognitive effects of PCBs. METHODS: We used newly generated neurons to examine the effects of PCBs in mice following maternal exposure. Newborn dentate granule cells were tagged with enhanced green fluorescent protein using a transgenic mouse line. The transcriptome of the newly generated granule cells was assessed using RNA sequencing. RESULTS: Gestational and lactational exposure to 6 mg/kg/day of Aroclor 1254 disrupted the mRNA expression of 1,308 genes in newborn granule cells. Genes involved in mitochondrial functions were highly enriched with 154 genes significantly increased in exposed compared to control mice. The upregulation of genes involved in oxidative phosphorylation was accompanied by signs of endoplasmic reticulum stress and an increase in lipid peroxidation, a marker of oxidative stress, in the subgranular zone of the dentate gyrus but not in mature granule cells in the granular zone. Aroclor 1254 exposure also disrupted the expression of synaptic genes. Using laser-captured subgranular and granular zones, this effect was restricted to the subgranular zone, where newborn neurons are located. CONCLUSION: Our data suggest that gene expression in newborn granule cells is disrupted by Aroclor 1254 and provide clues to the effects of endocrine-disrupting chemicals on the brain.
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Bifenilos Policlorados , Humanos , Femenino , Embarazo , Niño , Ratones , Animales , Bifenilos Policlorados/farmacología , Hipocampo , Neuronas/fisiología , Ratones Transgénicos , Encéfalo , Estrés Oxidativo , Expresión Génica , Giro Dentado , NeurogénesisRESUMEN
Polychlorinated biphenyls (PCBs) are a typical type of persistent organic pollutant. PCB exposure is associated to the occurrence and development of osteoarthritis (OA); however, the involved mechanisms have yet to be elucidated. Here, we investigated the pro-osteoarthritic effect of 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl (PCB153), and the involvement of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) and the RICTOR/Akt/mTOR signaling pathways. PCB153 of 20 and 30 µM increased the expression of MMP13 and decreased the expression of type II collagen, in a concentration-dependent manner. PCB153 treatment reduced the expression of Beclin 1 and LC3B, but increased the expression of p62 by upregulating miR-155 levels. PCB153 treatment activated the PI3K/Akt/mTOR signaling pathway by upregulating miR-155 levels. RICTOR was involved in activating the Akt/mTOR signaling pathway, and was also regulated by miR-155. In conclusion, PCB153 could promote the degradation of the extracellular matrix of chondrocytes by upregulating miR-155 via a mechanism related to the activation of the PI3K/Akt/mTOR and RICTOR/Akt/mTOR signaling pathway, which suppressed autophagy and facilitated the development of OA. MiR-155 may represent potential therapeutic targets to alleviate the development of OA.
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MicroARNs , Osteoartritis , Bifenilos Policlorados , Animales , Ratas , Autofagia , Condrocitos , Mamíferos/metabolismo , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Bifenilos Policlorados/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia ArribaRESUMEN
Endocrine-disrupting chemicals (EDCs) are ubiquitous in daily life, but their harmful effects on the human body have not been fully explored. Recent studies have shown that EDCs exposure could lead to infertility, menstrual disorder and menopause, resulting in subsequent effects on female health. Therefore, it is of great significance to clarify and summarize the impacts of EDCs on ovarian aging for explaining the etiology of ovarian aging and maintaining female reproductive health. Here in this review, we focused on the impacts of ten typical environmental contaminants on the progression of ovarian aging during adult exposure, including epidemiological data in humans and experimental models in rodents, with their clinical phenotypes and underlying mechanisms. We found that both persistent (polychlorinated biphenyls, perfluoroalkyl and polyfluoroalkyl substances) and non-persistent (phthalates) EDCs exposure could increase an overall risk of ovarian aging, leading to the diminish of ovarian reserve, decline of fertility or fecundity, irregularity of the menstrual cycle and an earlier age at menopause, and/or premature ovarian insufficiency/failure in epidemiological studies. Among these, the loss of follicles can also be validated in experimental studies of some EDCs, such as BPA, phthalates, parabens and PCBs. The underlying mechanisms may involve the impaired ovarian follicular development by altering receptor-mediated pro-apoptotic pathways, inducing signal transduction and cell cycle arrest and epigenetic modification. However, there were inconsistent results in the impacts on fertility/fecundity, menstrual/estrous cycle and hormone changes response to different EDCs, and differences between human and animal studies. Our review summarizes the current state of knowledge on ovarian disrupters, highlights their risks to ovarian aging and identifies knowledge gaps in humans and animals. We therefore propose that females adopt healthy lifestyle changes to minimize their exposure to both persistent and non-persistent chemicals, that have the potential damage to their reproductive function.
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Disruptores Endocrinos , Reserva Ovárica , Bifenilos Policlorados , Envejecimiento , Animales , Disruptores Endocrinos/toxicidad , Exposición a Riesgos Ambientales , Femenino , Ovario , Bifenilos Policlorados/farmacologíaRESUMEN
Endocrine disruptors are natural or man-made chemicals that interfere with the body's endocrine system leading to hormone synthesis and production defects. These chemicals are categorized as plasticizers and cosmetic chemicals, heavy metals, phytoestrogens, pesticides, detergents, surfactants, and flame retardants. Some of the most common endocrine disruptors are dioxins, bisphenol A, phthalates, perchlorate, perfluoroalkyl, and poly-fluoroalkyl substances (PFAs), phytoestrogens, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCB), triclosan, atrazine, lead, arsenic, mercury, organophosphate pesticides, and glycol ethers. Epigenetic alterations such as DNA methylation, histone modification, and miRNA regulation have been observed to play a major role in many diseases such as cancer, neurodegenerative diseases, PCOS, cardiovascular diseases, and various other disorders. In recent times, there has been a focus on endocrine-disrupting chemicals in epigenetic alterations. This review concentrates on estrogen and androgen disrupting effects, placental, and fetal effects, thyroid disrupting effects, and transgenerational effects of endocrine disruptors.
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Arsénico , Atrazina , Dioxinas , Disruptores Endocrinos , Retardadores de Llama , Fluorocarburos , Mercurio , MicroARNs , Plaguicidas , Bifenilos Policlorados , Triclosán , Andrógenos , Detergentes , Disruptores Endocrinos/toxicidad , Epigénesis Genética , Femenino , Glicoles , Éteres Difenilos Halogenados , Humanos , Organofosfatos , Percloratos , Plaguicidas/toxicidad , Fitoestrógenos/toxicidad , Placenta , Plastificantes , Bifenilos Policlorados/farmacología , EmbarazoRESUMEN
To assess the effect of polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) on thyroid hormone [TH: thyroxine (T4) and triiodothyronine (T3)] secretion, the concentrations of iodothyronine deiodinases (DIO1, DIO2, DIO3), and mRNA expression of genes involved in TH synthesis (TSHR, NIS, TPO, TG), metabolism (DIO1, DIO2, DIO3), and transport (OATP1C1, MCT8, MCT10, LAT1), chicken thyroid explants were incubated in medium supplemented with TSH (250 mU/ml), PCB118, PCB153, 4-OH-PCB107, and 3-OH-PCB153 (0.5 × 10-8 M), and TSH together with each PCB and OH-PCB. The results of the in vitro experiment revealed that, except for 4-OH-PCB107, all applied PCBs and OH-PCBs inhibited basal and TSH-stimulated T4 secretion. Moreover, they increased basal and reduced TSH-stimulated T3 secretion. PCBs and OH-PCBs decreased the TSH-stimulated TSHR expression. Following PCB and OH-PCB exposure, significant changes in mRNA expression of NIS, TPO, and TG were observed. PCBs and OH-PCBs affected DIO1 and DIO3 transcript levels and protein abundances of each DIO. Furthermore, PCB-dependent effects on OATP1C1, MCT8, and MCT10 mRNA expression were found. In conclusion, both PCB118 and PCB153 and their OH-PCBs affect TH synthesis and deiodination processes in the chicken thyroid gland and influence TH transport across the thyrocyte membrane. In addition, the effects of PCBs and OH-PCBs depended mainly on the type of PCB congener and the exposure time. These results indicate that not only parental PCBs but also OH-PCBs are hazardous for the thyroid gland and may disrupt its endocrine function. Further studies are necessary to explain a mechanism of PCB and OH-PCB action in the avian thyroid gland.
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Bifenilos Policlorados , Animales , Pollos/metabolismo , Bifenilos Policlorados/metabolismo , Bifenilos Policlorados/farmacología , Glándula Tiroides/metabolismo , Tiroxina/metabolismo , Tiroxina/farmacología , Triyodotironina/metabolismoRESUMEN
Sphingolipids (SLs) are important signaling molecules and functional components of cellular membranes. Although SLs are known as crucial regulators of neural cell physiology and differentiation, modulations of SLs by environmental neurotoxicants in neural cells and their neuronal progeny have not yet been explored. In this study, we used in vitro models of differentiated neuron-like cells, which were repeatedly exposed during differentiation to model environmental toxicants, and we analyzed changes in sphingolipidome, cellular morphology and gene expression related to SL metabolism or neuronal differentiation. We compared these data with the results obtained in undifferentiated neural cells with progenitor-like features. As model polychlorinated organic pollutants, we used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3'-dichlorobiphenyl (PCB11) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153). PCB153 revealed itself as the most prominent deregulator of SL metabolism and as potent toxicant during early phases of in vitro neurogenesis. TCDD exerted only minor changes in the levels of analysed lipid species, however, it significantly changed the rate of pro-neuronal differentiation and deregulated expression of neuronal markers during neurogenesis. PCB11 acted as a potent disruptor of in vitro neurogenesis, which induced significant alterations in SL metabolism and cellular morphology in both differentiated neuron-like models (differentiated NE4C and NG108-15 cells). We identified ceramide-1-phosphate, lactosylceramides and several glycosphingolipids to be the most sensitive SL species to exposure to polychlorinated pollutants. Additionally, we identified deregulation of several genes related to SL metabolism, which may be explored in future as potential markers of developmental neurotoxicity.
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Neuronas/efectos de los fármacos , Bifenilos Policlorados/farmacología , Bifenilos Policlorados/toxicidad , Dibenzodioxinas Policloradas/toxicidad , Esfingolípidos/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Contaminantes Ambientales/toxicidad , Neurogénesis/efectos de los fármacos , Neuronas/metabolismo , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/genéticaRESUMEN
Autocrine/paracrine factors generated in response to 17ß-estradiol (E2) within the fallopian tube (FT) facilitate fertilization and early embryo development for implantation. Since cyclic AMP (cAMP) plays a key role in reproduction, regulation of its synthesis by E2 may be of biological/pathophysiological relevance. Herein, we investigated whether cAMP production in FT cells (FTCs) is regulated by E2 and environmental estrogens (EE's; xenoestrogens and phytoestrogens). Under basal conditions, low levels of extracellular cAMP were detectable in bovine FTCs (epithelial cells and fibroblasts; 1:1 ratio). Treatment of FTCs with forskolin (AC; adenylyl cyclase activator), isoproterenol (ß-adrenoceptor agonist) and IBMX (phosphodiesterase (PDE) inhibitor) dramatically (>10 fold) increased cAMP; whereas LRE1 (sAC; soluble AC inhibitor) and 2',5'-dideoxyadenosine (DDA; transmembrane AC (tmAC)) inhibitor decreased cAMP. Comparable changes in basal and stimulated intracellular cAMP were also observed. Ro-20-1724 (PDE-IV inhibitor), but not milrinone (PDE-III inhibitor) nor mmIBMX (PDE-I inhibitor), augmented forskolin-stimulated cAMP levels, suggesting that PDE-IV dominates in FTCs. E2 increased cAMP levels and CREB phosphorylation in FTCs, and these effects were mimicked by EE's (genistein, 4-hydroxy-2',4',6'-trichlorobiphenyl, 4-hydroxy-2',4',6'-dichlorobiphenyl). Moreover, the effects of E2 and EE were blocked by the tmAC inhibitor DDA, but not by the ERα/ß antagonist ICI182780. Moreover, BAPTA-AM (intracellular-Ca2+ chelator) abrogated the effects of E2, but not genistein, on cAMP suggesting differential involvement of Ca2+. Treatment with non-permeable E2-BSA induced cAMP levels and CREB-phosphorylation; moreover, the stimulatory effects of E2 and EEs on cAMP were blocked by G15, a G protein-coupled estrogen receptor (GPER) antagonist. E2 and IBMX induced cAMP formation was inhibited by LRE1 and DDA suggesting involvement of both tmAC and sAC. Our results provide the first evidence that in FTCs, E2 and EE's stimulate cAMP synthesis via GPER. Exposure of the FT to EE's and PDE inhibitors may result in abnormal non-cyclic induction of cAMP levels which may induce deleterious effects on reproduction.
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AMP Cíclico/metabolismo , Disruptores Endocrinos/farmacología , Células Epiteliales/efectos de los fármacos , Estrógenos/farmacología , Trompas Uterinas/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Animales , Bovinos , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Células Epiteliales/metabolismo , Estradiol/farmacología , Trompas Uterinas/citología , Trompas Uterinas/metabolismo , Femenino , Fibroblastos/metabolismo , Genisteína/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Fosforilación , Bifenilos Policlorados/farmacología , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Unique bacterial associations were formed in the polluted soils from territory of the industrial factories Open Joint Stock Company "The Middle Volga Chemical Plant," Chapaevsk, Russia and Open Joint Stock Company "Lubricant Producing Plant," Perm, Russia. This study evaluates the influence of the biphenyl/polychlorinated biphenyls (PCB) on the formation of aerobic bacterial associations and their biodegradative potential. Enrichment cultivation of the soil samples from the territories of these industrial factories with PCB (commercial mixture Sovol) was lead for forming aerobic bacterial enrichment cultures showing a unique composition. The dominating in these bacterial cultures was the phylum Proteobacteria (Beta- and Gammaproteobacteria). Using biphenyl as a carbon source led to decrease of biodiversity in the final stable bacterial associations. Periodic cultivation experiments demonstrated that the association PN2-B has a high degradative potential among the six studied bacterial associations. PN2-B degraded 100% mono-chlorobiphenyls (94.5 mg/L), 86.2% di-chlorobiphenyls (22.3 mg/L), 50.9% Sovol, and 38.4% Delor 103 (13.8 mg/L). Qualitative analysis of metabolites showed that association performed transformation of chlorobenzoic acids (PCB degradation intermediates) into metabolites of citrate cycle. Twelve individual strain-destructors were isolated. The strains were found to degrade 17.7-100% PCB1, 36.2-100% PCB2, 18.8-100% PCB3 (94.5 mg/L), and 15.7-78.2% PCB8 (22.3 mg/L). The strains were shown to metabolize chlorobenzoic acids formed during degradation of chlorobiphenyls. A unique ability of strains Micrococcus sp. PNS1 and Stenotrophomonas sp. PNS6 to degrade ortho-, meta-, and para-monosubstituted chlorobenzoic acids was revealed. Our results suggest that PN2-B and individual bacterial strains will be perspective for cleaning of the environment from polychlorinated biphenyls.
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Bacterias Aerobias , Biodegradación Ambiental , Interacciones Microbianas , Bifenilos Policlorados , Bacterias Aerobias/efectos de los fármacos , Bacterias Aerobias/metabolismo , Biodegradación Ambiental/efectos de los fármacos , Interacciones Microbianas/efectos de los fármacos , Bifenilos Policlorados/análisis , Bifenilos Policlorados/farmacología , Microbiología del Suelo , Contaminantes del Suelo/análisis , Contaminantes del Suelo/farmacologíaRESUMEN
The widespread environmental pollutant 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) is a non-dioxin-like toxicant. It is a potential carcinogen compound able to induce gap junction (GJ) intercellular communication impairment, probably the first non-genomic event leading to tumor promotion. Although PCBs have been known for many years, the molecular mode of PCB153 action is still unclear. Recent studies from our research group have shown that the toxicant elicits a transient modulation of connexin (Cx) 43-formed GJs in hepatic stem-like WB-F344 cells involving sphingosine 1-phosphate (S1P) path. Taking into account that other strictly related bioactive sphingolipids, such as ceramide (Cer), may have different effects from S1P, here we aim to clarify the signaling paths engaged by PCB153 in the control of GJs, focusing primarily on the role of Cer. Accordingly, we have achieved a combined biomolecular and electrophysiological analysis of GJs in cultured WB-F344 cells treated with PCB153 at different time points. We have found that the toxicant elicited a time-dependent regulation of GJs formed by different Cx isoforms, through a transient modulation of Cer/Cer kinase (CerK) axis and, in turn, of protein phosphatase 2A (PP2A). Our new findings demonstrate the existence of a specific molecular mechanism downstream to Cer, which distinctly affects the voltage-dependent and -independent GJs in liver stem-like cells, and open new opportunities for the identification of additional potential targets of these environmental toxicants.
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Ceramidas/metabolismo , Uniones Comunicantes/patología , Hígado/patología , Bifenilos Policlorados/farmacología , Proteína Fosfatasa 2/metabolismo , Células Madre/patología , Animales , Comunicación Celular , Células Cultivadas , Uniones Comunicantes/efectos de los fármacos , Uniones Comunicantes/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Proteína Fosfatasa 2/genética , Ratas , Transducción de Señal , Células Madre/efectos de los fármacos , Células Madre/metabolismoRESUMEN
BACKGROUND: Polychlorinated biphenyls (PCBs) are a group of synthetic organic chlorine compounds known as an organic pollutant in food sources, which play important roles in malignancies. The present study aimed to investigate the direct effects of prevalent PCBs in food in hormone-responsive and non-responsive cell lines. METHODS: In the current study, MCF-7, LNCap, and MDA-MB231 cell lines were treated with serial concentrations (0.001-100 µM) of PCBs for 48 h and cell viability assessment was performed using MTT assay. The best concentration then applied and the expression level of PON1 was evaluated using real-time PCR. Besides, molecular docking was performed to determine the binding mechanism and predicted binding energies of PBCs compounds to the AhR receptor. RESULTS: Unlike MCF-7 and LNCap cells, the viability of MDA-MB231 cells did not significantly change by different concentrations of PCBs. Meanwhile, quantitative gene expression analysis showed that the PON1 was significantly more expressed in MCF-7 and LNCap lines treated with PCB28 and PCB101. However, the expression level of this gene in other groups and also MDA-MB231cells did not demonstrate any significantly change. Also, the results of molecular docking showed that PBCs had steric interaction with AhR receptor. CONCLUSIONS: Current results showed that despite of hormone non-responsive cells the PCBs have a significant positive effect on hormone-responsive cell. Therefore, and regarding to the existence of PCBs contamination in food there should be serious concern about their impact on the prevalence of different malignancies which certainly should result in a standard limit for this material. This study aimed to investigate the direct effects of prevalent PCBs in food in hormone-responsive and non-responsive cell lines. Cell lines were treated with serial concentrations of PCBs and cell viability assessment was performed using MTT assay. The expression level of PON1 was evaluated using real-time PCR. Molecular docking was performed to determine the binding mechanism and predicted binding energies of PBCs compounds to the AhR receptor. PCBs contamination in food there should be serious concern about their impact on the prevalence of different malignancies which certainly should result in a standard limit for this material.
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Contaminantes Ambientales/farmacología , Contaminación de Alimentos , Bifenilos Policlorados/farmacología , Arildialquilfosfatasa/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
Environmental endocrine disruptor chemicals are substances that can alter the homeostasis of the endocrine system in living organisms. They can be released from several products used in daily activities. Once in the organism, they can disrupt the endocrine function by mimicking or blocking naturally occurring hormones due to their similar chemical structure. This endocrine disruption is the most important cause of the wellknown hormoneassociate types of cancer. Additionally, it is decisive to determine the susceptibility of each organ to these compounds. Therefore, the present review aimed to summarize the effect of different environmental substances such as bisphenol A, dichlorodiphenyltrichloroethane and polychlorinated biphenyls in both the mammary and the prostate tissues. These organs were chosen due to their association with the hormonal system and their common features in carcinogenic mechanisms. Outcomes derived from the present review may provide evidence that should be considered in future debates regarding the effects of endocrine disruptors on carcinogenesis.
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Disruptores Endocrinos/farmacología , Contaminantes Ambientales/farmacología , Glándulas Mamarias Animales/efectos de los fármacos , Próstata/efectos de los fármacos , Animales , Compuestos de Bencidrilo/farmacología , DDT/farmacología , Femenino , Humanos , Masculino , Glándulas Mamarias Humanas/efectos de los fármacos , Fenoles/farmacología , Bifenilos Policlorados/farmacologíaRESUMEN
Polychlorinated bisphenols (PCBs) continue to contaminate food chains globally where they concentrate in tissues and disrupt the endocrine systems of species throughout the ecosphere. Hydroxylated PCBs (OH-PCBs) are major PCB metabolites and high-affinity inhibitors of human estrogen sulfotransferase (SULT1E1), which sulfonates estrogens and thus prevents them from binding to and activating their receptors. OH-PCB inhibition of SULT1E1 is believed to contribute significantly to PCB-based endocrine disruption. Here, for the first time, the molecular basis of OH-PCB inhibition of SULT1E1 is revealed in a structure of SULT1E1 in complex with OH-PCB1 (4'-OH-2,6-dichlorobiphenol) and its substrates, estradiol (E2), and PAP (3'-phosphoadenosine-5-phosphosulfate). OH-PCB1 prevents catalysis by intercalating between E2 and catalytic residues and establishes a new E2-binding site whose E2 affinity and positioning are greater than and competitive with those of the reactive-binding pocket. Such complexes have not been observed previously and offer a novel template for the design of high-affinity inhibitors. Mutating residues in direct contact with OH-PCB weaken its affinity without compromising the enzyme's catalytic parameters. These OH-PCB resistant mutants were used in stable transfectant studies to demonstrate that OH-PCBs regulate estrogen receptors in cultured human cell lines by binding the OH-PCB binding pocket of SULT1E1.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Estrógenos/farmacología , Bifenilos Policlorados/farmacología , Sulfotransferasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Estrógenos/química , Humanos , Hidroxilación , Modelos Moleculares , Bifenilos Policlorados/química , Receptores de Estrógenos/metabolismo , Sulfotransferasas/química , Sulfotransferasas/metabolismoRESUMEN
The developing brain is highly sensitive to the hormonal milieu, with gonadal steroid hormones involved in neurogenesis, neural survival, and brain organization. Limited available evidence suggests that endocrine-disrupting chemicals (EDCs) may perturb these developmental processes. In this study, we tested the hypothesis that prenatal exposure to a mixture of polychlorinated biphenyls (PCBs), Aroclor 1221, would disrupt the normal timing of neurogenesis in two hypothalamic regions: the ventromedial nucleus (VMN) and the preoptic area (POA). These regions were selected because of their important roles in the control of sociosexual behaviors that are perturbed in adulthood by prenatal EDC exposure. Pregnant Sprague-Dawley rats were exposed to PCBs from Embryonic Day 8 (E8) to E18, encompassing the period of neurogenesis of all hypothalamic neurons. To determine the birth dates of neurons, bromo-2-deoxy-5-uridine (BrdU) was administered to dams on E12, E14, or E16. On the day after birth, male and female pups were perfused, brains immunolabeled for BrdU, and numbers of cells counted. In the VMN, exposure to PCBs significantly advanced the timing of neurogenesis compared to vehicle-treated pups, without changing the total number of BrdU+ cells. In the POA, PCBs did not change the timing of neurogenesis nor the total number of cells born. This is the first study to show that PCBs can shift the timing of neurogenesis in the hypothalamus, specifically in the VMN but not the POA. This result has implications for functions controlled by the VMN, especially sociosexual behaviors, as well as for sexual selection more generally.
Asunto(s)
Disruptores Endocrinos/farmacología , Hipotálamo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Animales , Arocloros/farmacología , Femenino , Feto/efectos de los fármacos , Neuronas/efectos de los fármacos , Bifenilos Policlorados/farmacología , Embarazo , Área Preóptica/citología , Área Preóptica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Conducta Sexual/efectos de los fármacos , Núcleo Hipotalámico Ventromedial/citología , Núcleo Hipotalámico Ventromedial/efectos de los fármacosRESUMEN
Polychlorinated biphenyls (PCBs) are persistent organic pollutants, and the widespread use of PCBs has had adverse effects on human and animal health. This study experiment explored the effects of 2,3',4,4',5-pentachlorobiphenyl (PCB118) on the mammalian reproductive system. PCB118 was administered to pregnant mice from 7.5 to 12.5 days of gestation; F1 mice were obtained and the reproductive system of F1 male mice was examined. PCB118 damaged the reproductive system in male F1 mice, as evidenced by negative effects on the testicular organ coefficient (testes weight/bodyweight), a decrease in the diameter of seminiferous tubules and a significant reduction in the anogenital distance in 35-day-old F1 mice. In addition, methylation levels of genomic DNA were reduced, with reductions in the expression of the DNA methyltransferases DNMT1, DNMT3A and DNMT3B, as well as that of the epigenetic regulatory factor ubiquitin like with PHD and ring finger domains 1 (Uhrf1). Together, the results of this study provide compelling evidence that exposure of pregnant mice to PCB118 during primordial germ cell migration in the fetus affects the reproductive system of the offspring and decreases global methylation levels in the testis.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Bifenilos Policlorados/farmacología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Testículo/efectos de los fármacos , Animales , Femenino , Masculino , Exposición Materna/efectos adversos , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Testículo/metabolismoRESUMEN
Polychlorinated biphenyls (PCBs) are notorious persistent organic pollutants that were banned in the last century. However, PCBs still remain ubiquitous in the ecosystem due to their persistence and bioaccumulative potency against environmental and biological degradation. Albeit there is no longer the permission of commercial production of PCBs, they were continuously released into global biota via illegal disposal of e-waste or as byproducts of industrial supplies. The role of oxidative stress is often implicated in PCBs' toxicology. PCBs, especially coplanar ones, have a high affinity toward aryl hydrocarbon receptors and inducing CYP1A1, which is considered as a source of oxidative stress. Although commercial PCBs and coplanar individual PCBs, for example, PCB 77 and 126, induced oxidative stresses have been extensively investigated, PCB metabolite-induced oxidative stress has received less attention. PCBs can undergo phase I metabolism which metabolizes the parent PCBs into hydroquinone/semiquinone/quinone metabolites as a futile redox cycle, producing downstream reactive oxygen species (ROS) as byproducts. PCBs can also undergo phase II metabolism yielding methylsulfonyl metabolites that deplete glutathione and such. PCB metabolites induce oxidative stress generally via direct production of ROS or indirect scavenge antioxidant and inhibit antioxidant enzymes, disturbing cellular redox balance. This review aims to provide a critical summary of PCBs metabolism, PCBs parents, and daughter metabolite-induced oxidative stress. We especially focus on the connection between parent PCBs and downstream metabolites, to encourage research associated with PCB metabolite-induced oxidative stress.
Asunto(s)
Bifenilos Policlorados/metabolismo , Estrés Oxidativo/efectos de los fármacos , Bifenilos Policlorados/farmacologíaRESUMEN
The Ah receptor (AhR) is a ligand-dependent transcriptional factor that mediates the effects of structurally diverse chemicals. Ligand binding stimulates nuclear translocation of the AhR and leads to AhR DNA binding and increased gene expression. Studies of the molecular mechanisms by which ligands bind to and activate the AhR and AhR-dependent signal transduction require methods to easily examine each step of the AhR signaling pathway. While current assays can measure ligand and DNA binding in vitro and gene expression in cells, there is no simple method to monitor AhR nuclear translocation. We developed a stably transfected mouse hepatoma cell line (yAHAYc6) that expresses yellow fluorescent protein-tagged AhR (yAhR) for use in qualitative or semiquantitative assessment of nuclear/cytoplasmic distribution of yAhR in living cells by fluorescent microscopy. yAhR nuclear translocation was stimulated in a concentration- and time-dependent manner by AhR agonists and inhibited by antagonists. Inhibition of nuclear export channels by leptomycin B, resulted in increased nuclear accumulation of yAhR in the absence of added ligand, indicating endogenous nucleocytoplasmic shuttling of unliganded AhR and demonstrating the utility of these cells. This novel cell line can be used to detect and characterize AhR ligands and will facilitate mechanistic studies of AhR signaling.
Asunto(s)
Línea Celular Tumoral , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Células COS , Chlorocebus aethiops , Genes Reporteros , Ligandos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Plásmidos , Bifenilos Policlorados/farmacología , Dibenzodioxinas Policloradas/farmacología , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/genética , Proteínas Recombinantes de Fusión/genética , Transducción de Señal , TransfecciónRESUMEN
The arginine vasotocin (AVT)-V1a receptor mediates critical reproductive behaviors of the nonapeptide vasotocin in the teleost brain. In this study, we report the molecular characterization of the AVT-V1a2 receptor and its messenger RNA (mRNA) and protein expressions in the Atlantic croaker brain after exposure to the planar polychlorinated biphenyl congener 3,3',4,4'-tetrachlorobiphenyl (PCB77). The full-length sequence of croaker AVT-V1a2 receptor complementary DNA (cDNA) is highly homologous to other teleost AVT-V1a2 receptor cDNAs. Double-labeled immunohistochemistry showed coexpression of AVT-V1a2 receptor and gonadotropin-releasing hormone-I (GnRH-I, a neuropeptide that regulates gonadotropin secretion) in hypothalamic neurons, thereby providing the anatomical basis for possible AVT modulation of croaker reproduction through alterations in GnRH-I secretion. AVT-V1a2 receptor mRNA and protein levels as well as GnRH-I mRNA levels were markedly decreased in hypothalamic tissues of croaker exposed to PCB77 (dose: 2 and 8 µg/g body weight for 4 weeks) compared with levels in untreated (control) fish. In contrast, hypothalamic cytochrome P450 1A (CYP1A, a monooxygenase enzyme) and interleukin-1ß (IL-1ß, a cytokine indicator of inflammation and response to neuronal damage) mRNA levels, and plasma protein carbonyl (PC, an indicator of reactive oxygen species) contents, important biomarkers of neural stress, were increased in PCB77-exposed fish compared with controls. Collectively, these results suggest that the downregulation of hypothalamic AVT-V1a2 receptor and GnRH-I transcripts due to PCB77 exposure is associated with induction of CYP1A, cellular inflammation and oxidative stress in Atlantic croaker, a marine teleost that inhabits estuaries along the US Atlantic coast and the Gulf of Mexico that are often contaminated with persistent organic pollutants such as PCBs.