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1.
Sci Total Environ ; 804: 150015, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34509843

RESUMO

Our previous studies showed hydrophobic organic compounds (HOCs) in the sediments of drinking water reservoirs caused DNA damage in human cells (Caco-2) after chlorination. However, the main mechanisms remained unclear. This study compared oxidative damage and EROD activity in Caco-2 cells upon exposure to chlorinated HOCs, and the role of antioxidants (catalase, vitamin C and epigallocatechin gallate (EGCG)) in reducing the toxicities was examined. The result showed that chlorinated HOCs induced a 4-fold increase in production of reactive oxygen species (ROS) compared with HOCs. Antioxidants supplement significantly reduced ROS yields and DNA peroxidation. HOCs with relatively higher TEQbio were greatly reduced (about 98%) after chlorination, indicating dioxin-like toxicity is not the main factor inducing oxidative damage by chlorinated HOCs. Yet, ROS and the associated oxidative damage seem to be more responsible for causing DNA damage in the cells. Antioxidants including catalase, Vitamin C and EGCG showed protective effect against chlorination.


Assuntos
Água Potável , Antioxidantes , Células CACO-2 , Citocromo P-450 CYP1A1 , Humanos , Estresse Oxidativo , Espécies Reativas de Oxigênio
2.
Pestic Biochem Physiol ; 179: 104959, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34802538

RESUMO

This research aimed to assess curcumin (CUR) effects on fenitrothion (FNT), a broad-spectrum organophosphate insecticide, -induced hepatorenal damage. Thirty adult male Wistar rats were allocated at random to five equal groups orally administered distilled water containing 1% carboxyl methylcellulose, corn oil (1 mL/rat), CUR (100 mg/kg b.wt.), FNT (5 mg/kg b.wt.), or CUR + FNT. CUR and FNT were dosed three times a week for two months. At the end of this trial, blood and tissue samples (liver and kidney) were subjected to molecular, biochemical, and histopathological assessments. The results revealed that CUR significantly diminished the FNT-induced up-regulation of hepatic CYP1A1 and CYP1A2 transcriptional levels. Moreover, CUR significantly suppressed the increment of the serum levels of hepatic alanine aminotransferase, gamma-glutamyl transferase, and kidney damage indicators (urea and creatinine) in FNT-intoxicated rats. Furthermore, in the hepatic and renal tissues, CUR remarkably restored the FNT-associated depletion of the antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione S transferase, catalase, and superoxide dismutase). In addition, CUR notably reduced the FNT-induced increment in malondialdehyde content in the hepatic and renal tissues. Besides, the pathological aberrations in liver and kidney tissues resulting from FNT exposure were significantly abolished in FNT + CUR treated rats. Overall, CUR could be an effective ameliorative agent against negative pesticide impacts like FNT.


Assuntos
Curcumina , Fenitrotion , Animais , Antioxidantes/metabolismo , Curcumina/farmacologia , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Fenitrotion/toxicidade , Fígado/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar
3.
Sci Rep ; 11(1): 17991, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504212

RESUMO

To determine the baseline threat of microplastics and polycyclic aromatic hydrocarbons (PAHs) in an important seafood fish from Vueti Navakavu locally managed marine area, a multibiomarker risk assessment was conducted on the thumbprint emperor fish Lethrinus harak. Condition factor, a measure of relative general health condition of fish, was significantly lower in samples from the wet season compared to the dry season but no significant differences were observed for hepatosomatic index, a measure of relative stored energy/nutrition, between seasonal groups. PAHs levels of four metabolites in emperor fish from Fiji waters are reported here for the first time; seasonal groups showed no significant differences, but all samples presented levels of biliary PAHs. Each specimen also contained at least one microplastic in its gastrointestinal system; fibres were the predominant form-type and ingestion levels showed that more than 80% of fragment sizes were below 1.0 mm. Biochemical responses were observed for ethoxyresorufin-O-deethylase and glutathione S-transferase biotransformation activity, oxidative stress (glutathione peroxidase and glutathione reductase activity; lipid peroxidation) and genotoxicity (micronuclei assay). Though there were no statistically significant differences found, there were biological significances that were important to note; relatively low levels of pollutant exposure and low levels of biochemical responses showed enzymes response in thumbprint emperor were as expected to their roles in the body. In this multibiomarker approach, the observation of pollutants presence and histopathological injuries are considered biologically relevant from a toxicological perspective and serve as a baseline for future pollution studies in seafood fishes in Fiji, with site differences and the inclusion of fish species comparison. We recommend adopting a suite of biomarkers in future regional biomonitoring studies to develop holistic baseline information for other marine settings in Fiji and other Pacific Island countries.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Peixes/metabolismo , Glutationa Transferase/metabolismo , Microplásticos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Fiji , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Mutagenicidade , Poluição Química da Água/análise , Qualidade da Água
4.
Ecotoxicology ; 30(10): 1969-1982, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34505200

RESUMO

Heavy metals accumulated in the environment due to the mining industry may impact on the health of exposed wild animals with consequences at the population level via survival and selection of the most resistant individuals. The detection and quantification of shifts in gene frequencies or in the genetic structure in populations inhabiting polluted sites may be used as early indicators of environmental stress and reveal potential 'candidate gene biomarkers' for environmental health assessment. We had previously observed that specimens of the Greater white-toothed shrew (Crocidura russula) from two heavy metal mines in Southern Portugal (the Aljustrel and the Preguiça mines) carried physiological alterations compared to shrews from an unpolluted site. Here, we further investigated whether these populations showed genetic differences in genes relevant for physiological homeostasis and/or that are associated with pathways altered in animals living under chronic exposure to pollution, and which could be used as biomarkers. We analysed the mitochondrial cytochrome b (Cytb) gene and intronic and/or exonic regions of four nuclear genes: CYP1A1, LCAT, PRPF31, and p53. We observed (1) population differences in allele frequencies, types of variation, and diversity parameters in the Cytb, CYP1A1, and p53 genes; (2) purifying selection of Cytb in the mine populations; (3) genetic differentiation of the two mine populations from the reference by the p53 gene. Adding to our previous observations with Mus spretus, we provide unequivocal evidence of a population effect exerted by the contaminated environment of the mines on the local species of small mammals.


Assuntos
Metais Pesados , Musaranhos , Animais , Biomarcadores , Citocromo P-450 CYP1A1 , Citocromos b , Monitoramento Ambiental , Humanos , Metais Pesados/metabolismo , Metais Pesados/toxicidade , Camundongos , Musaranhos/metabolismo , Proteína Supressora de Tumor p53
5.
J Biol Chem ; 297(4): 101147, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34520756

RESUMO

The heterogeneity of respirable particulates and compounds complicates our understanding of transcriptional responses to air pollution. Here, we address this by applying precision nuclear run-on sequencing and the assay for transposase-accessible chromatin sequencing to measure nascent transcription and chromatin accessibility in airway epithelial cells after wood smoke particle (WSP) exposure. We used transcription factor enrichment analysis to identify temporally distinct roles for ternary response factor-serum response factor complexes, the aryl hydrocarbon receptor (AHR), and NFκB in regulating transcriptional changes induced by WSP. Transcription of canonical targets of the AHR, such as CYP1A1 and AHRR, was robustly increased after just 30 min of WSP exposure, and we discovered novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L. Transcription of these genes and associated enhancers rapidly returned to near baseline by 120 min after exposure. The kinetics of AHR- and NFκB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining NFκB-mediated responses through 120 min of exposure. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFκB signaling in controlling proinflammatory gene expression. This work also defines an integrated genomics-based strategy for deconvoluting multiplexed transcriptional responses to heterogeneous environmental exposures.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Fumaça/efeitos adversos , Transcrição Genética , Madeira , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Transformada , Montagem e Desmontagem da Cromatina , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , DNA (Citosina-5-)-Metiltransferases/biossíntese , DNA (Citosina-5-)-Metiltransferases/genética , Humanos , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Células NIH 3T3 , Receptores de Hidrocarboneto Arílico/genética , Proteínas Repressoras/genética
6.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502168

RESUMO

Autism spectrum disorder (ASD) is an umbrella term that includes many different disorders that affect the development, communication, and behavior of an individual. Prevalence of ASD has risen exponentially in the past couple of decades. ASD has a complex etiology and traditionally recognized risk factors only account for a small percentage of incidence of the disorder. Recent studies have examined factors beyond the conventional risk factors (e.g., environmental pollution). There has been an increase in air pollution since the beginning of industrialization. Most environmental pollutants cause toxicities through activation of several cellular receptors, such as the aryl hydrocarbon receptor (AhR)/cytochrome P450 (CYPs) pathway. There is little research on the involvement of AhR in contributing to ASD. Although a few reviews have discussed and addressed the link between increased prevalence of ASD and exposure to environmental pollutants, the mechanism governing this effect, specifically the role of AhR in ASD development and the molecular mechanisms involved, have not been discussed or reviewed before. This article reviews the state of knowledge regarding the impact of the AhR/CYP pathway modulation upon exposure to environmental pollutants on ASD risk, incidence, and development. It also explores the molecular mechanisms involved, such as epigenesis and polymorphism. In addition, the review explores possible new AhR-mediated mechanisms of several drugs used for treatment of ASD, such as sulforaphane, resveratrol, haloperidol, and metformin.


Assuntos
Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/metabolismo , Suscetibilidade a Doenças , Poluentes Ambientais/efeitos adversos , Receptores de Hidrocarboneto Arílico/metabolismo , Poluição do Ar/efeitos adversos , Animais , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Biomarcadores , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Modelos Animais de Doenças , Exposição Ambiental/efeitos adversos , Poluição Ambiental/efeitos adversos , Epigênese Genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais
7.
Phys Chem Chem Phys ; 23(36): 20230-20246, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34474468

RESUMO

Research on action selectivity between CYP1A1 and CYP1B1 is particularly valuable for cancer chemoprevention and chemotherapy. However, they share a very close similarity in their ligand-binding pockets that α-naphthoflavone (ANF) is the co-crystal ligand for both isoforms, which poses a major challenge in revealing their selectivity mechanism. Therefore, three selective CYP1B1 inhibitors derived from ANF were selected to illustrate the structural basis for the selectivity between the two isoforms via a comprehensive computational strategy. It was found that the sustainability of the π-π stacking interactions with the phenylalanine residues of the two isoforms, namely, Phe123, Phe224, and Phe258 for CYP1A1, and Phe134, Phe231, and Phe268 for CYP1B1, played a crucial role in determining the selectivity of ligands with a classic aromatic conjugation system like ANF and its derivatives for CYP1B1 versus CYP1A1. Of note, the structural flexibility of the corresponding protein domains mainly orchestrated the sustainability of the corresponding π-π stacking interactions, thereby determining the binding selectivity. Therefore, the structure modification of naphthoflavone lead compounds into preferable binding configurations to satisfy the π-π stacking interactions of the key phenylalanine residues within CYP1B1 would be an inspiring strategy devised to improve the inhibitory selectivity towards CYP1B1. Collectively, this study revealed valuable insight into understanding the selective mechanism between CYP1A1 and CYP1B1 from the perspective of structural flexibility, which sheds light on the future rational design of CYP1B1 selective inhibitors.


Assuntos
Benzoflavonas/farmacologia , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1B1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Benzoflavonas/química , Citocromo P-450 CYP1A1/química , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/química , Citocromo P-450 CYP1B1/metabolismo , Inibidores Enzimáticos/química , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular
8.
Toxicol Lett ; 352: 26-33, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34571075

RESUMO

Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants. They are constantly detected in terrestrial, ocean, and atmospheric systems, and it is of particular concern that these fat-soluble xenobiotics may have a negative impact on human health. This study aimed to evaluate the toxic effect and underlying mechanism of decabromodiphenyl ether (BDE-209) on human liver in a HepG2 cell model. The results showed that BDE-209 significantly induced HepG2 cells apoptosis, increased intracellular reactive oxygen species (ROS), disturbed [Ca 2+] homeostasis and mitochondrial membrane potential (MMP), and caused nuclear shrinkage and DNA double-strand breaks. BDE-209 also significantly decreased the activities of antioxidant parameters, superoxide dismutase (SOD), total antioxygenic capacity (T-AOC), glutathione (GSH), and total glutathione (T-GSH). The up-regulation of the Aryl hydrocarbon receptor (AhR)/cytochrome P4501A1 (CYP1A1) signaling pathway indicates that after long-term and high-dose exposure, BDE-209 may be a liver carcinogen. Interestingly, HepG2 cells attempt to metabolize BDE-209 through the Nrf2-mediated antioxidant pathway. These findings help elucidate the mechanisms of BDE-209-induced hepatotoxicity in humans.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Éteres Difenil Halogenados/toxicidade , Hepatócitos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Antioxidantes/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Citocromo P-450 CYP1A1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/genética
9.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360828

RESUMO

The environmental pollutant benzo[a]pyrene (BaP) is a human carcinogen that reacts with DNA after metabolic activation catalysed by cytochromes P450 (CYP) 1A1 and 1B1 together with microsomal epoxide hydrolase. The azo dye Sudan I is a potent inducer of CYP1A1/2. Here, Wistar rats were either treated with single doses of BaP (150 mg/kg bw) or Sudan I (50 mg/kg bw) alone or with both compounds in combination to explore BaP-derived DNA adduct formation in vivo. Using 32P-postlabelling, DNA adducts generated by BaP-7,8-dihydrodiol-9,10-epoxide were found in livers of rats treated with BaP alone or co-exposed to Sudan I. During co-exposure to Sudan I prior to BaP treatment, BaP-DNA adduct levels increased 2.1-fold in comparison to BaP treatment alone. Similarly, hepatic microsomes isolated from rats exposed to Sudan I prior to BaP treatment were also the most effective in generating DNA adducts in vitro with the activated metabolites BaP-7,8-dihydrodiol or BaP-9-ol as intermediates. DNA adduct formation correlated with changes in the expression and/or enzyme activities of CYP1A1, 1A2 and 1B1 in hepatic microsomes. Thus, BaP genotoxicity in rats in vivo appears to be related to the enhanced expression and/or activity of hepatic CYP1A1/2 and 1B1 caused by exposure of rats to the studied compounds. Our results indicate that the industrially employed azo dye Sudan I potentiates the genotoxicity of the human carcinogen BaP, and exposure to both substances at the same time seems to be hazardous to humans.


Assuntos
Benzo(a)pireno/toxicidade , Citocromo P-450 CYP1A1/metabolismo , Adutos de DNA/toxicidade , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Naftóis/toxicidade , Animais , Carcinógenos Ambientais/toxicidade , Corantes/toxicidade , Masculino , Ratos , Ratos Wistar
10.
Environ Pollut ; 285: 117526, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34380224

RESUMO

Benzo[a]pyrene (BaP) is a high-risk contaminant of elevated toxicity. Its biotransformation process occurs as the expression of CYP1A1 increases and produces toxic metabolites. In turn, α-naphthoflavone (aNF) represents an inhibitor of CYP1A1, preventing BaP metabolism. Toxicological studies in anurans show alterations in the melanomacrophage (MM) detoxification cell after exposure to xenobiotics. In this study, the production of melanin by MMs was evaluated, as were morphological alterations in the cytoskeleton, phagocytosis and the genotoxicity effects after exposure of an anuran species to BaP and aNF. Physalaemus cuvieri received subcutaneous injections of 2 mg/kg and/or 20 mg/kg aNF. For phagocytosis analyses, animals received an intraperitoneal injection with 0.4% trypan blue. The results revealed that melanin synthesis increased by 503.2% in animals exposed to BaP after 48 h, which was related to the antioxidant action of melanin, whereas the decreased in synthesis of 25.6% with the BaP + aNF interaction resulted in high toxicity to MMs and cell degeneration. The phagocytic activity reduced to 37.6% in animals exposed to BaP, characterizing a functional impairment; however, the BaP + aNF interaction led to the restoration of phagocytosis, reaching 419.23%. The decreased rate or absence of abnormalities may be explained by the fact that only the less damaged erythrocytes remained in the bloodstream, whereas the most damaged cells died. In conclusion, BaP and aNF are toxic to P. cuvieri, bringing risks to herpetofauna.


Assuntos
Anuros , Benzo(a)pireno , Animais , Benzo(a)pireno/toxicidade , Benzoflavonas , Citocromo P-450 CYP1A1 , Eritrócitos
11.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371875

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) have been recognized to cause neurobehavioral dysfunctions and disorder of cognition and behavioral patterns in childhood. Momordica charantia L. (MC) has been widely known for its nutraceutical and health-promoting properties. To date, the effect of MC for the prevention and handling of PAHs-induced neurotoxicity has not been reported. In the current study, the neuroprotective effects of MC and its underlying mechanisms were investigated in mouse hippocampal neuronal cell line (HT22); moreover, in silico analysis was performed with the phytochemicals MC to decipher their potential function as neuroprotectants. MC was demonstrated to possess neuroprotective effect by reducing reactive oxygen species' (ROS') production and down-regulating cyclin D1, p53, and p38 mitogen-activated protein kinase (MAPK) protein expressions, resulting in the inhibition of cell apoptosis and the normalization of cell cycle progression. Additionally, 28 phytochemicals of MC and their competence on inhibiting cytochrome P450 (CYP: CYP1A1, CYP1A2, and CYP1B1) functions were resolved. In silico analysis of vitamin E and stigmasterol revealed that their binding to either CYP1A1 or CYP1A2 was more efficient than the binding of each positive control (alizarin or purpurin). Together, MC is potentially an interesting neuroprotectant including vitamin E and stigmasterol as probable active components for the prevention for PAHs-induced neurotoxicity.


Assuntos
Hipocampo/efeitos dos fármacos , Momordica charantia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Estigmasterol/farmacologia , Vitamina E/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Momordica charantia/química , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Estigmasterol/isolamento & purificação , Vitamina E/isolamento & purificação
12.
Sci Rep ; 11(1): 16997, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417533

RESUMO

Nanoparticulate matter activates the aryl hydrocarbon receptor (AhR) pathway in the respiratory system in a process involving the AhR nuclear translocator (ARNT) and cytochrome P450 family 1, member A1 (CYP1A1). We examined changes in AhR-related pathways following intranasal instillation of nanoparticulate matter in the olfactory bulb and cerebral cortex. Twice a day for 5 days per week for 1 week or 2 weeks, 8-week-old Sprague-Dawley rats were intranasally instilled with 10 µL nanoparticulate matter (nano group; n = 36). An equal volume of saline was intranasally instilled in control rats (n = 36). One week after intranasal instillation, olfactory function and Y-maze tests were performed. The expression levels of AhR in the olfactory bulb and temporal cortex were analyzed using western blotting and immunofluorescence assays. The expression levels of AhR, CYP1A1, inducible nitric oxide synthase (iNOS), and five genes encoding cation transporters (ARNT, ATP7B, ATPB1, OCT1, and OCT2) in the olfactory bulb were analyzed using quantitative reverse transcription. The olfactory discrimination capability was reduced in the nano group compared with the control group. Proportional changes in the Y-maze test were not significantly different between the nano and control groups. AhR mRNA and protein expression in the olfactory bulb increased 1.71-fold (P < 0.001) and 1.60-fold (P = 0.008), respectively. However, no significant changes were observed in the temporal cortex. In the olfactory bulb, the expression of ARNT, ATP7B, ATPB1, and OCT2 was downregulated. CYP1A1 and iNOS expression in the olfactory bulb was upregulated compared with that in the temporal cortex. The intranasal instillation of nanoparticulate matter decreased the olfactory discrimination ability, which was accompanied by upregulation of AhR expression and downregulation of cation transporters in the olfactory bulb.


Assuntos
Nanopartículas/administração & dosagem , Bulbo Olfatório/fisiologia , Administração Intranasal , Animais , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Regulação da Expressão Gênica , Metais Pesados/análise , Nanopartículas/ultraestrutura , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Bulbo Olfatório/ultraestrutura , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Olfato
13.
Sci Rep ; 11(1): 16629, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404832

RESUMO

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , COVID-19/tratamento farmacológico , Carbazóis/farmacologia , Omeprazol/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , COVID-19/virologia , Carbazóis/uso terapêutico , Chlorocebus aethiops , Citocromo P-450 CYP1A1/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Omeprazol/uso terapêutico , RNA-Seq , Receptores de Hidrocarboneto Arílico/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Células Vero , Internalização do Vírus/efeitos dos fármacos
14.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299011

RESUMO

Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF.


Assuntos
Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Fraturas do Fêmur/genética , Fraturas do Fêmur/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Citocromo P-450 CYP1A1/química , Difosfonatos/uso terapêutico , Fraturas do Fêmur/enzimologia , Humanos , Incidência , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Filogenia , Alinhamento de Sequência
15.
Sci Rep ; 11(1): 14572, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272429

RESUMO

Reports of genetic association of polymorphisms with lung cancer in the Indian subcontinent are often conflicting. To summarise and replicate published evidence for association with lung cancer and its subgroups. We performed a meta-analysis of candidate associations on lung cancer, its histological subtypes and smoking status in the Indian subcontinent following PRISMA guidelines. Multiple testing corrections were done by the Benjamini-Hochberg method through assessment of significance at a false discovery rate of 10%. We genotyped and investigated rs1048943/CYP1A1 in a case-control sample from eastern India, followed by its global meta-analysis using a similar protocol. Meta-analysis of 18 variants of 11 genes reported in 39 studies (7630 cases and 8169 controls) showed significant association of rs1048943/CYP1A1 [2.07(1.49-2.87)] and rs4646903/CYP1A1 [1.48(1.93-1.95)] with overall lung cancer risk at 10% FDR, while nominal association (p < 0.05) was observed for del1/GSTT1, del2/GSTM1, rs1695/GSTP1 and rs17037102/ DKK2. Subtype analysis showed a significant association of del1/GSTT1 with adenocarcinoma, rs4646903/CYP1A1 with squamous carcinoma, and rs1048943/CYP1A1 with both. Association of rs4646903/CYP1A1 in smokers and effect modification by meta-regression analysis was observed. Genotyping of rs1048943/CYP1A1 that presented significant heterogeneity (p < 0.1) revealed an association with adenocarcinoma among eastern Indian smokers, while a global meta-analysis in 10458 cases and 10871 controls showed association with lung cancer and its subgroups. This study identified the susceptibility loci for lung cancer and its covariate-subgroups.


Assuntos
Adenocarcinoma de Pulmão/genética , Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A1/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Variação Genética , Técnicas de Genotipagem , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar , Adulto Jovem
16.
Environ Toxicol Pharmacol ; 87: 103704, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34273545

RESUMO

A luciferase reporter gene-based bioassay battery consisting of stress-activated receptors from fish, complemented with traditional fish cell-based bioassays, were used to assess the toxicity of marine sediment samples from the Byfjorden area around the city of Bergen (Norway). The reporter assays covered a wide range of cellular signalling and metabolic pathways, representing different molecular initiating events in the adverse outcome pathway framework. Cytotoxicity, generation of reactive oxygen-species, and induction of 7-ethoxyresorufin-O-deethylase activity were analysed using fish liver and gill cell lines. Chemical analyses of the sediment extracts revealed complex contamination profiles, especially at the innermost stations, which contained a wide array of persistent organic pollutants, polycyclic aromatic hydrocarbons, and metals. Sediment extracts from these sites were more potent in activating the stress-activated receptors than the other extracts, reflecting their toxicant profiles. Importantly, receptor- and cell-based bioassays complemented the chemical analyses and provided important data for future environmental risk assessments of urban marine sediments.


Assuntos
Sedimentos Geológicos , Poluentes Químicos da Água/toxicidade , Animais , Bioensaio , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP1A1/metabolismo , Peixes , Genes Reporter , Éteres Difenil Halogenados/análise , Éteres Difenil Halogenados/toxicidade , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/toxicidade , Luciferases/genética , Metais Pesados/análise , Metais Pesados/toxicidade , Noruega , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Poluentes Químicos da Água/análise
17.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201250

RESUMO

Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.


Assuntos
Cuminum/química , Estradiol/toxicidade , Estrogênios/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Mamárias Experimentais/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , MicroRNAs/genética , Ratos , Ratos Endogâmicos ACI
18.
Environ Toxicol Pharmacol ; 87: 103699, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34237467

RESUMO

Tris (2-chloroethyl) phosphate (TCEP) is an emerging aquatic environmental pollutant. In the present study, juvenile yellow catfish (Pelteobagrus fulvidraco) were exposed to environmentally relevant concentrations of TCEP for 30 days. The results showed that TCEP exposure decreased the survival rate (100 µg/L), body weight (10 and 100 µg/L) and specific growth rate (10 and 100 µg/L) of juvenile yellow catfish. Exposure to TCEP resulted in pronounced damages of gill structures. Gene transcription analysis showed that the antioxidant capacity of the liver and gills was affected; CYP1A1 might contribute to phase I metabolism of TCEP in the liver rather than CYP1B1; TCEP stress might increase the demand of ion transport in fish gill; TCEP could stimulate the immune response and might induce apoptosis via a p53-Bax pathway and caspase-dependent pathway in gills. Collectively, these findings provide new insights into the toxic effects of TCEP on fish.


Assuntos
Peixes-Gato , Retardadores de Chama/toxicidade , Organofosfatos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Peixes-Gato/genética , Peixes-Gato/crescimento & desenvolvimento , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Proteínas de Peixes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Brânquias/patologia , Glutationa Transferase/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Osmorregulação/efeitos dos fármacos , Osmorregulação/genética , Oxirredutases/genética
19.
Genet Test Mol Biomarkers ; 25(7): 486-495, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34280004

RESUMO

Objective: Breast cancer (BC), the most prevalent cancer in women, has been associated with several genetic factors, including the CYP19A1 rs700519 polymorphism; however, the conclusions have not been consistent. This case-control study and meta-analysis aimed to further assess the relationship between the CYP19A1 rs700519 polymorphism and BC susceptibility. Materials and Methods: We conducted a case-control study to assess the relationship of the CYP19A1 rs700519 polymorphism with the risk and prognosis of BC. Subsequently, we performed a meta-analysis of the case-control studies. Results: In the case-control study, we found a significant negative relationship between the rs700519 AA genotype and risk (χ2 = 7.503, p < 0.01) and disease-free survival rates (hazard rate = 0.400, 95% confidence interval [CI] = 0.181-0.883, p < 0.01) of patients with BC, especially in postmenopausal hormone receptor-positive (HR+) patients. Nine case-control studies were included in the meta-analysis. The CYP19A1 rs700519 polymorphism was significantly associated with BC susceptibility in the dominant (odds ratio [OR] = 0.95, 95% CI = 0.90-1.00, p = 0.05) and allelic models (OR = 0.84, 95% CI = 0.75-0.93, p < 0.01), but not in the recessive model. Sensitivity analysis revealed that the study results were stable, whereas the funnel plot revealed some publication bias. Conclusions: The CYP19A1 rs700519 polymorphism is related to breast tumorigenesis.


Assuntos
Aromatase/genética , Neoplasias da Mama/genética , Adulto , Alelos , Estudos de Casos e Controles , China/epidemiologia , Citocromo P-450 CYP1A1/genética , Suscetibilidade a Doenças , Intervalo Livre de Doença , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Fatores de Risco
20.
Sci Rep ; 11(1): 14927, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290363

RESUMO

Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR-/- mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with µCT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.


Assuntos
Benzo(a)pireno/efeitos adversos , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Citocromo P-450 CYP1A1/metabolismo , Osteoartrite/genética , Osteoartrite/prevenção & controle , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Articulação Temporomandibular/metabolismo , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Citocromo P-450 CYP1A1/genética , Modelos Animais de Doenças , Redução da Medicação , Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Osteogênese/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/genética , Fumar/efeitos adversos
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