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1.
Toxicol Lett ; 332: 146-154, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32683294

RESUMO

Occludin is an important tight junction (TJ) protein in pulmonary epithelial cells. In this study, we identified changes in occludin in arsenic-induced lung injury in vivo and in vitro. Upon intratracheal instillation with arsenic trioxide (As2O3) at a daily dose of 30 µg/kg for 1 week, levels of occludin mRNA and protein expression decreased significantly in mouse lung tissue. Levels of occludin mRNA and protein expression in BEAS-2B cells were reduced upon exposure to As2O3 in a concentration- and time-dependent manner. In addition, exposure to As2O3 significantly increased expression of p-p38, p-ERK1/2, p-ELK1, and MLCK in mouse lung tissue and BEAS-2B cells. Treatment with As2O3 induced oxidative stress in mouse lung tissue and BEAS-2B cells. In BEAS-2B cells, exposure to As2O3 reduced transepithelial resistance, which was partially restored with N-acetyl-cysteine (NAC) treatment. Reduced expression of occludin mRNA and protein induced by As2O3 was entirely restored with NAC and resveratrol. However, SB203580, PD98059, and ML-7 partially blocked As2O3-induced occludin reduction in BEAS-2B cells. These results indicate that As2O3 inhibits occludin expression in vivo and in vitro at least partially via the ROS/ERK/ELK1/MLCK and ROS/p38 MAPK signaling pathways.


Assuntos
Arsenitos/toxicidade , Pulmão/metabolismo , Ocludina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocludina/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/efeitos dos fármacos , Peptídeos/metabolismo , Espécies Reativas de Oxigênio , Superóxido Dismutase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos
2.
Ecotoxicol Environ Saf ; 201: 110802, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531573

RESUMO

Extended exposure to inorganic arsenic through contaminated drinking water has been linked with increased incidence of diabetes mellitus. The most common exposure occurs through the consumption of contaminated drinking water mainly through geogenic sources of inorganic arsenic. Epigenetic modifications are important mechanisms through which environmental pollutants could exert their toxic effects. Bisulfite sequencing polymerase chain reaction method followed by Sanger sequencing was performed for DNA methylation analysis. Our results showed that sodium arsenite treatment significantly reduced insulin secretion in pancreatic islets. It was revealed that the methylation of glucose transporter 2 (Glut2) gene was changed at two cytosine-phosphate-guanine (CpG) sites (-1743, -1734) in the promoter region of the sodium arsenite-treated group comparing to the control. No changes were observed in the methylation status of peroxisome proliferator-activated receptor-gamma (PPARγ), pancreatic and duodenal homeobox 1 (Pdx1) and insulin 2 (Ins2) CpG sites in the targeted regions. Measuring the gene expression level showed increase in Glut2 expression, while the expression of insulin (INS) and Pdx1 were significantly affected by sodium arsenite treatment. This study revealed that exposure to sodium arsenite changed the DNA methylation pattern of Glut2, a key transporter of glucose entry into the pancreatic beta cells (ß-cells). Our data suggested possible epigenetic-mediated toxicity mechanism for arsenite-induced ß-cells dysfunction. Further studies are needed to dissect the precise epigenetic modulatory activity of sodium arsenite that affect the biogenesis of insulin.


Assuntos
Arsenitos/toxicidade , Metilação de DNA/efeitos dos fármacos , Transportador de Glucose Tipo 2/genética , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Compostos de Sódio/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Epigênese Genética/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Técnicas In Vitro , Insulina/genética , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Transativadores/genética
3.
Chem Biol Interact ; 327: 109162, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32524993

RESUMO

Hundreds of millions of people worldwide are exposed to unacceptable levels of carcinogenic inorganic arsenic. Animal models have shown that selenium and arsenic are mutually protective through the formation and elimination of the seleno-bis(S-glutathionyl) arsinium ion [(GS)2AsSe]-. Consistent with this, human selenium deficiency in arsenic-endemic regions is associated with arsenic-induced disease, leading to the initiation of human selenium supplementation trials. In contrast to the protective effect observed in vivo, in vitro studies have suggested that selenite increases arsenite cellular retention and toxicity. This difference might be explained by the rapid conversion of selenite to selenide in vivo. In the current study, selenite did not protect the human hepatoma (HepG2) cell line against the toxicity of arsenite at equimolar concentrations, however selenide increased the IC50 by 2.3-fold. Cytotoxicity assays of arsenite + selenite and arsenite + selenide at different molar ratios revealed higher overall mutual antagonism of arsenite + selenide toxicity than arsenite + selenite. Despite this protective effect, in comparison to 75Se-selenite, HepG2 cells in suspension were at least 3-fold more efficient at accumulating selenium from reduced 75Se-selenide, and its accumulation was further increased by arsenite. X-ray fluorescence imaging of HepG2 cells also showed that arsenic accumulation, in the presence of selenide, was higher than in the presence of selenite. These results are consistent with a greater intracellular availability of selenide relative to selenite for protection against arsenite, and the formation and retention of a less toxic product, possibly [(GS)2AsSe]-.


Assuntos
Arsenitos/toxicidade , Substâncias Protetoras/farmacologia , Ácido Selenioso/farmacologia , Compostos de Selênio/farmacologia , Arsênico/metabolismo , Arsenitos/metabolismo , Células Hep G2 , Humanos , Inativação Metabólica/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Radioisótopos/metabolismo , Ácido Selenioso/metabolismo , Selênio/metabolismo , Compostos de Selênio/metabolismo , Radioisótopos de Selênio/metabolismo
4.
Ecotoxicol Environ Saf ; 201: 110820, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531574

RESUMO

Growth hormone (GH)/insulin-like growth factor (IGF) axis plays a critical role in fetal development. However, the effect of arsenite exposure on the GH/IGF axis and its toxic mechanism are still unclear. Zebrafish embryos were exposed to a range of NaAsO2 concentrations (0.0-10.0 mM) between 4 and 120 h post-fertilization (hpf). Development indexes of survival, malformation, hatching rate, heart rate, body length and locomotor behavior were measured. Hormone levels, GH/IGF axis-related genes, and nerve-related genes were also tested. The results showed that survival rate, hatching rate, heart rate, body length and locomotor behavior all decreased, while deformity increased. At 120 hpf, the survival rate of zebrafish in 1.5 mM NaAsO2 group was about 70%, the deformity rate exceeded 20%, and the body length shortened to 3.35 mm, the movement distance of zebrafish decreased approximately 63.6% under light condition and about 52.4% under dark condition. The level of GH increased and those of IGF did not change significantly, while the expression of GH/IGF axis related genes (ghra, ghrb, igf2r, igfbp3, igfbp2a, igfbp5b) and nerve related genes (dlx2, shha, ngn1, elavl3, gfap) decreased. In 1.5 mM NaAsO2 group, the decrease of igfbp3 and igfbp5b was almost obvious, about 78.2% and 72.2%. The expression of nerve genes in 1.5 mM NaAsO2 group all have declined by more than 50%. These findings suggested that arsenite exerted disruptive effects on the endocrine system by interfering with the GH/IGF axis, leading to zebrafish embryonic developmental toxicity.


Assuntos
Arsenitos/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Somatomedinas/metabolismo , Peixe-Zebra , Animais , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/genética , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/embriologia , Sistema Endócrino/metabolismo , Hormônio do Crescimento/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Transdução de Sinais , Somatomedinas/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
5.
Ecotoxicol Environ Saf ; 201: 110735, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32480163

RESUMO

Methyl jasmonate (Me-JA) is a plant growth regulator known for modulating plant responses to various abiotic and biotic stresses. The unavoidable arsenic (As) contamination in rice (Oryza sativa) results in reduced crop yield and greater carcinogenic risk to humans. The present work examines the significance of Me-JA induced molecular signaling and tolerance towards arsenic toxicity in rice. The arsenite (AsIII; 25 µM) stress hampered the overall growth and development of the rice seedling. However, the co-application (25 µM AsIII+0.25 µM Me-JA) resulted in increased biomass, chlorophyll content, enhanced antioxidant enzyme activities as compared to AsIII treated plants. The co-application also demonstrated a marked decrease in malondialdehyde content, electrolyte leakage and accumulation of total AsIII content (root + shoot) as compared to AsIII treated plants. The co-application also modulated the expression of genes involved in downstream JA signaling pathway (OsCOI, OsJAZ3, OsMYC2), AsIII uptake (OsLsi1, OsLsi2, OsNIP1;1, OsNIP3;1), translocation (OsLsi6, and OsINT5) and detoxification (OsNRAMP1, OsPCS2, and OsABCC2) which revealed the probable adaptive response of the rice plant to cope up arsenic stress. Our findings reveal that Me-JA alleviates AsIII toxicity by modulating signaling components involved in As uptake, translocation, and detoxification and JA signaling in rice. This study augments our knowledge for the future use of Me-JA in improving tolerance against AsIII stress.


Assuntos
Acetatos/farmacologia , Arsênico/toxicidade , Ciclopentanos/farmacologia , Oryza/efeitos dos fármacos , Oxilipinas/farmacologia , Reguladores de Crescimento de Planta/farmacologia , Acetatos/metabolismo , Arsênico/metabolismo , Arsenitos/metabolismo , Arsenitos/toxicidade , Transporte Biológico , Ciclopentanos/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Humanos , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Oxilipinas/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos
6.
Nucleic Acids Res ; 48(12): 6855-6873, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32406909

RESUMO

Cells limit energy-consuming mRNA translation during stress to maintain metabolic homeostasis. Sequestration of mRNAs by RNA binding proteins (RBPs) into RNA granules reduces their translation, but it remains unclear whether RBPs also function in partitioning of specific transcripts to polysomes (PSs) to guide selective translation and stress adaptation in cancer. To study transcript partitioning under cell stress, we catalogued mRNAs enriched in prostate carcinoma PC-3 cell PSs, as defined by polysome fractionation and RNA sequencing (RNAseq), and compared them to mRNAs complexed with the known SG-nucleator protein, G3BP1, as defined by spatially-restricted enzymatic tagging and RNAseq. By comparing these compartments before and after short-term arsenite-induced oxidative stress, we identified three major categories of transcripts, namely those that were G3BP1-associated and PS-depleted, G3BP1-dissociated and PS-enriched, and G3BP1-associated but also PS-enriched. Oxidative stress profoundly altered the partitioning of transcripts between these compartments. Under arsenite stress, G3BP1-associated and PS-depleted transcripts correlated with reduced expression of encoded mitochondrial proteins, PS-enriched transcripts that disassociated from G3BP1 encoded cell cycle and cytoprotective proteins whose expression increased, while transcripts that were both G3BP1-associated and PS-enriched encoded proteins involved in diverse stress response pathways. Therefore, G3BP1 guides transcript partitioning to reprogram mRNA translation and support stress adaptation.


Assuntos
DNA Helicases/genética , Estresse Oxidativo/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Biossíntese de Proteínas/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , RNA Mensageiro/genética , Arsenitos/toxicidade , Carcinoma/genética , Carcinoma/metabolismo , Grânulos Citoplasmáticos/genética , Metabolismo Energético/genética , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas de Ligação a RNA/genética
7.
Ecotoxicol Environ Saf ; 200: 110743, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464441

RESUMO

Gill, as the organ of fish to contact most directly with xenobiotics, suffered more threat. To evaluate the impact of arsenite (AsIII) on the gill of fish, we measured the antioxidative responses (superoxide dismutase (SOD) and catalase (CAT) activities) and oxidative damage (malondialdehyde (MDA) content), histological changes and mRNA transcriptional responses of zebrafish gill, after exposure to AsIII (0, 10, 50, 100, and 150 µg L-1) solutions for 28 days. We found that AsIII increased the activities of CAT by 46%-87%, decreased the activities of SOD and the contents of MDA by 19% and 21%-32%. Furthermore, CuZnSOD and MnSOD mRNA transcription levels were also inhibited, decreasing by 62%-82% and 70%-77%. Besides, ≥ 100 µg L-1 AsIII also caused histological changes (a loss of mucus and desquamation in the surface of the epithelial cells) on zebrafish gill. These results showed that low concentrations of AsIII influenced biochemical and physiological performances of fish gill, which probably aggravates the toxic effect of AsIII on fish.


Assuntos
Arsenitos/toxicidade , Brânquias/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Brânquias/metabolismo , Brânquias/patologia , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
8.
Ecotoxicol Environ Saf ; 200: 110742, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470681

RESUMO

The accumulation of arsenic in rice has become a worldwide concern. In this study, dose-dependency in tissues (intestine, liver and kidney) and blood distribution of inorganic arsenicals and their methylated metabolites were investigated in male C57BL/6 mice exposed to four arsenic species (arsenite [iAs]III, arsenate [iAs]V, monomethylarsonate [MMA]V, and dimethylarsinate [DMA]V) at four doses (control [C]: 0 µg/g, simulation [S]: 0.91 µg/g, medium [M]: 9.1 µg/g and high [H]: 30 µg/g) according to the arsenical composition in rice for 8 and 16 weeks. No adverse effects were observed, while body weight gain decreased in group H. Increases in total arsenic concentrations (CtAs) and histopathological changes in the tissues occurred in all of the test groups. CtAs presented a tendency of kidney > intestine > liver > blood and were time-/dose-dependent in the liver and kidney in groups M and H. In the intestine and blood, abundant iAs (23%-28% in blood and 36%-49% in intestine) was detected in groups M and H, and CtAs decreased in group H from the 8th week to the 16th week. PMI decreased in the liver and SMI decreased in the kidney. These results indicate that the three tissues are injured through food arsenic. The intestine can also accumulate food arsenic, and the high arsenic dose will cause a deficiency in the absorbing function of the intestine. Thus, long-term exposure to arsenic-contaminated rice should be taken seriously attention.


Assuntos
Intoxicação por Arsênico , Arsenicais/farmacocinética , Animais , Arseniatos/farmacocinética , Arseniatos/toxicidade , Intoxicação por Arsênico/metabolismo , Intoxicação por Arsênico/patologia , Arsenitos/farmacocinética , Arsenitos/toxicidade , Ácido Cacodílico/farmacocinética , Ácido Cacodílico/toxicidade , Exposição Dietética , Intestinos/efeitos dos fármacos , Intestinos/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oryza/metabolismo
9.
Ecotoxicology ; 29(5): 613-624, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32385600

RESUMO

Arsenic is ubiquitously present in the aquatic environment. We investigated the acute toxic effects of arsenite [As(III)] exposure on rare minnows (Gobiocypris rarus) in vivo. The 96-h LC50 value for exposure to As(III) was 13.73 mg/L. As(III) bioaccumulation in different tissues was measured using inductively-coupled plasma mass spectrometry, and the extent of As(III) accumulation was, from greatest to least, liver > intestine > gills > muscle > kidney > testis > brain. Histological examination revealed that in As(III)-treated fish, numerous cellular and tissue alterations were present in the gill, liver, and intestine tissues. Moreover, transmission electron microscopy showed ultrastructural alterations in hepatocytes. We also performed transcriptome analyses to investigate As(III)-induced toxicity response in the liver of As(III)-treated fish; various oxidative-related genes were differentially expressed, and their expression levels were further validated using qPCR. This study is one of the many steps we aim to take on the way to promote the rare minnow to an international standard laboratory animal.


Assuntos
Arsenitos/toxicidade , Cyprinidae/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Perfilação da Expressão Gênica , Masculino , Testes de Toxicidade
10.
Chemosphere ; 251: 126466, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32443253

RESUMO

Arsenic is a naturally occurring environmental toxicant. Chronic exposure to arsenic is linked with neurological damage. Although the mechanisms remain to be elucidated, it is currently believed that neural cell apoptosis is one of the underlying mechanisms of arsenic-induced neurotoxicity. Calreticulin (CRT) is a quality control chaperone located in the lumen of the endoplasmic reticulum (ER), which participates in many signaling pathways including apoptosis. However, the role of CRT in apoptosis is controversial. Whether CRT plays a role in arsenite-induced apoptosis and the relationship between CRT and ER stress-mediated apoptosis have not been mentioned before. In this study, we found that CRT expression as well as the cell apoptosis levels increased in a dose dependent manner upon arsenite exposure in HT-22 cells, a mouse hippocampal neural cell line. In addition, arsenite exposure resulted in the up-regulation of ER stress indicator GRP78 and ER stress-related proteins including p-PERK, ATF4, CHOP, calpain2 and cleaved caspases-12, accompanied by the down-regulation of Bcl-2 and up-regulation of Bax and cleaved caspase-3. Silence of CRT remarkably alleviated arsenite-induced apoptosis and reversed the expression of the proteins above. Our findings confirmed the role of CRT in the induction of apoptosis upon arsenite exposure and suggested that CRT mediated the intrinsic apoptotic cell death including both mitochondria-dependent (PERK/ATF4/CHOP/Bcl-2) and independent (calpain2/caspases-12) pathways initiated by ER stress, which we believed to be a previously undocumented property of arsenite-induced apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Arsenitos/toxicidade , Calreticulina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Linhagem Celular , Regulação para Baixo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Camundongos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Regulação para Cima
11.
Ecotoxicol Environ Saf ; 199: 110675, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32402895

RESUMO

An oral painless dietary therapy is also indispensable in the management of arsenic toxicity despite of its conventional painful therapeutic management. The present study focused on the management of arsenic mediated female reproductive dysfunctions by dietary therapy of N-acetyl cysteine (NAC). Here, sodium arsenite was given at the dose of 10 mg/kg body weight orally for the first 8 day. Day 9 onwards up to day 16 these arsenicated rats were provided with NAC (250 mg/kg body weight) enriched basal diet once daily. Arsenic intoxicated group exhibited a comparable inactivation of antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) due to oxidative stress in reproductive organs along with a simultaneous elevation of lipid peroxidation state and decline in non-protein soluble thiols (NPSH) level in female reproductive organs. Arsenic intoxication also accomplished with the up-regulation of inflammatory markers tumour necrosis factor (TNF α) and nuclear factor κB (NF κB). Pro-apoptotic Bax gene and p53 gene expressions were also raised due to arsenic intoxication while anti-apoptotic Bcl-2 gene expression was suppressed. In fact, arsenication decreased the circulating level of vitamin B12 and folic acid. Dietary NAC supplementation significantly reversed back the activity of antioxidant enzymes in arsenite fed rats towards normalcy and also sustained the normal reproductive cyclicity, utero-ovarian histo-morphology and estradiol receptor α (ER-α) expression in these reproductive organs. Dietary NAC exerted its positive action against arsenic intoxication by up-regulation of Bcl-2 gene expression along with the suppression of pro-apoptotic Bax gene and p53 gene. Thus, dietary NAC also plays anti-apoptotic, anti-inflammatory, and anti-oxidative role against arsenic toxicity. NAC also regulates the components (vitamin B12 and folic acid) of S-adenosylmethionine pool in the way of probable removal of arsenic from the system.


Assuntos
Acetilcisteína/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Arsenitos/toxicidade , Expressão Gênica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Apoptose/genética , Suplementos Nutricionais , Feminino , Masculino , Ovário/metabolismo , Ovário/patologia , Ovário/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Útero/metabolismo , Útero/patologia , Útero/fisiopatologia
12.
Ecotoxicol Environ Saf ; 197: 110554, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302855

RESUMO

Copper (Cu) is a toxic substance of heavy metals, and arsenic (As) is a toxic substance of metalloids. They all cause oxidative stress and have been widely studied in recent years. Studies have reported that Cu and As can cause inflammation in chicken brain tissue. To assess the toxicological effects of Cu and/or As chronic exposure on chicken thalamus, we used toxicologically relevant concentrations of Cu and As in the chicken diet for 12 weeks. By comparative analysis, we found that higher malondialdehyde (MDA), total antioxidant capacity (T-AOC), and proinflammatory mediator (NF-κB) were observed in the Cu and/or As co-exposed group, indicating that oxidation stress and inflammation are produced. In addition, we also observed mitochondrial kinetics and the generation of apoptosis. These include the gene and protein expression levels of Drp1, Opa1, Mfn1, Mfn2 and Bcl-2, Bax, p53. In conclusion, we believe that in the chronic poisoning of Cu and/or As, inflammation occurs in the chicken thalamus, causing oxidative stress and mitochondrial kinetics, which eventually leads to apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Arsenitos/toxicidade , Cobre/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Tálamo/lesões , Animais , Galinhas , Exposição Ambiental/efeitos adversos , Inflamação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia
13.
Toxicol Appl Pharmacol ; 394: 114959, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32201329

RESUMO

Arsenic is a ubiquitous environmental toxicant, found in high concentrations worldwide. Although abundant research has dealt with arsenic-induced cancers, studies on mechanisms of non-malignant lung diseases have not been complete. In addition, decades of research have mostly concentrated on high-dose arsenic exposure, which has very limited use in modeling the biological effects of today's low-dose exposures. Indeed, accumulated evidence has shown that low-dose arsenic exposure (i.e. ≤100 ppb) may also alter lung homeostasis by causing host susceptibility to viral infection. However, the underlying mechanism of this alteration is unknown. In this study, we found that low-dose sodium arsenite (As (III)) repressed major airway mucins-MUC5AC and MUC5B at both mRNA and protein levels. We further demonstrated that this repression was not caused by cellular toxicity or mediated by the reduction of a common mucin-inducing pathway-EGFR. Other established mucin activators- dsRNA, IL1ß or IL17 were not able to override As (III)-induced mucin repression. Interestingly, the suppressing effect of As (III) appeared to be partially reversible, and supplementation of all trans retinoic acid (t-RA) doses dependently restored mucin gene expression. Further analyses indicated that As (III) treatment significantly reduced the protein level of retinoic acid receptors (RARα, γ and RXRα) as well as RARE promoter reporter activity. Therefore, our study fills in an important knowledge gap in the field of low-dose arsenic exposure. The interference of RA signaling, and mucin gene expression may be important pathogenic factors in low-dose arsenic induced lung toxicity.


Assuntos
Arsênico/toxicidade , Mucinas/biossíntese , Mucosa Respiratória/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína , Arsenitos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mucina-5AC/antagonistas & inibidores , Mucina-5AC/genética , Mucina-5B/antagonistas & inibidores , Mucina-5B/genética , Mucosa Respiratória/efeitos dos fármacos , Compostos de Sódio/toxicidade
14.
Ecotoxicol Environ Saf ; 194: 110360, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32151864

RESUMO

Ferroptosis is a newly identified form of cell death characterized by accumulation of intracellular iron and requirement of lipid peroxidation. However, whether arsenite triggers testicular cell death via ferroptosis remains unclear. In this study, after administrating of adult male mice with 0.5, 5 and 50 mg/L arsenite for six months via drinking water, the results showed that arsenite caused the pathological changes in mouse testis and significantly reduced the number of sperm. Mitochondrial injuries were observed as the major ultrastructural damages induced by arsenite, and these damages were accompanied by the apparent mitochondrial oxidative damage in the testis, manifested by accumulation of iron, production of reactive oxygen species and lipid peroxidation products. We also demonstrated that arsenite significantly activated ferroptosis-related signal pathways in the mouse testis. To further verify the results obtained in the animal model, GC-2spd cells were employed as the in vitro culture system. Consistently, the results revealed arsenite remarkably triggered the ferroptotic cell death in vitro, and inhibition of ferroptosis by ferrostatin-1 could attenuate this adverse effect in cells. These findings together indicate that arsenite can trigger oxidative stress thus leading to testicular cell death by ferroptosis, suggesting that inhibition of ferroptosis would be a potential strategy for treatment of arsenite-related male reproductive toxicity.


Assuntos
Arsenitos/toxicidade , Ferroptose/fisiologia , Estresse Oxidativo/fisiologia , Testículo/efeitos dos fármacos , Animais , Arsenitos/metabolismo , Morte Celular , Cicloexilaminas , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/metabolismo , Oxirredução , Fenilenodiaminas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testículo/metabolismo , Testes de Toxicidade
15.
Ecotoxicol Environ Saf ; 195: 110458, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32193021

RESUMO

Arsenic (As) is a pollutant of major concern worldwide, posing as a threat to both human health and the environment. Phytoremediation has been proposed as a viable mechanism to remediate As-contaminated soil environments. Pot experiments were performed to evaluate the phytoextraction efficiency of As by Pteris vittata, a known As hyperaccumulating fern, from soil amended with different concentrations of arsenate [As(V)] and arsenite [As(III)], the more common, inorganic As forms in soil. The greatest accumulation of As (13.3 ± 0.36 g/kg Dwt) was found in fronds of plants grown in soil spiked with 1.0 g As(V)/kg. The maximum As-bioaccumulation factor (27.3 ± 1.9) was achieved by plants grown in soil amended with 0.05 g As(V)/kg. A total of 864 bacterial cultures were isolated and examined for their ability to enhance phytoremediation of As-contaminated soils. Traits examined included tolerance to As (III and V), production of siderophores, and/or ability to solubilize calcium phosphate and indole acetic acid (IAA) production. A culture-based survey shows greater numbers of viable and As-resistant bacteria were found in the rhizosphere of As-grown plants compared to bulk and unplanted soils. The percentage of bacteria resistant to As(V) was greater (P < 0.0001) than those resistant to As(III) in culture medium containing 0.5, 1, 1.5, and 2 g As/L. Higher (P < 0.0001) percentages of siderophore producing (77%) and phosphate solubilizing (61%) bacteria were observed among cultures isolated from unplanted soil. About 5% (44 of 864) of the isolates were highly resistant to both As (III) and As (V) (2 g/L), and were examined for their As-transformation ability and IAA production. A great proportion of the isolates produced IAA (82%) and promoted As (V)-reduction (95%) or As(III)-oxidation (73%), and 71% exhibited dual capacity for both As(V) reduction and As(III) oxidation. Phylogenetic analysis indicated that 67, 23, and 10% of these isolates belonged to Proteobacteria, Actinobacteria, and Firmicutes, respectively. Analysis of the 16S rRNA gene sequences confirmed that these isolates were closely related to 12 genera and 25 species of bacteria and were dominated by members of the genus Pseudomonas (39%). These results show that these isolates could potentially be developed as inocula for enhancing plant uptake during large scale phytoremediation of As-impacted soils.


Assuntos
Arseniatos/farmacocinética , Arsenitos/farmacocinética , Pteris/metabolismo , Microbiologia do Solo , Poluentes do Solo/farmacocinética , Arseniatos/toxicidade , Arsenitos/toxicidade , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biodegradação Ambiental , Ácidos Indolacéticos/metabolismo , Rizosfera , Sideróforos/metabolismo , Poluentes do Solo/toxicidade
16.
Toxicol Appl Pharmacol ; 393: 114955, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32171569

RESUMO

Inorganic arsenic is among the major contaminants of groundwater in the world. Worldwide population-based studies demonstrate that chronic arsenic exposure is associated with poor cognitive performance among children and adults, while research in animal models confirms learning and memory deficits after arsenic exposure. The aim of this study was to investigate the long-term effects of environmentally relevant arsenic exposure in the myelination process of the prefrontal cortex (PFC) and corpus callosum (CC). A longitudinal study with repeated follow-up assessments was performed in male Wistar rats exposed to 3 ppm sodium arsenite in drinking water. Animals received the treatment from gestation until 2, 4, 6, or 12 months of postnatal age. The levels of myelin basic protein (MBP) were evaluated by immunohistochemistry/histology and immunoblotting from the PFC and CC. As plausible alterations associated with demyelination, we considered mitochondrial mass (VDAC) and two axonal damage markers: amyloid precursor protein (APP) level and phosphorylated neurofilaments. To analyze the microstructure of the CC in vivo, we acquired diffusion-weighted images at the same ages, from which we derived metrics using the tensor model. Significantly decreased levels of MBP were found in both regions together with significant increases of mitochondrial mass and slight axonal damage at 12 months in the PFC. Ultrastructural imaging demonstrated arsenic-associated decreases of white matter volume, water diffusion anisotropy, and increases in radial diffusivity. This study indicates that arsenic exposure is associated with a significant and persistent negative impact on microstructural features of white matter tracts.


Assuntos
Intoxicação por Arsênico/patologia , Doenças Desmielinizantes/patologia , Envelhecimento , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Intoxicação por Arsênico/diagnóstico por imagem , Arsenitos/toxicidade , Axônios/patologia , Corpo Caloso/patologia , Doenças Desmielinizantes/diagnóstico por imagem , Imagem de Tensor de Difusão , Água Potável , Imuno-Histoquímica , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína Básica da Mielina/metabolismo , Proteínas de Neurofilamentos/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Ratos Wistar , Compostos de Sódio/toxicidade , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
17.
Toxicology ; 437: 152440, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32197950

RESUMO

Arsenic is an endocrine disruptor that promotes breast cancer (BCa) development. Estrogen synthesis, through aromatase activation, is essential for BCa promotion and progression through activating the G-coupled estrogen receptor 1 (GPER1), regulating rapid nongenomic effects involved in cell proliferation and migration of BCa cells. Herein, was studied the role of aromatase activation and the GPER1 pathway on sodium arsenite-induced promotion and progression of MDA-MB-231 and MDA-MB-453 BCa cell lines. Our results demonstrated that 0.1 µM of sodium arsenite induces cell proliferation, migration, invasion, and stimulates aromatase activity of BCa cell lines MDA-MB-231, MDA-MB-453, MCF-7, but not in a nontumorigenic breast epithelial cell line (MCF-12A). Using letrozole (an aromatase inhibitor) and G-15 (a GPER1-selective antagonist), we demonstrated that sodium arsenite-induced proliferation and migration is mediated by induction of aromatase enzyme and, at least in part, by GPER1 activation in MDA-MB-231 and MDA-MB-453 cells. Sodium arsenite induced phosphorylation of Src that participated in sodium arsenite-induced aromatase activity, and -cell proliferation of MDA-MB-231 cell line. Overall, data suggests that sodium arsenite induces a positive-feedback loop, resulting in the promotion and progression of BCa cells, through induction of aromatase activity, E2 production, GPER1 stimulation, and Src activation.


Assuntos
Aromatase/metabolismo , Arsenitos/toxicidade , Neoplasias da Mama/enzimologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativadores de Enzimas/toxicidade , Compostos de Sódio/toxicidade , Neoplasias da Mama/patologia , Ativação Enzimática , Estradiol/metabolismo , Feminino , Humanos , Células MCF-7 , Invasividade Neoplásica , Fosforilação , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo
18.
Toxicol Appl Pharmacol ; 391: 114912, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014540

RESUMO

Arsenic, an environmental contaminant in drinking water worldwide is well-established to increase cardiovascular diseases (CVDs) in humans. Of these, thrombotic events represent a major adverse effect associated with arsenic exposure, for which an abundance of epidemiological evidence exists. Platelet aggregation constitutes a pivotal step in thrombosis but arsenic alone doesn't induce aggregation and the mechanism underlying arsenic-induced thrombosis still remains unclear. Here we demonstrated that arsenic induces morphological changes of platelets, i.e., contraction and pseudopod projection, the primal events of platelet activation, which can increase platelet reactivity. Arsenite induced prominent platelet shape changes in a dose-dependent manner in freshly isolated human platelets. Of note, arsenite suppressed focal adhesion kinase (FAK) activity, which in turn activated RhoA, leading to altered actin assembly through LIMK activation, and subsequent cofilin inactivation. Arsenic-induced platelet shape change appeared to increase the sensitivity to thrombin and ADP-induced aggregation. Supporting this, latrunculin A, an inhibitor of actin-dynamics abolished it. Taken together, we demonstrated that arsenic induces cytoskeletal changes and shape changes of platelets through FAK-mediated alteration of actin dynamics, which renders platelets reactive to activating stimuli, ultimately contributing to increased thrombosis.


Assuntos
Actinas/metabolismo , Arsenitos/toxicidade , Plaquetas/patologia , Plaquetas/ultraestrutura , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Compostos de Sódio/toxicidade , Difosfato de Adenosina/farmacologia , Adolescente , Adulto , Humanos , Técnicas In Vitro , Quinases Lim/antagonistas & inibidores , Masculino , Selectina-P/biossíntese , Agregação Plaquetária/efeitos dos fármacos , Adulto Jovem , Proteína rhoA de Ligação ao GTP
19.
Toxicology ; 435: 152409, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32068019

RESUMO

Arsenic is a known human carcinogen. Early-life exposure to inorganic arsenic induces tumors in humans and in C3H mice. We hypothesized that arsenic exposure in utero may induce epigenetic changes at the level of DNA methylation and miRNA alterations that could lead to greater postnatal susceptibility to cancer. To test this hypothesis, pregnant C3H mice were given sodium arsenite at doses known to cause liver cancer (42.5 and 85 ppm in the drinking water) from gestation day 8-19, and the livers from male fetal mice were collected for analysis. The antibody against 5-methylcytosine was used to perform chromatin-immunoprecipitation coupled with sequencing (ChIP-Seq) to determine genome-wide methylation alterations. In utero arsenic exposure produced global DNA hypomethylation and an array of gene-specific DNA methylation changes, including hypomethylation of Cyclin D1 and hypermethylation of Tp53. Illumina Correlation Engine analysis revealed 260 methylation alterations that would affect 143 microRNAs. MicroRNA array further revealed 140 aberrantly expressed miRNAs out of the 718 miRNAs. The increased expression of miR-205, miR-203, miR-215, miR-34a, and decreased expression of miR-217 were confirmed by qPCR. Comparison of the methylation changes to those of microarray analyses indicates little if any correspondence between gene methylation and gene expression. The increased expression of Xist, Prrc2, Krit1, Nish, and decreased expression of Prss2, Spp1, Col1a2, and Lox were confirmed by qPCR. In summary, in utero arsenic exposure induced global alterations in DNA methylation and aberrant miRNA expression that might contribute to adult adverse outcomes including liver cancer.


Assuntos
5-Metilcitosina/metabolismo , Arsenitos/toxicidade , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fígado/efeitos dos fármacos , MicroRNAs/metabolismo , Compostos de Sódio/toxicidade , Animais , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Fígado/embriologia , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Exposição Materna , Camundongos Endogâmicos C3H , MicroRNAs/genética , Gravidez
20.
Ecotoxicol Environ Saf ; 191: 110162, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31935557

RESUMO

It is essential and challenged to understand the atmospheric arsenic pollution because it is much more complicated than in water and top-soil. Herein the different behavior of arsenic species firstly were discovered within the ambient PM2.5 collected during daytime and nighttime, winter and summer. The diurnal variation of arsenic species in PMs is significantly correlated with the presence of metallic oxides, specifically, ferrous, titanium and zinc oxides, which might play a key role in the process of the photo-oxidation of As(III) to As(V) with the meteorological parameters and regional factors excluded. Subsequently, the photo conversion of arsenite was detected on metal-loaded glass-fiber filters under visible light. The photo-generated superoxide radical was found to be predominantly responsible for the oxidation of As(III). In order to reveal toxicity differences induced by oxidation As(III), HepG2 cells were exposed to various arsenic mixture solution. We found that the antioxidant enzyme activities suppressed with increasing the As(III)/As(V) ratio in total, followed by the accumulation of intracellular ROS level. The glucose consumption and glycogen content also displayed an obvious reduction in insulin-stimulated cells. Compared to the expression levels of IRS-1, AKT and GLUT4, GLUT2 might be more vulnerable to arsenic exposure and lead to the abnormalities of glucose metabolism in HepG2 cells. Taken together, these findings clarify that the health risk posed by inhalation exposure to As-pollution air might be alleviated owing to the photo-driven conversion in presence of metal oxides.


Assuntos
Poluentes Atmosféricos/análise , Arseniatos/análise , Arsenitos/análise , Glucose/metabolismo , Luz , Metais Pesados/análise , Material Particulado/análise , Poluentes Atmosféricos/efeitos da radiação , Poluentes Atmosféricos/toxicidade , Arseniatos/efeitos da radiação , Arseniatos/toxicidade , Arsenitos/efeitos da radiação , Arsenitos/toxicidade , Células Hep G2 , Humanos , Exposição por Inalação/análise , Modelos Teóricos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Óxidos/análise , Material Particulado/efeitos da radiação , Material Particulado/toxicidade
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