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1.
Environ Pollut ; 287: 117586, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34426386

RESUMO

Arsenite [As(III)] toxicity causes impeded growth, inadequate productivity of plants and toxicity through the food chain. Using various chemical residues for priming is one of the approaches in conferring arsenic tolerance in crops. We investigated the mechanism of abscisic acid (ABA)-induced As(III) tolerance in rice genotypes (cv. Swarna and Swarna Sub1) pretreated with 10 µM of ABA for 24 h and transferred into 0, 25 and 50 µM arsenic for 10 days. Plants showed a dose-dependent bioaccumulation of As(III), oxidative stress indicators like superoxide, hydrogen peroxide, thiobarbituric acid reactive substances and the activity of lipoxygenase. As(III) had disrupted cellular redox that reflecting growth indices like net assimilation rate, relative growth rate, specific leaf weight, leaf mass ratio, relative water content, proline, delta-1-pyrroline-5-carboxylate synthetase and electrolyte leakage. ABA priming was more protective in cv. Swarna Sub1 than Swarna for retrieval of total glutathione pool, non-protein thiols, cysteine, phytochelatin and glutathione reductase. Phosphate metabolisms were significantly curtailed irrespective of genotypes where ABA had moderated phosphate uptake and its metabolizing enzymes like acid phosphatase, alkaline phosphatase and H+/ATPase. Rice seedlings had regulated antioxidative potential with the varied polymorphic expression of those enzymes markedly with antioxidative enzymes. The results have given the possible cellular and physiological traits those may interact with ABA priming in the establishment of plant tolerance with As(III) over accumulation and, thereby, its amelioration for oxidative damages. Finally, cv. Swarna Sub1 was identified as a rice genotype as a candidate for breeding program for sustainability against As(III) stress with cellular and physiological traits serving better for selection pressure.


Assuntos
Arsenitos , Oryza , Ácido Abscísico , Arsenitos/toxicidade , Genótipo , Oryza/genética , Locos de Características Quantitativas , Plântula
2.
Toxicol Lett ; 349: 40-50, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34118311

RESUMO

Previously, we reported that prolonged arsenic exposure impaired neuronal insulin signaling. Here we have further identified novel molecular mechanisms underlying neuronal insulin signaling impairment by arsenic. Arsenic treatment altered insulin dose-response curve and reduced maximum insulin response in differentiated human neuroblastoma SH-SY5Y cells, suggesting that arsenic hindered neuronal insulin signaling in a non-competitive like manner. Mechanistically, arsenic suppressed insulin receptor (IR) kinase activity, as witnessed by a decreased insulin-activated autophosphorylation of IR at Y1150/1151. Arsenic decreased the level of insulin receptor substrate 1 (IRS1) but increased the protein ratio between PI3K regulatory subunit, p85, and PI3K catalytic subunit, p110. Interestingly, co-immunoprecipitation demonstrated that arsenic did not alter a level of PI3K-p110/PI3K-p85 complex while increased PI3K-p85 levels in a PI3K-p110 depletion supernatant resulted from PI3K-p110 immunoprecipitation. These results indicated that arsenic increased PI3K-p85 which was free from PI3K-p110 binding. In addition, arsenic significantly increased interaction between IRS1 and PI3K-p85 but not PI3K-p110, suggesting that there may be a fraction of free PI3K-p85 interacting with IRS1. In vitro PI3K activity demonstrated that arsenic lowered PI3K activity in both basal and insulin-stimulated conditions. These results suggested that the increase in free PI3K-p85 by arsenic might compete with PI3K heterodimer for the same IRS1 binding site, in turn blocking the activation of its catalytic subunit, PI3K-p110. Taken together, our results provide additional insights into mechanisms underlying the impairment of neuronal insulin signaling by arsenic through the reduction of IR autophosphorylation, the increase in free PI3K-p85, and the impeding of PI3K activity.


Assuntos
Arsenitos/toxicidade , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Insulina/farmacologia , Neurônios/efeitos dos fármacos , Compostos de Sódio/toxicidade , Antígenos CD/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Neurônios/enzimologia , Neurônios/patologia , Fosforilação , Ligação Proteica , Receptor de Insulina/agonistas , Receptor de Insulina/metabolismo , Transdução de Sinais
3.
J Cell Sci ; 134(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085697

RESUMO

The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified Saccharomyces cerevisiae deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis. This article has an associated First Person interview with the first authors of the paper.


Assuntos
Arsênio , Arsenitos , Proteínas de Saccharomyces cerevisiae , Arsenitos/toxicidade , Agregados Proteicos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
4.
J Environ Sci (China) ; 105: 22-32, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34130836

RESUMO

Foliar application of Si can generally reduce As translocation from roots to shoots in rice; however, it does not always work, particularly under high As stress. Here, the effects of foliar application of nanoscale silica sol on As accumulation in rice were investigated under low (2 µmol/L) and high (8 µmol/L) arsenite stress. The results revealed that foliar Si application significantly decreased the As concentration in shoots under low arsenite stress, but showed different effects under high arsenite stress after 7 days of incubation. The reduction in root-to-shoot As translocation under the 2As+Si treatment was related to the down-regulation of OsLsi1 and OsLsi2 expression and up-regulation of OsABCC1 expression in roots. In the 8As+Si treatment, the expressions of OsLsi1, OsLsi2, and OsABCC1 were significantly promoted, which resulted in substantially higher As accumulation in both the roots and shoots. In the roots, As predominantly accumulated in the symplasts (90.6%-98.3%), in which the majority of As was sequestered in vacuoles (79.0%-94.0%) under both levels of arsenite stress. Compared with that of the 8As treatment, the 8As+Si treatment significantly increased the As concentration in cell walls, but showed no difference in the vacuolar As concentration, which remained constant at approximately 69.1-71.7 mg/kg during days 4-7. It appeared that the capacity of root cells to sequester As in the vacuoles had a threshold, and the excess As tended to accumulate in the cell walls and transfer to the shoots via apoplasts under high arsenite stress. This study provides a better understanding of the different effects of foliar Si application on As accumulation in rice from the view of arsenite-related gene expression and As subcellular distribution in roots.


Assuntos
Arsênio , Arsenitos , Oryza , Arsenitos/toxicidade , Raízes de Plantas , Silício , Dióxido de Silício
5.
Toxicol Appl Pharmacol ; 422: 115561, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33957193

RESUMO

Arsenic is a global health concern that causes toxicity through ingestion of contaminated water and food. In vitro studies suggest that arsenic reduces stem and progenitor cell differentiation. Thus, this study determined if arsenic disrupted intestinal stem cell (ISC) differentiation, thereby altering the number, location, and/or function of intestinal epithelial cells. Adult male C57BL/6 mice were exposed to 0 or 100 ppb sodium arsenite (AsIII) through drinking water for 5 weeks. Duodenal sections were collected to assess changes in morphology, proliferation, and cell types. qPCR analysis revealed a 40% reduction in Lgr5 transcripts, an ISC marker, in the arsenic-exposed mice, although there were no changes in the protein expression of Olfm4. Secretory cell-specific transcript markers of Paneth (Defa1), Goblet (Tff3), and secretory transit amplifying (Math1) cells were reduced by 51%, 44%, and 30% respectively, in the arsenic-exposed mice, indicating significant impacts on the Wnt-dependent differentiation pathway. Further, protein levels of phosphorylated ß-catenin were reduced in the arsenic-exposed mice, which increased the expression of Wnt-dependent transcripts CD44 and c-myc. PCA analysis, followed by MANOVA and regression analyses, revealed significant changes and correlations between Lgr5 and the transit amplifying (TA) cell markers Math1 and Hes1, which are in the secretory cell pathway. Similar comparisons between Math1 and Defa1 show that terminal differentiation into Paneth cells is also reduced in the arsenic-exposed mice. The data suggests that ISCs are not lost following arsenic exposure, but rather, specific Wnt-dependent progenitor cell formation and terminal differentiation in the small intestine is reduced.


Assuntos
Arsenitos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Duodeno/efeitos dos fármacos , Celulas de Paneth/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Compostos de Sódio/toxicidade , Células-Tronco/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação para Baixo , Duodeno/metabolismo , Duodeno/patologia , Masculino , Camundongos Endogâmicos C57BL , Celulas de Paneth/metabolismo , Celulas de Paneth/patologia , Receptores Acoplados a Proteínas G/genética , Células-Tronco/metabolismo , Células-Tronco/patologia , Fator Trefoil-3/genética , Fator Trefoil-3/metabolismo , Via de Sinalização Wnt , alfa-Defensinas/genética , alfa-Defensinas/metabolismo
6.
J Toxicol Sci ; 46(4): 187-192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814512

RESUMO

Tissue factor (TF) is the initiator of the coagulation cascade, constitutively expressed in subendothelial cells such as vascular smooth muscle cells and initiating rapid coagulation when the vascular vessel is damaged. TF has been shown to be involved in the development and progression of atherosclerosis. Arsenic, an environmental pollutant, is related to the progression of atherosclerosis, although the pathogenic mechanisms are not fully elucidated. In the present study, we investigated the effect of arsenite on the expression of TF in human aortic smooth muscle cells (HASMCs) and the underlying molecular mechanisms. We found that (1) arsenite stimulated TF synthesis and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in HASMCs, (2) sulforaphane, an Nrf2 activator, also stimulated TF synthesis in HASMCs, and (3) arsenite-induced upregulation of TF synthesis was prevented by Nrf2 knockdown in HASMCs. These results suggest that arsenite promotes TF synthesis by activating the Nrf2 pathway in HASMCs and that the induction of TF expression by arsenite may be related to the progression of atherosclerosis.


Assuntos
Aorta/citologia , Arsenitos/toxicidade , Miócitos de Músculo Liso/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Tromboplastina/metabolismo , Aterosclerose/etiologia , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Humanos , Isotiocianatos/toxicidade , Fator 2 Relacionado a NF-E2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos/toxicidade , Tromboplastina/genética
7.
Mutat Res ; 865: 503337, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865543

RESUMO

Environmental exposure to arsenite (As+3) is known to induce immunotoxicity. Natural killer (NK) cells are innate lymphoid cells act as professional killers of tumor cells. Our previous report indicated that 500 ppb As+3 drinking water exposure induced significant DNA damage in the NK cells of C57BL/6 mice. Myricetin is a plant-derived flavonoid known as a strong antioxidant. In this study, daily administration of myricetin at 20 mg/kg was found to alleviate the cell population decrease and DNA damage in the NK cells of BALB/c mice exposed to 500 and 1000 ppb As+3 via drinking water. Oxidative stress and poly(ADP-ribose) polymerase 1 (PARP-1) inhibition were induced by As+3 at 1 and 2 µM in isolated mouse NK cells in vitro, which were attenuated by 20 µM myricetin. The mitigatory effect of myricetin on the PARP-1 inhibition in NK cells treated with As+3 was also found to be the result of its prevention of the zinc loss induced by As+3 on PARP-1. Collectively, these results demonstrated, for the first time, that myricetin could protect NK cells from As+3 induced DNA through attenuating oxidative stress and retaining PARP-1 activity, indicating that myricetin may be utilized for the prevention of the immunotoxicity induced by As+3 in NK cells.


Assuntos
Arsenitos/toxicidade , Flavonoides/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Citoproteção/imunologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Imunidade Inata/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estresse Oxidativo/genética
8.
Food Chem Toxicol ; 151: 112114, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33722599

RESUMO

Ferroptosis is a novel form of cell death that involves in the pathophysiological process of diverse brain diseases. However, how arsenite induces ferroptosis in the neuronal cells remains unsolved. In this study, by using in vitro and in vivo models, we demonstrated that arsenite was able to trigger ferroptosis in the neuronal cells. Exposure of arsenite for 6 months at 0.5, 5 and 50 mg/L arsenite via drinking water significantly reduced the number of neurons and caused the pathological changes in the mitochondria of hippocampus. Treatment of arsenite elevated the contents of lipid peroxidation products, disrupted the iron homeostasis, altered the expressions of ferroptosis-related proteins in the hippocampus and PC-12 cells. The results also showed that arsenite significantly decreased the expressions of ferritin and NCOA4, but sharply enhanced the level of autophagy marker LC3B, suggesting the activation of ferritinophagy by arsenite. Co-treatment of arsenite with ferroptosis inhibitor ferrostatin-1, or autophagy inhibitors 3-MA and BafA1, all remarkably attenuated the cytotoxic effects of arsenite. These findings not only present a novel mechanism that arsenite triggers ferroptosis in the neuronal cells via activation of ferritinophagy, but also indicate that regulating ferritinophagy to control iron level may provide a clue for prevention against arsenite neurotoxicity.


Assuntos
Arsenitos/farmacologia , Ferritinas/metabolismo , Ferroptose/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Arsenitos/toxicidade , Morte Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Hipocampo/citologia , Hipocampo/metabolismo , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Fenilenodiaminas/farmacologia , Ratos , Sinapses/efeitos dos fármacos
9.
Environ Sci Pollut Res Int ; 28(28): 37918-37928, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33721167

RESUMO

The morphology and oxidation state of arsenic in its compounds affects the skin cell toxicity. Accordingly, the present study was conducted to explore the effects of two different arsenic compounds on the proliferation and survival of Liaoning cashmere goat skin fibroblasts. Based on MTT assay results, at 24 h, the proliferation concentration, critical concentration, and half inhibitory concentration (IC50) of sodium arsenite were 0.50, 5.00, and 45.66 µmol/L, respectively. The corresponding values for dimethyl arsenic acid were 0.85, 1.00, and 38.68 mmol/L. Immunofluorescence, transmission electron microscopy, and mitochondria membrane potential (MMP) assays showed that sodium arsenite promotes microtubule polymerization and increases MMP, while cells treated with dimethyl arsenic acid exhibited cytoskeletal collapse and decreased MMP. In the IC50 groups for both arsenic agents, the cytoskeletons collapsed, microtubules were gathered into bundles, and MMP was significantly decreased. Dimethyl arsenic acid had a stronger effect on MMP than sodium arsenite. Flow cytometry revealed a slightly lower occurrence of apoptosis in the sodium arsenite proliferation group, while it was slightly increased in the dimethyl arsenic acid proliferation group. Apoptosis was increased more significantly in the sodium arsenite IC50 group than in the dimethyl arsenic acid IC50 group. These results indicate that the differences in cell proliferation and cytotoxicity induced by inorganic and organic arsenic are related to their effects on cellular structures.


Assuntos
Arsênio , Arsenitos , Animais , Arseniatos , Arsenitos/toxicidade , Ácido Cacodílico , Fibroblastos , Cabras , Compostos de Sódio/toxicidade
10.
J Hazard Mater ; 415: 125579, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-33721782

RESUMO

Although carbon nanomaterials (CNMs) commonly exist throughout the aquatic environment, their effect on arsenic (As) distribution and toxicity is unclear. In this study, arsenite accumulation, transformation, subcellular distribution, and enzyme activity were assessed in adult zebrafish (Danio rerio) intestines, heads and muscles, following co-exposure to arsenite and CNMs with different structures (single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs), fullerene (C60), graphene oxide (GO), and graphene (GN)). Results show that GN and GO promoted As toxicity in D. rerio, as carriers increasing total As accumulation in the intestine, resulting in arsenite adsorbed by GO and GN being released and transformed mainly into moderately-toxic monomethylarsonic acid (MMA), which was mostly distributed in organelles and metallothionein-like proteins (MTLPs). Moreover, GO and GN influenced As species distribution in D. rerio due to the excellent electron transfer ability. However, the effect was marginal for SWCNT, MWCNT and C60, because of the different structure and suspension stability in fish-culture water. In addition, in the muscle and head tissues, As was mainly distributed in cellular debris in the forms of dimethylarsinic acid (DMA) and arsenobetaine (AsB). These findings help better understand the influence of CNMs on the mechanism of As toxicity in natural aquatic environments.


Assuntos
Arsenitos , Fulerenos , Nanotubos de Carbono , Animais , Arsenitos/toxicidade , Água Doce , Nanotubos de Carbono/toxicidade , Peixe-Zebra
11.
Ecotoxicol Environ Saf ; 215: 112130, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33743404

RESUMO

Environmental exposure to arsenic can cause a variety of health problems. Epidemiological and experimental studies have established a diabetogenic role for arsenic, but the mechanisms responsible for arsenic-induced impairment of insulin action are unclear. MicroRNAs (miRNAs) are involved in various metabolic disorders, particularly in the development of insulin resistance. The present study investigated whether arsenite, an active form of arsenic, induces hepatic insulin resistance and the mechanisms underlying it. After male C57BL/6J mice were exposed to arsenite (0 or 20 ppm) in drinking water for 12 months, intraperitoneal glucose tolerance tests (IPGTTs) and insulin tolerance tests (ITTs) revealed an arsenite-induced glucose metabolism disorder. Hepatic glycogen levels were lower in arsenite-exposed mice. Further, for livers of mice exposed to arsenite, miR-191 levels were higher, and protein levels of insulin receptor substrate 1 (IRS1), p-IRS1, and phospho-protein kinase B (p-AKT) were lower. Further, glucose transporter 4 (GLUT4) had lower levels on the plasma membrane. For insulin-treated L-02 cells, arsenite decreased glucose consumption and glycogen levels, increased miR-191 levels, and inhibited the IRS1/AKT pathway and the translocation of GLUT4 from the cytoplasm to the plasma membrane. For insulin-treated L-02 cells, the decreases of glucose consumption, glycogen levels, GLUT4 on the plasma membrane, and p-AKT levels induced by arsenite were reversed by SC79 (agonist of AKT) and an miR-191 inhibitor; these effects caused by miR-191 inhibitor were restored by IRS1 siRNA. In insulin-treated L-02 cells, miR-191, via IRS1, was involved in the arsenite-induced decreases of glucose consumption and glycogen levels and in inhibition of the translocation of GLUT4. Thus, miR-191 blocking the translocation of GLUT4 was involved in arsenite-induced hepatic insulin resistance through inhibiting the IRS1/AKT pathway. Our study reveals a mechanism for arsenite-induced hepatic insulin resistance, which provides clues for discovering biomarkers for the development of type 2 diabetes and for prevention and treatment of arsenic poisoning.


Assuntos
Arsenitos/toxicidade , Transportador de Glucose Tipo 4/metabolismo , Resistência à Insulina/fisiologia , MicroRNAs/metabolismo , Animais , Arsenitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Bull Environ Contam Toxicol ; 106(5): 786-791, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33787975

RESUMO

The studies on how humic acid (HA) influences the oxidative stress of arsenic in aquatic organism is limited. Using Danio rerio as case study, we explored the oxidative stress effects in aquatic organism after 96 h exposure to the HA and arsenic. Results revealed the co-exposure of HA and arsenite elevated the superoxide dismutase activities and downgraded the malondialdehyde. Thus, we speculate that HA may alleviate the oxidative stress induced by arsenite, which may be caused by the HA's coating in combination with the complexation of arsenite and HA. In addition, HA acted as the reactive oxygen species scavenger, promising to eliminate the oxygen free radicals. Contrastingly, HA may impact little on the arsenate exposure. This study can help better understand oxidative stress mechanism of co-exposure of arsenic and HA in aquatic environment.


Assuntos
Arsênio , Arsenitos , Animais , Arseniatos/toxicidade , Arsenitos/toxicidade , Substâncias Húmicas , Estresse Oxidativo , Peixe-Zebra
13.
Toxicol Lett ; 345: 1-11, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781819

RESUMO

Arsenic is an environmental contaminant, which is widely distributed in soil, air, and water. There is sufficient evidence to indicate that arsenic increases the risk of bladder cancer in humans. However, its underlying mechanisms remain elusive. Glutamine (Gln) has multiple functions that promote carcinogenesis. Indeed, Gln transporters on cancer cells surface are often upregulated. Elevated expression levels of Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) have been reported in many types of human tumors. This study characterized the role of SLC1A5 in cell proliferation in arsenite-treated cells. In short-term experiments, SV-40 immortalized human uroepithelial (SV-HUC-1) cells were treated with Sodium arsenite (NaAsO2) (0, 0.5, 1, 2, 4, 8 µM) for 24 h. In long-term experiments, SV-HUC-1 cells were exposed to 0.5 µM NaAsO2 for 40 weeks. In both short-term and long-term experiments, arsenite increased expression of SLC1A5 by 1.89-fold and 2.25-fold, respectively. Arsenite increased Gln consumption of SV-HUC-1 cells, and Gln starvation inhibited cell proliferation in long-term arsenite-treated cells. Importantly, inhibiting SLC1A5 blocked cell proliferation by downregulating mTORC1 in long-term arsenite-treated cells. Moreover, SLC1A5 regulated mTORC1 in an αKG-dependent manner. Our results suggest that SLC1A5 plays an important role in cell proliferation of arsenite-treated SV-HUC-1 cells.


Assuntos
Sistema ASC de Transporte de Aminoácidos/metabolismo , Arsenitos/toxicidade , Proliferação de Células/efeitos dos fármacos , Glutamina/deficiência , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Compostos de Sódio/toxicidade , Urotélio/efeitos dos fármacos , Sistema ASC de Transporte de Aminoácidos/genética , Linhagem Celular , Regulação para Baixo , Humanos , Ácidos Cetoglutáricos/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Urotélio/enzimologia , Urotélio/patologia
14.
Environ Health Prev Med ; 26(1): 34, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33706700

RESUMO

BACKGROUND: Arsenic is a developmental neurotoxicant. It means that its neurotoxic effect could occur in offspring by maternal arsenic exposure. Our previous study showed that developmental arsenic exposure impaired social behavior and serotonergic system in C3H adult male mice. These effects might affect the next generation with no direct exposure to arsenic. This study aimed to detect the social behavior and related gene expression changes in F2 male mice born to gestationally arsenite-exposed F1 mice. METHODS: Pregnant C3H/HeN mice (F0) were given free access to tap water (control mice) or tap water containing 85 ppm sodium arsenite from days 8 to 18 of gestation. Arsenite was not given to F1 or F2 mice. The F2 mice were generated by mating among control F1 males and females, and arsenite-F1 males and females at the age of 10 weeks. At 41 weeks and 74 weeks of age respectively, F2 males were used for the assessment of social behavior by a three-chamber social behavior apparatus. Histological features of the prefrontal cortex were studied by ordinary light microscope. Social behavior-related gene expressions were determined in the prefrontal cortex by real time RT-PCR method. RESULTS: The arsenite-F2 male mice showed significantly poor sociability and social novelty preference in both 41-week-old group and 74-week-old group. There was no significant histological difference between the control mice and the arsenite-F2 mice. Regarding gene expression, serotonin receptor 5B (5-HT 5B) mRNA expression was significantly decreased (p < 0.05) in the arsenite-F2 male mice compared to the control F2 male mice in both groups. Brain-derived neurotrophic factor (BDNF) and dopamine receptor D1a (Drd1a) gene expressions were significantly decreased (p < 0.05) only in the arsenite-F2 male mice of the 74-week-old group. Heme oxygenase-1 (HO-1) gene expression was significantly increased (p < 0.001) in the arsenite-F2 male mice of both groups, but plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) and cyclooxygenase-2 (COX-2) gene expression were not significantly different. Interleukin-1ß (IL-1ß) mRNA expression was significantly increased only in 41-week-old arsenite-F2 mice. CONCLUSIONS: These findings suggest that maternal arsenic exposure affects social behavior in F2 male mice via serotonergic system in the prefrontal cortex. In this study, COX-2 were not increased although oxidative stress marker (HO-1) was increased significantly in arsnite-F2 male mice.


Assuntos
Arsênio/toxicidade , Arsenitos/toxicidade , Poluentes Ambientais/toxicidade , Expressão Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Comportamento Social , Compostos de Sódio/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Marcadores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/genética , Serotonina/metabolismo
15.
Sci Total Environ ; 775: 145685, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-33631581

RESUMO

Arsenic (As) contamination in mangrove wetlands has become a major concern. However, the impact of As on mangroves and the rhizospheric mechanism remains unclarified. In this study, various properties and responses of mangrove seedlings were investigated after exposure to arsenite (As3+). The results indicate that low-level As promoted the secretion of Low-molecular-weight organic acids (LMWOA, 4.5-6.59 mg/kg root in dry weight) and Fe plaque formation in their rhizospheres. Citric, oxalic, and malic acid were the three main components (84.3%-86.8%). Low-level As (5 and 10 µmol/L) also inhibited the rate of radial oxygen loss (ROL) but increased the accumulation of plant As (stem > leaf > root) and plaque As (0.23-1.13 mg/kg root in dry weight). We selected model LMWOAs to further examine As migration and speciation over time in As-enriched sediments (0, 20 and 40 mg/kg). The results reveal that LMWOAs promoted sediment As mobilisation and followed the order of citric acid > malic acid > oxalic acid. The hydrolysis and precipitation of Fe3+ and the complexation with organic ligand led to aqueous As and Fe sedimentation and, conversely, increased solution pH and re-translocated free As. The tolerance mechanisms include lowering ROL, translocating As and releasing LMWOAs to reduce its toxicity, and facilitating the fixation in sediment of oxidised As. The present study highlights the fact that mangroves are potentially favourable for As phytoextraction, removal and detoxification.


Assuntos
Arsênio , Arsenitos , Avicennia , Arsenitos/toxicidade , Raízes de Plantas , Plântula
16.
Am J Physiol Heart Circ Physiol ; 320(4): H1321-H1336, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481702

RESUMO

Arsenic exposure though drinking water is widespread and well associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which iAS induces these effects are largely unknown. Recently, an epidemiological study in an American population with a low burden of cardiovascular risk factors found that iAS exposure was associated with altered left ventricular geometry. Considering the possibility that iAS directly induces cardiac remodeling independently of hypertension, we investigated the impact of an environmentally relevant iAS exposure on the structure and function of male and female hearts. Adult male and female C56BL/6J mice were exposed to 615 µg/L iAS for 8 wk. Males exhibited increased systolic blood pressure via tail cuff photoplethysmography, left ventricular wall thickening via transthoracic echocardiography, and increased plasma atrial natriuretic peptide via enzyme immunoassay. RT-qPCR revealed increased myocardial RNA transcripts of Acta1, Myh7, and Nppa and decreased Myh6, providing evidence of pathological hypertrophy in the male heart. Similar changes were not detected in females, and nitric oxide-dependent mechanisms of cardioprotection in the heart appeared to remain intact. Further investigation found that Rcan1 was upregulated in male hearts and that iAS activated NFAT in HEK-293 cells via luciferase assay. Interestingly, iAS induced similar hypertrophic gene expression changes in neonatal rat ventricular myocytes, which were blocked by calcineurin inhibition, suggesting that iAS may induce pathological cardiac hypertrophy in part by targeting the calcineurin-NFAT pathway. As such, these results highlight iAS exposure as an independent cardiovascular risk factor and provide biological impetus for its removal from human consumption.NEW & NOTEWORTHY This investigation provides the first mechanistic link between an environmentally relevant dose of inorganic arsenic (iAS) and pathological hypertrophy in the heart. By demonstrating that iAS exposure may cause pathological cardiac hypertrophy not only by increasing systolic blood pressure but also by potentially activating calcineurin-nuclear factor of activated T cells and inducing fetal gene expression, these results provide novel mechanistic insight into the theat of iAS exposure to the heart, which is necessary to identify targets for medical and public health intervention.


Assuntos
Arsenitos/toxicidade , Hipertrofia Ventricular Esquerda/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Sódio/toxicidade , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Calcineurina/metabolismo , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Preparação de Coração Isolado , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/metabolismo , Fatores Sexuais , Transdução de Sinais , Fatores de Tempo
17.
Biochem Biophys Res Commun ; 537: 85-92, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33387887

RESUMO

Transactive response DNA-binding protein of 43 kDa (TDP-43) abnormally forms aggregates in certain subtypes of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). The pathological forms of TDP-43 have reported to be associated with poly(ADP-ribose) (PAR), which regulates the properties of these aggregates. A recent study has indicated that tankyrase, a member of the PAR polymerase (PARP) family, regulates pathological TDP-43 formation under conditions of stress, and tankyrase inhibitors suppress TDP-43 aggregate formation and cytotoxicity. Since we reported the development of tankyrase inhibitors that are more specific than conventional inhibitors, in this study, we examined their effects on the formation of TDP-43 aggregates in cultured cells. Time-lapse imaging showed that TDP-43 aggregates appeared in the nucleus within 30 min of treatment with sodium arsenite. Several tankyrase inhibitors suppressed the formation of aggregates and decreased the levels of the tankyrase protein. Immunohistochemical studies demonstrated that tankyrase was localized to neuronal cytoplasmic inclusions in the spinal cords of patients with ALS. Moreover, the tankyrase protein levels were significantly higher in the brains of patients with FTLD than in the brains of control subjects. These findings suggest that the inhibition of tankyrase activity protects against TDP-43 toxicity. Tankyrase inhibitors may be a potential treatment to suppress the progression of TDP-43 proteinopathies.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Agregados Proteicos , Tanquirases/antagonistas & inibidores , Arsenitos/toxicidade , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Poli Adenosina Difosfato Ribose/toxicidade , Agregados Proteicos/efeitos dos fármacos , Proteinopatias TDP-43/patologia , Tanquirases/metabolismo
18.
Toxicol Appl Pharmacol ; 413: 115404, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33434570

RESUMO

Arsenic is a ubiquitous metalloid element present in both inorganic and organic forms in the environment. The liver is considered to be a primary organ of arsenic biotransformation and methylation, as well as the main target of arsenic toxicity. Studies have confirmed that Chang human hepatocytes have an efficient arsenic methylating capacity. Our previous studies have proven that arsenite activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in hepatocytes. This study aimed to explore the activation of the Nrf2 pathway upon treatment of arsenic in various forms, including inorganic and organic arsenic. Our results showed that inorganic arsenic-both As2O3 and Na2HAsO4 significantly induced the expression of Nrf2 protein and mRNA, enhanced the transcription activity of Nrf2, and induced the expression of downstream target genes. These results confirmed the inorganic arsenic-induced Nrf2 pathway activation in hepatocytes. Although all arsenic chemicals used in the study induced Nrf2 protein accumulation, the organic arsenic C2H7AsO2 did not affect the expression of Nrf2 downstream genes which were elevated by inorganic arsenic exposures. Through qRT-PCR and Nrf2 luciferase reporter assays, we further confirmed that C2H7AsO2 neither increased Nrf2 mRNA level nor activated the Nrf2 transcription activity. Mechanistically, our results confirmed inorganic arsenic-induced both the nuclear import of Nrf2 and export of Bach1 (BTB and CNC homology 1), which is an Nrf2 transcriptional repressor, while organic arsenic only induced Nrf2 translocation. The unique pattern of Nrf2 regulation by organic arsenic underlines the critical role of Nrf2 and Bach1 in the arsenic toxicology.


Assuntos
Arseniatos/toxicidade , Trióxido de Arsênio/toxicidade , Arsenitos/toxicidade , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Ácido Cacodílico/toxicidade , Núcleo Celular/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Compostos de Sódio/toxicidade , Transporte Ativo do Núcleo Celular , Linhagem Celular , Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/genética , Transcrição Genética
19.
Environ Sci Pollut Res Int ; 28(6): 7180-7190, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33026618

RESUMO

Arsenic exposure is well documented to cause serious health hazards, such as cardiovascular abnormalities, neurotoxicity and nephrotoxicity. In the present study, we intended to explore the role of bosentan, an endothelial receptor antagonist, against sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Sodium arsenite (5 mg/kg, oral) was administered for 4 weeks to induce renal dysfunction in rats. Sodium arsenite intoxicated rats were treated with bosentan (50 and 100 mg/kg, oral) for 4 weeks. Arsenic led renal damage was demonstrated by significant increase in serum creatinine, urea, uric acid, potassium, fractional excretion of sodium, microproteinuria and decreased creatinine clearance in rats. Sodium arsenite resulted in marked oxidative stress in rat kidneys as indicated by profound increase in lipid peroxides, and superoxide anion generation alongwith decrease in reduced glutathione levels. Hydroxyproline assay highlighted arsenic-induced renal fibrosis in rats. Hematoxylin-eosin staining indicated glomerular and tubular changes in rat kidneys. Picrosirius red staining highlighted collagen deposition in renal tissues of arsenic treated rats. Immunohistological results demonstrated the reduction of renal eNOS expression in arsenic treated rats. Notably, treatment with bosentan attenuated arsenic-induced renal damage and resisted arsenic-led reduction in renal eNOS expression. In addition, sodium arsenite-induced alteration in hepatic parameters (serum aspartate aminotransferase, alanine transferase, alkaline phosphatase, bilirubin), oxidative stress and histological changes were abrogated by bosentan treatment in rats. Hence, we conclude that bosentan treatment attenuated sodium arsenite-induced oxidative stress, fibrosis and reduction in renal eNOS expression in rat kidneys. Moreover, bosentan abrogated arsenic led hepatic changes in rats.


Assuntos
Arsenitos , Nefropatias , Animais , Arsenitos/toxicidade , Bosentana , Antagonistas dos Receptores de Endotelina , Nefropatias/induzido quimicamente , Estresse Oxidativo , Ratos , Compostos de Sódio/toxicidade
20.
Environ Toxicol ; 36(2): 204-212, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32930475

RESUMO

Long-term arsenic exposure can promote cancer through epigenetic mechanisms, and arsenite methyltransferase (AS3MT) plays an important role in this process. However, the expression patterns and mechanisms of AS3MT in arsenic carcinogenesis remain unclear. In this study, we found that the AS3MT was overexpressed in arsenic exposed population, non-small cell lung cancer (NSCLC) tissues, and A549 cells with sodium arsenite (NaAsO2 ) treatment for 48 hours. Besides, the level of AS3MT expression was positively correlated with the concentrations of urinary total arsenic (tAs), inorganic arsenic (iAs), methanearsonic acid (MMA), and dimethylarsinic acid (DMA) in all subjects. Functional experiments demonstrated that siRNA-mediated knockdown of AS3MT significantly inhibited proliferation of A549 cells. Mechanism investigation revealed that silencing of AS3MT inhibited proliferation by increasing mRNA expression levels of p21 and E2F1, and inhibiting CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin E1, Cyclin E2, and PCNA mRNA expression. Therefore, arsenic increased AS3MT expression in vivo and in vitro, which could directly act on the cell and affect the progression of NSCLC by regulating cell cycle genes.


Assuntos
Arsenitos/toxicidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes cdc , Neoplasias Pulmonares/patologia , Metiltransferases/genética , Células A549 , Arsenitos/farmacocinética , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Metiltransferases/metabolismo , Regulação para Cima
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