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1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
2.
Dev Biol ; 478: 122-132, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34224682

RESUMO

Sexual systems are surprisingly diverse, considering the ubiquity of sexual reproduction. Sequential hermaphroditism, the ability of an individual to change sex, has emerged multiple times independently across the animal kingdom. In molluscs, repeated shifts between ancestrally separate sexes and hermaphroditism are generally found at the level of family and above, suggesting recruitment of deeply conserved mechanisms. Despite this, molecular mechanisms of sexual development are poorly known. In molluscs with separate sexes, endocrine disrupting toxins bind the retinoid X receptor (RXR), activating ectopic male development in females, suggesting the retinoid pathway as a candidate controlling sexual transitions in sequential hermaphrodites. We therefore tested the role of retinoic acid signaling in sequentially hermaphroditic Crepidula snails, which develop first into males, then change sex, maturing into females. We show that retinoid agonists induce precocious penis growth in juveniles and superimposition of male development in females. Combining RXR antagonists with retinoid agonists significantly reduces penis length in induced juveniles, while similar treatments using retinoic acid receptor (RAR) antagonists increase penis length. Transcripts of both receptors are expressed in the induced penis. Our findings therefore show that retinoid signaling can initiate molluscan male genital development, and regulate penis length. Further, we show that retinoids induce ectopic male development in multiple Crepidula species. Species-specific influence of conspecific induction of sexual transitions correlates with responsiveness to retinoids. We propose that retinoid signaling plays a conserved role in molluscan male development, and that shifts in the timing of retinoid signaling may have been important for the origins of sequential hermaphroditism within molluscs.


Assuntos
Organismos Hermafroditas/crescimento & desenvolvimento , Retinoides/metabolismo , Caramujos/crescimento & desenvolvimento , Caramujos/metabolismo , Animais , Família 26 do Citocromo P450/genética , Feminino , Organismos Hermafroditas/genética , Organismos Hermafroditas/metabolismo , Masculino , Pênis/crescimento & desenvolvimento , Pênis/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/agonistas , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Transdução de Sinais , Caramujos/anatomia & histologia , Caramujos/genética , Especificidade da Espécie , Tretinoína/metabolismo , Compostos de Trialquitina/farmacologia
3.
Food Chem Toxicol ; 149: 112039, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33549631

RESUMO

Organotin compounds (OTs) act as potent endocrine disruptors that are often found in polluted food and water. UDP-glucuronosyltransferases (UGTs) are responsible for termination of multiple endogenous hormones. This study was conducted to investigate the inhibitory effects of two tri-submitted OTs tributyltin (TBT) and triphenyltin (TPT), against activities of UGTs. It is revealed that TBT and TPT act as two potent inhibitors for multiple UGTs. UGT1A8 and -2B15 were coinhibited by the two OTs. UGT1A1 and -1A10 were inhibited by TPT, whereas UGT 2B4 and -2B7 were inhibited by TBT. Kinetic analyses further indicated that TBT and TPT are two competitive nanomolar inhibitors of UGT2B15, with Ki values of 0.45 and 0.46 µM, respectively. Ki values for the other UGTs are determined to be a few micromolars. In addition, the two OTs displayed effective inhibition against UGT2B15 in catalyzing dihydrotestosterone glucuronidation, with IC50 values both in nano-molar range. TPT can additionally inhibit activities of UGT1A1 and -1A10 in estradiol-3-O-glucuronidation, with IC50 values of a few micro-molars. These results indicated that the two OTs can extensively interfere with glucuronidation of endogenous hormones, which may act as a new potential mechanism resulting in endocrine disrupting actions.


Assuntos
Disruptores Endócrinos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/classificação , Compostos Orgânicos de Estanho/farmacologia , Compostos de Trialquitina/farmacologia , Animais , Relação Dose-Resposta a Droga , Glucuronosiltransferase/metabolismo , Humanos , Cinética , Microssomos Hepáticos , Isoformas de Proteínas
4.
Int J Mol Sci ; 21(21)2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33143349

RESUMO

Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA interference markedly increased the anti-tumor efficacy of the compound. Moreover, as a consequence of ROS production, TBT-F increased the levels of glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER stress markers. Interestingly, Grp78 silencing produced significant decreasing effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 decreased in CHOP-silenced cells. Taken together, these results indicate that ROS-dependent ER stress and autophagy play a major role in the TBT-F action mechanism in colon cancer cells and open a new perspective to consider the compound as a potential candidate for colon cancer treatment.


Assuntos
Autofagia , Neoplasias do Colo/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Compostos de Trialquitina/farmacologia , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 2 Relacionado a NF-E2/genética , Células Tumorais Cultivadas
5.
Sci Rep ; 10(1): 10605, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32606384

RESUMO

Oyster reefs are vital to estuarine health, but they experience multiple stressors and globally declining populations. This study examined effects of hypoxia and tributyltin (TBT) on adult Eastern oysters (Crassostrea virginica) exposed either in the laboratory or the field following a natural hypoxic event. In the laboratory, oysters were exposed to either hypoxia followed by a recovery period, or to hypoxia combined with TBT. mRNA expression of HIF1-α and Tß-4 along with hemocyte counts, biomarkers of hypoxic stress and immune health, respectively, were measured. In field-deployed oysters, HIF1-α and Tß-4 expression increased, while no effect on hemocytes was observed. In contrast, after 6 and 8 days of laboratory-based hypoxia exposure, both Tß-4 expression and hemocyte counts declined. After 8 days of exposure to hypoxia + TBT, oysters substantially up-regulated HIF1-α and down-regulated Tß-4, although hemocyte counts were unaffected. Results suggest that hypoxic exposure induces immunosuppression which could increase vulnerability to pathogens.


Assuntos
Crassostrea , Expressão Gênica/efeitos dos fármacos , Hemócitos/metabolismo , Hipóxia/metabolismo , RNA Mensageiro/metabolismo , Compostos de Trialquitina/farmacologia , Animais , Hemócitos/efeitos dos fármacos , Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , RNA Mensageiro/genética
6.
Epigenetics Chromatin ; 13(1): 5, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051014

RESUMO

BACKGROUND: Recent studies indicate that exposure to environmental chemicals may increase susceptibility to developing metabolic diseases. This susceptibility may in part be caused by changes to the epigenetic landscape which consequently affect gene expression and lead to changes in lipid metabolism. The epigenetic modifier enhancer of zeste 2 (Ezh2) is a histone H3K27 methyltransferase implicated to play a role in lipid metabolism and adipogenesis. In this study, we used the zebrafish (Danio rerio) to investigate the role of Ezh2 on lipid metabolism and chromatin status following developmental exposure to the Ezh1/2 inhibitor PF-06726304 acetate. We used the environmental chemical tributyltin (TBT) as a positive control, as this chemical is known to act on lipid metabolism via EZH-mediated pathways in mammals. RESULTS: Zebrafish embryos (0-5 days post-fertilization, dpf) exposed to non-toxic concentrations of PF-06726304 acetate (5 µM) and TBT (1 nM) exhibited increased lipid accumulation. Changes in chromatin were analyzed by the assay for transposase-accessible chromatin sequencing (ATAC-seq) at 50% epiboly (5.5 hpf). We observed 349 altered chromatin regions, predominantly located at H3K27me3 loci and mostly more open chromatin in the exposed samples. Genes associated to these loci were linked to metabolic pathways. In addition, a selection of genes involved in lipid homeostasis, adipogenesis and genes specifically targeted by PF-06726304 acetate via altered chromatin accessibility were differentially expressed after TBT and PF-06726304 acetate exposure at 5 dpf, but not at 50% epiboly stage. One gene, cebpa, did not show a change in chromatin, but did show a change in gene expression at 5 dpf. Interestingly, underlying H3K27me3 marks were significantly decreased at this locus at 50% epiboly. CONCLUSIONS: Here, we show for the first time the applicability of ATAC-seq as a tool to investigate toxicological responses in zebrafish. Our analysis indicates that Ezh2 inhibition leads to a partial primed state of chromatin linked to metabolic pathways which results in gene expression changes later in development, leading to enhanced lipid accumulation. Although ATAC-seq seems promising, our in-depth assessment of the cebpa locus indicates that we need to consider underlying epigenetic marks as well.


Assuntos
Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Metabolismo dos Lipídeos , Proteínas de Peixe-Zebra/metabolismo , Adipogenia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Cromatina/química , Montagem e Desmontagem da Cromatina , Sequenciamento de Cromatina por Imunoprecipitação , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Compostos de Trialquitina/farmacologia , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores
7.
J Inorg Biochem ; 205: 110999, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31986423

RESUMO

Ferulic acid (FA) is a natural phenolic phytochemical that has low toxicity and exhibits therapeutic effects against various diseases, behaving as an antioxidant. FA also displays modest antitumor properties that have been reported at relatively high concentrations. With the aim of improving the anti-tumor efficacy of FA, we synthesized the novel compound tributyltin(IV) ferulate (TBT-F). The coordination environment at the tin center was investigated spectroscopically. Following synthesis, chemical characterization and computational analysis, we evaluated TBT-F effects in colon cancer cells. The results showed that TBT-F, at nanomolar range concentrations, was capable of reducing the viability of HCT116, HT-29 and Caco-2 colon cancer cells. On the other hand, FA was completely inefficacious at the same treatment conditions. Cell viability reduction induced by TBT-F was associated with G2/M cell cycle arrest, increase in membrane permeabilization and appearance of typical morphological signs. TBT-F-induced cell death seemed not to involve apoptotic or necroptotic markers whereas autophagic vacuoles appearance and increase in LC3-II and p62 autophagic proteins were observed after treatment with the compound. The autophagy inhibitor bafylomicin A1 markedly prevented the effect of TBT-F on colon cancer cells, thus indicating that autophagy is triggered as a cell death process. Taken together, our results strongly suggest that the novel ferulic derivative TBT-F is a promising therapeutic agent for colon cancer since it is capable of triggering autophagic (type-II) cell death that may be important in case of resistance to classic apoptosis.


Assuntos
Antineoplásicos , Morte Celular Autofágica/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Ácidos Cumáricos , Compostos de Trialquitina , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CACO-2 , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Células HCT116 , Células HT29 , Humanos , Compostos de Trialquitina/síntese química , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia
8.
Toxicol Lett ; 318: 22-29, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634547

RESUMO

An attempt has been made to delineate the role of natural and synthetic retinoid receptor ligands on vimentin expression in the human triple-negative breast cancer cells. The effects of currently synthesized triorganotin derivatives of the general formula R3SnX (R is butyl or phenyl, X is isothiocyanate), which are considered RXR ligands, were investigated in the human MDA-MB-231 breast cancer cell line. Studies were evaluated in the presence and absence of all-trans retinoic acid (ATRA), a natural RAR ligand. Vimentin represents the major protein associated with epithelial-mesenchymal transition (EMT), an essential process when the primary tumour transforms into a malignant one. mRNA and proteomic data obtained in this study, based on the PDQuest software protein evaluation and further quantification of proteins by iTRAQ analysis, suggest that vimentin was significantly reduced in the combination of RAR ligand and RXR ligand treatment. Both tested triorganotin compounds showed similarly reduced expression of vimentin, but tributyltin isothiocyanate (TBT-ITC) proved to be more effective than triphenyltin isothiocyanate (TPT-ITC). Furthermore, the effect of natural (9cRA) and synthetic RXR ligands, both chloride and isothiocyanate derivatives, on vimentin expression was compared.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteômica/métodos , Receptores X de Retinoides/agonistas , Compostos de Trialquitina/farmacologia , Vimentina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Eletroforese em Gel Bidimensional , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Compostos Orgânicos de Estanho/farmacologia , Receptores X de Retinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Tretinoína/farmacologia
9.
PLoS One ; 14(11): e0224405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31710612

RESUMO

A subset of environmental chemicals acts as "obesogens" as they increase adipose mass and lipid content in livers of treated rodents. One of the most studied class of obesogens are the tin-containing chemicals that have as a central moiety tributyltin (TBT), which bind and activate two nuclear hormone receptors, Peroxisome Proliferator Activated Receptor Gamma (PPARG) and Retinoid X Receptor Alpha (RXRA), at nanomolar concentrations. Here, we have tested whether TBT chloride at such concentrations may affect the neutral lipid level in two cell line models of human liver. Indeed, using high content image analysis (HCA), TBT significantly increased neutral lipid content in a time- and concentration-dependent manner. Consistent with the observed increased lipid accumulation, RNA fluorescence in situ hybridization (RNA FISH) and RT-qPCR experiments revealed that TBT enhanced the steady-state mRNA levels of two key genes for de novo lipogenesis, the transcription factor SREBF1 and its downstream enzymatic target, FASN. Importantly, pre-treatment of cells with 2-deoxy-D-glucose reduced TBT-mediated lipid accumulation, thereby suggesting a role for active glycolysis during the process of lipid accumulation. As other RXRA binding ligands can promote RXRA protein turnover via the 26S proteasome, TBT was tested for such an effect in the two liver cell lines. We found that TBT, in a time- and dose-dependent manner, significantly reduced steady-state RXRA levels in a proteasome-dependent manner. While TBT promotes both RXRA protein turnover and lipid accumulation, we found no correlation between these two events at the single cell level, thereby suggesting an additional mechanism may be involved in TBT promotion of lipid accumulation, such as glycolysis.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptor X Retinoide alfa/metabolismo , Compostos de Trialquitina/farmacologia , Linhagem Celular , Desoxiglucose/farmacologia , Relação Dose-Resposta a Droga , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hibridização in Situ Fluorescente , Receptor X Retinoide alfa/genética
10.
Int J Mol Sci ; 20(5)2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30857277

RESUMO

The cytotoxicity of two recently synthesized triorganotin isothiocyanate derivatives, nuclear retinoid X receptor ligands, was tested and compared in estrogen-receptor-positive MCF 7 and -negative MDA-MB-231 human breast carcinoma cell lines. A 48 h MTT assay indicated that tributyltin isothiocyanate (TBT-ITC) is more cytotoxic than triphenyltin isothiocyanate (TPT-ITC) in MCF 7 cells, and the same trend was observed in the MDA-MB-231 cell line. A comet assay revealed the presence of both crosslinks and increasing DNA damage levels after the 17 h treatment with both derivatives. Differences in cytotoxicity of TBT-ITC and TPT-ITC detected by FDA staining correspond to the MTT data, communicating more pronounced effects in MCF 7 than in the MDA-MB-231 cell line. Both derivatives were found to cause apoptosis, as shown by the mitochondrial membrane potential (MMP) depolarization and caspase-3/7 activation. The onset of caspase activation correlated with MMP dissipation and the total cytotoxicity more than with the amount of active caspases. In conclusion, our data suggest that the DNA damage induced by TBT-ITC and TPT-ITC treatment could underlie their cytotoxicity in the cell lines studied.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Isotiocianatos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Receptores X de Retinoides/metabolismo , Compostos de Trialquitina/farmacologia , Antineoplásicos/química , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Isotiocianatos/química , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Orgânicos de Estanho/química , Compostos de Trialquitina/química
11.
Chemosphere ; 220: 687-695, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30605811

RESUMO

The ubiquitous environmental obesogens tributyltin (TBT) and perfluorooctane sulfonate (PFOS) may accumulate in parent and be transferred to their offspring, resulting in trans-generational adverse effects. In this study, we investigated the combined toxic and obesogenic effects of TBT and PFOS on the early life stages of Japanese medaka (Oryzias latipes). In ovo nanoinjection was used to simulate the maternal transfer process. Doses were controlled at 0, 0.05, 0.5, and 2.5 ng/egg (TBT) and at 0, 0.05, 0.5, and 5.0 ng/egg (PFOS), with a full factorial design for mixture formulations. Relatively high doses of agents in mixtures were needed to induce significant mortality (TBT ≥ 0.5 ng/egg) or delayed hatching (PFOS = 5.0 ng/egg) of embryos. The interaction between TBT and PFOS in mixtures had significant effects on the observed hatching delay, but not on acute mortality. Compared with controls, separate exposure to TBT (or PFOS) notably elevated adipose areas at the doses of 0.05 and 0.5 ng/egg, but not at the highest doses. Combined exposure significantly promoted the fat accumulation in newly hatched larvae, even when the doses of TBT and PFOS were both at the levels that did not show obesogenic effect. The interactive effect of TBT and PFOS could aggravate the total obesogenic effect of their mixtures, indicating a synergistic interaction. These results highlight the importance of paying close attention to interaction effects when addressing the impacts of mixtures of environmental obesogens.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Ácidos Alcanossulfônicos/farmacologia , Fluorcarbonetos/farmacologia , Oryzias/metabolismo , Compostos de Trialquitina/farmacologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Sinergismo Farmacológico , Embrião não Mamífero/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Exposição Materna/efeitos adversos , Obesidade/induzido quimicamente , Oryzias/embriologia
12.
J Cell Biochem ; 120(1): 715-726, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30191590

RESUMO

Tributyltin oxide (TBTO) has been widely used as marine antifouling composition, preservative, biocide, and a stabilizer in plastic industry. Previous studies have indicated that TBTO can cause immunotoxicity as an environmental pollutant. However, little is known about its reproductive toxicity, especially on female oocyte maturation and the underlying mechanisms. In this study, mouse oocytes were cultured with different concentrations of TBTO in vitro, and several crucial events during meiotic maturation were evaluated. We found that the first polar body extrusion rate was significantly reduced, which reflected the disruption of meiotic maturation. The rate of abnormal spindle organization increased significantly, accompanied with a higher rate of chromosome misalignment. In addition, TBTO treatment increased reactive oxygen species generation markedly, which also accelerated the early-stage apoptosis. Moreover, heterogeneous mitochondrial distribution, mitochondrial dysfunction, and higher rate of aneuploidy were detected, which consequently disrupted in vitro fertilization. In conclusion, our results indicated that TBTO exposure could impair mouse oocyte maturation by affecting spindle organization, chromosome alignment, mitochondria functions, oxidative stress, and apoptosis.


Assuntos
Aneugênicos/farmacologia , Oogênese/efeitos dos fármacos , Corpos Polares/metabolismo , Compostos de Trialquitina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Troca Genética/efeitos dos fármacos , Feminino , Fertilização In Vitro/efeitos dos fármacos , Meiose/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fuso Acromático/metabolismo
13.
Biochim Biophys Acta Biomembr ; 1861(1): 316-326, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29908139

RESUMO

Metarhizium robertsii, a butyltin-resistant filamentous fungus, can rapid and complete biodegradation of di- (DBT) and tributyltin (TBT) under conditions of intensive aeration and ascorbic acid supplementation. In this paper, lipidomic investigations were performed to find the membrane adaptations necessary for effective butyltins degradation. HPLC-MS/MS analysis showed that the phospholipid profile was greatly modified during M. robertsii batch cultivation (pO2 ≥ 20%), contributing to increased membrane fluidity and facilitated mass transfer, which could enhance butyltins biodegradation. Intensified biosynthesis of phospholipids, sphingolipids and ergosterol by the mycelia exposed to butyltins was noted. DIOC6(3) fluorescence intensity for TBT-treated mycelium increased 9-fold pointing to membrane hyperpolarization. Fluorescent studies showed improved membrane rigidity and integrity in response to butyltins presence. Vitamin C supplementation restored membrane composition and dynamic properties, followed by supposed acceleration of transport of monobutyltin and its biodegradation thus protecting the M. robertsii cells against oxidative and nitrosative stress.


Assuntos
Metarhizium/metabolismo , Compostos Orgânicos de Estanho/farmacologia , Compostos de Trialquitina/farmacologia , Adaptação Fisiológica , Ácido Ascórbico/farmacologia , Biodegradação Ambiental , Suplementos Nutricionais , Ergosterol/metabolismo , Bicamadas Lipídicas/metabolismo , Metarhizium/efeitos dos fármacos , Micélio/metabolismo , Estresse Nitrosativo , Oxirredução , Estresse Oxidativo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Propriedades de Superfície , Espectrometria de Massas em Tandem
14.
Cell Tissue Res ; 374(3): 587-594, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30078105

RESUMO

Tributyltin (TBT), an antifouling agent found in boat paints, is a common contaminant of marine and freshwater ecosystems. It is rapidly absorbed by organic materials and accumulated in many aquatic animals. Human exposure may depend on ingestion of contaminated food or by indirect exposure from household items containing organotin compounds. TBT is defined as an endocrine disruptor compound (EDC) because it binds to androgen receptors. Moreover, it is also included on the list of metabolic disruptors. The brain is a known target of TBT and this compound interferes with the orexigenic system, inducing a strong decrease in NPY expression in the hypothalamus. In the present experiment, we investigated the effect of a chronic treatment with TBT on the mouse anorexigenic system in both sexes, to look at the pro-opiomelanocortin (POMC) expression in the paraventricular (PVN), dorsomedial (DMN), ventromedial (VMN), and arcuate (ARC) hypothalamic nuclei. The results show a sexually dimorphic effect of TBT on both systems. TBT induced a significant decrease of POMC-positive structures only in female mice in DMN, ARC, and in PVN for both sexes. Apparently, these results show that TBT may interfere with the anorexigenic system in hypothalamic areas involved in the control of food intake, by inhibiting POMC in a sexually dimorphic way. In conclusion, in addition to having a direct effect on fat tissue, the effects of TBT as metabolic disruptor, may be due to gender-specific actions on both orexigenic and anorexigenic hypothalamic systems.


Assuntos
Envelhecimento/metabolismo , Hipotálamo/metabolismo , Pró-Opiomelanocortina/metabolismo , Caracteres Sexuais , Compostos de Trialquitina/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Feminino , Masculino , Camundongos , Ganho de Peso/efeitos dos fármacos
15.
Endocrinology ; 159(8): 2863-2883, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860300

RESUMO

Early life exposure to endocrine-disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator-activated receptor (PPAR) γ and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ vs RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators ("rexinoids," 4204 and TBT) attenuate glucose uptake, blunt expression of the antidiabetic hormone adiponectin, and fail to downregulate proinflammatory and profibrotic transcripts, as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Ciclopropanos/farmacologia , Disruptores Endócrinos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Receptores X de Retinoides/agonistas , Compostos de Trialquitina/farmacologia , Adipócitos/citologia , Tecido Adiposo Branco , Animais , Diferenciação Celular/efeitos dos fármacos , Feminino , Hipoglicemiantes/farmacologia , Células-Tronco Mesenquimais/citologia , Camundongos , PPAR gama/agonistas , Rosiglitazona/farmacologia
16.
Sci Rep ; 8(1): 5734, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29636531

RESUMO

Tributyltin (TBT), an endocrine disrupting chemical, can be found in food (particular in fish and seafood) and drinking water by contamination. Here, we elucidated the effects and possible mechanisms of low-dose TBT on the growth and function of pancreatic ß-cells and glucose metabolism in mice. Submicromolar-concentration of TBT significantly induced ß-cell cytotoxicity and apoptosis, which were accompanied by poly (ADP-ribose) polymerase cleavage and mitogen-activated protein kinases-JNK and ERK1/2 phosphorylation. TBT could also suppress the glucose-stimulated insulin secretion in ß-cells and isolated mouse islets. TBT increased reactive oxygen species production. TBT-induced ß-cell cytotoxicity and apoptosis were significantly prevented by antioxidant N-acetylcysteine (NAC) and JNK inhibitor SP600125, but not ERK1/2 inhibitor PD98059 and p38 inhibitor SB203580. Both NAC and SP600125 inhibited JNK phosphorylation and reduced cell viability in TBT-treated ß-cells. Four-week exposure of TBT (0.25 mg/kg) to mice revealed the decreased plasma insulin, increased blood glucose and plasma malondialdehyde, suppressed islet insulin secretion, and increased islet caspase-3 activity, which could be reversed by NAC treatment. After removing the TBT exposure for 2 weeks, the TBT-induced glucose metabolism alteration was significantly reversed. These results suggest that low-dose TBT can induce ß-cell apoptosis and interfere with glucose homeostasis via an oxidative stress-related pathway.


Assuntos
Apoptose/efeitos dos fármacos , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinas/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos de Trialquitina/farmacologia , Animais , Biomarcadores , Linhagem Celular , Glucose/metabolismo , Hiperglicemia/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismo
17.
Metallomics ; 10(2): 337-345, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29345269

RESUMO

Tributyltin (TBT), a common organotin environmental pollutant, has been widely used as a component of marine antifouling paints. We previously reported that exposure to TBT inhibits the expression and DNA binding of nuclear respiratory factor-1 (NRF-1) and causes neurotoxicity. In the present study, we focused on the epigenetic effects of TBT and investigated whether TBT decreases NRF-1 expression via epigenetic modifications in SH-SY5Y human neuroblastoma cells. First, we found that exposure to 300 nM TBT decreases NRF-1 expression. We examined epigenetic changes induced by TBT, and showed that TBT causes hypermethylation of the NRF-1 promoter region, increases the amount of methyl-CpG-binding protein 2 (MeCP2) bound to the NRF-1 promoter, and alters the expression of DNA methyltransferases and ten-eleven translocation (TET) demethylation enzymes. These results suggest that epigenetic changes play an important role in regulation of NRF-1 expression. Next, we investigated effect of NRF-1 expression decrease on cells, and TBT reduces mitochondrial membrane potential and overexpression of NRF-1 rescued this reduction in membrane potential. Thus, we suggested that NRF-1 is important for maintaining mitochondrial membrane potential. Our study indicates that TBT causes epigenetic changes such as hypermethylation, which increases recruitment of MeCP2 to the NRF-1 promoter and probably lead to decreased of NRF-1 expression and mitochondrial membrane potential. Therefore, this research provides new evidence of the epigenetic action caused by organotin.


Assuntos
Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Potencial da Membrana Mitocondrial , Neuroblastoma/genética , Fator 1 Nuclear Respiratório/genética , Compostos de Trialquitina/farmacologia , Sobrevivência Celular , Genoma Humano , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Fator 1 Nuclear Respiratório/metabolismo , Regiões Promotoras Genéticas , Sulfitos , Células Tumorais Cultivadas
18.
J Cell Physiol ; 233(9): 7007-7021, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29380368

RESUMO

The retinoid X receptors (RXR), peroxisome proliferator activated receptor gamma (PPARγ), and liver X receptors (LXR) all have been shown to regulate bone homeostasis. Tributyltin (TBT) is an environmental contaminant that is a dual RXRα/ß and PPARγ agonist. TBT induces RXR, PPARγ, and LXR-mediated gene transcription and suppresses osteoblast differentiation in vitro. Bone marrow multipotent mesenchymal stromal cells derived from female C57BL/6J mice were more sensitive to suppression of osteogenesis by TBT than those derived from male mice. In vivo, oral gavage of 12 week old female, C57Bl/6J mice with 10 mg/kg TBT for 10 weeks resulted in femurs with a smaller cross-sectional area and thinner cortex. Surprisingly, TBT induced significant increases in trabecular thickness, number, and bone volume fraction. TBT treatment did not change the Rankl:Opg RNA ratio in whole bone, and histological analyses showed that osteoclasts in the trabecular space were minimally reduced. In contrast, expression of cardiotrophin-1, an osteoblastogenic cytokine secreted by osteoclasts, increased. In primary bone marrow macrophage cultures, TBT marginally inhibited the number of osteoclasts that differentiated, in spite of significantly suppressing expression of osteoclast markers Nfatc1, Acp5, and Ctsk and resorptive activity. TBT induced expression of RXR- and LXR-dependent genes in whole bone and in vitro osteoclast cultures. However, only an RXR antagonist, but not an LXR antagonist, significantly inhibited TBTs ability to suppress osteoclast differentiation. These results suggest that TBT has distinct effects on cortical versus trabecular bone, likely resulting from independent effects on osteoblast and osteoclast differentiation that are mediated through RXR.


Assuntos
Osso Esponjoso/efeitos dos fármacos , Osso Cortical/efeitos dos fármacos , Compostos de Trialquitina/farmacologia , Animais , Calcificação Fisiológica/efeitos dos fármacos , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas da Matriz Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , PPAR gama/metabolismo , Receptores X de Retinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Int J Biol Macromol ; 108: 1219-1226, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29126943

RESUMO

Tributyltin (TBT) used in a variety of industrial processes, subsequent discharge into the environment, its fate, toxicity and human exposure are topics of current concern. TBT degradation by alkaliphilic bacteria may be a key factor in the remediation of TBT in high pH contaminated sites. In this study, Stenotrophomonas chelatiphaga HS2 were isolated and identified from TBT contaminated site in Mediterranean Sea. S. chelatiphaga HS2 has vigor capability to transform TBT into dibutyltin and monobutyltin (DBT and MBT) at pH 9 and 7% NaCl (w/v). A gene was amplified and characterized from strain HS2 as SugE protein belongs to SMR protein family, a reverse transcription polymerase chain reaction analysis confirmed that SugE protein involved in the TBT degradation by HS2 strain. TBT bioremediation was investigated in stimulated TBT contaminated sediment samples (pH 9) using S chelatiphaga HS2 in association with E. coli BL21 (DE3)-pET28a(+)-sugE instead of S chelatiphaga HS2 alone reduced significantly the TBT half-life from 12d to 5d, although no TBT degradation appeared using E. coli BL21 (DE3)-pET28a(+)-sugE alone. This finding indicated that SugE gene increased the rate and degraded amount of TBT and is necessary in enhancing TBT bioremediation.


Assuntos
Proteínas de Bactérias/metabolismo , Stenotrophomonas/metabolismo , Compostos de Trialquitina/isolamento & purificação , Compostos de Trialquitina/metabolismo , Poluentes Químicos da Água/isolamento & purificação , Poluentes Químicos da Água/metabolismo , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Biodegradação Ambiental , Sedimentos Geológicos/microbiologia , Concentração de Íons de Hidrogênio , Compostos Orgânicos de Estanho/metabolismo , Stenotrophomonas/fisiologia , Compostos de Trialquitina/farmacologia , Poluentes Químicos da Água/farmacologia
20.
J Cell Biochem ; 119(5): 4021-4037, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29231996

RESUMO

Tributyltins (TBT) are ubiquitous and persistent environmental contaminants that disturb normal endocrine function including gonadal function in humans and marine organisms. TBT was administered through oral route to male Syrian hamsters at daily doses of 50, 100, and 150 ppm/kg for 65 days. Changes in testis morphology, immunohistochemistry of iNOS, 3ß-HSD, and 17ß-HSD, cholesterol transport receptor, nuclear receptors, and transcription factors were analyzed. TBT treatment affected each of these parameters to significant levels in a dose-dependent manner compared to vehicle treated control. Real-time PCR and protein analyses revealed that expression levels of ApoE and LDL-R mRNA were up-regulated in the testis of TBT-treated animals while the expression levels of SR-B1, LXR, PPARs α, ß, and γ, SCAP, SREBP 1 and 2, 3ß-HSD, 17ß-HSD, CYP17A1, and P450SCC were down-regulated. Leydig cells were isolated and separated adopting percoll gradient centrifugation under aseptic condition. The viability of Leydig cell was affected by TBT treatment in a dose- and time-dependent manner. Further, the mechanism of action of TBT was ascertained by siRNA transfection of ApoE, which was upregulated, and SREBP, which was down-regulated. These observations led us to infer that exposure to TBT hinders intracellular cholesterol transport resulting in abnormal sex steroid biosynthesis and alteration of steroidogenic enzyme activities. Finally, we could recognize ApoE and SREBP as the major factors regulating genes that control cholesterol biosynthesis and steroidogenesis that ultimately inhibit the synthesis of testosterone. Therefore, ApoE is one of the important molecular targets that can be intercepted in context of male infertility/male contraception.


Assuntos
Colesterol/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Testículo/metabolismo , Testosterona/biossíntese , Compostos de Trialquitina/farmacologia , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Cricetinae , Masculino , Mesocricetus
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