Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 72
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
2.
Fish Physiol Biochem ; 47(4): 797-810, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33665751

RESUMO

In the last decades, oestrogenic compounds have often been reported in environmentally relevant concentrations in aquatic environments around the world. Most laboratory studies of oestrogens try to understand the effects of a single contaminant, but in natural environments, the effects may be quite different due to interactions with other compounds. The present study aimed to compare the action of oestrone (E1) and bisphenol-A (BPA), acting singularly and in combination, on the spermatogenesis of Astyanax bimaculatus. After exposure to 100 ng/L of E1, BPA and a mixture of the two for 15 days, our results showed that E1 and the E1 + BPA mixture significantly altered the number of spermatogenic cells. BPA presented high cytotoxicity when compared to other treatments. Analysis of the two oestrogenic compounds suggests that the E1 + BPA mixture has no additive or synergistic effects. Together, the results of the present study indicate that endocrine-disrupting chemicals (EDCs) analysed alone may behave differently than when administered with other substances.


Assuntos
Compostos Benzidrílicos/toxicidade , Characidae , Disruptores Endócrinos/toxicidade , Estrogênios/toxicidade , Estrona/toxicidade , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Apoptose/efeitos dos fármacos , Characidae/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia , Vitelogeninas/metabolismo
3.
Sci Total Environ ; 757: 143736, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33243503

RESUMO

Estrone and BPA are two endocrine disrupting chemicals (EDCs) that are predicted to be less potent than estrogens such as 17ß-estradiol and 17α-ethinylestradiol. Human exposure concentrations to estrone and BPA can be as low as nanomolar levels. However, very few toxicological studies have focused on the nanomolar-dose effects. Low level of EDCs can potentially cause non-monotonic responses. In addition, exposures at different developmental stages can lead to different health outcomes. To identify the nanomolar-dose effects of estrone and BPA, we used zebrafish modeling to study the phenotypic and transcriptomic responses after extended duration exposure from 0 to 5 days post-fertilization (dpf) and short-term exposure at days 4-5 post fertilization. We found that non-monotonic transcriptomic responses occurred after extended duration exposures at 1 nM of estrone or BPA. At this level, estrone also caused hypoactivity locomotive behavior in zebrafish. After both extended duration and short-term exposures, BPA led to more apparent phenotypic responses, i.e. skeletal abnormalities and locomotion changes, and more significant transcriptomic responses than estrone exposure. After short-term exposure, BPA at concentrations equal or above 100 nM affected locomotive behavior and changed the expression of both estrogenic and non-estrogenic genes that are linked to neurological diseases. These data provide gaps of mechanisms between neurological genes expression and associated phenotypic response due to estrone or BPA exposures. This study also provides insights for assessing the acceptable concentration of BPA and estrone in aquatic environments.


Assuntos
Disruptores Endócrinos , Estrona , Animais , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estrona/toxicidade , Humanos , Fenóis , Transcriptoma , Peixe-Zebra/genética
4.
Ecotoxicol Environ Saf ; 209: 111754, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33321418

RESUMO

There are many kinds of estrogens, and endogenous estrogens produce a variety of estrogen metabolites with similar structure but with different physiological effects after metabolism in vivo. Studies have shown that estrone (E1) widely occurs in the environment and animal-derived food. Because of its estrogen effect, E1 can have adverse effects on the human body as an endocrine disruptor. In this study, we found that E1 and 2-hydroxyestrone (2-OH-E1), the hydroxylation metabolite of estrogen, have opposite proliferative effects on breast cancer cells (MCF-7) through cell proliferation experiments and comparison of their effects by molecular docking and detection of ROS, Ca2+, and cell pathway proteins. The effects of 2-methoxyestrone (2-MeO-E1) and 16α-hydroxyestrone (16α-OH-E1) on the biochemical and protein levels of MCF-7 were further studied to compare the effects of metabolic sites and modes on estrogen effects. Hydroxylation of E1 at the C2 site weakened the estrogen effect, down-regulated the expression of the mammalian target of rapamycin (mTOR) and protein kinase B (Akt) pathway proteins, inhibited the proliferation of cancer cells, and enhanced anti-oxidative stress and anti-inflammation. Methoxylation at the C2 position also inhibited the expression of inflammatory and oxidative stress pathway proteins but did not greatly affect the estrogen effects. However, hydroxylation on C16 had no significant effect on the biological effects of estrogen. Therefore, the structural changes of estrogen on C2 are important reasons for the different physiological effects of estrogen and its metabolites. Thus, by regulating the gene Cytochrome P450 1B1(CYP1B1), which affects the hydroxylation metabolism of estrogen, and promoting the hydroxylation of estrone at the C2 position, the estrogen effect of estrone can be effectively reduced, thus reducing the harm its poses in food and the environment.


Assuntos
Estrogênios/toxicidade , Estrona/toxicidade , Hidroxiestronas/toxicidade , Proliferação de Células , Disruptores Endócrinos , Estradiol/metabolismo , Estrogênios/metabolismo , Estrona/metabolismo , Feminino , Humanos , Hidroxilação , Inflamação , Células MCF-7 , Simulação de Acoplamento Molecular , Estresse Oxidativo , Testes de Toxicidade
5.
Ecotoxicol Environ Saf ; 207: 111513, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33254393

RESUMO

The responses of pure strains to contaminant (i.e., estrone, E1) exposure have been widely studied. However, few studies about the responses of multispecies microbial aggregates (e.g., periphytic biofilm) to E1 exposure are available. In this study, the changes in physiological activity and community composition of periphytic biofilms before and after E1 exposure were investigated. The results showed that periphytic biofilms exhibited high adaptability to E1 exposure at a concentration of 0.5 mg L-1 based on physiological results. The increase in productivity of extracellular polymeric substances (EPS) after exposure to E1 was the main factor preventing association between E1 and microbial cells. The increase in the activity of superoxide dismutase (SOD) and ATP enzyme activity and the change in the co-occurrence pattern of microbial communities (increasing the relative abundance of Xanthomonadaceae and Cryomorphacea) also protected biofilms from E1 exposure. However, exposure to a high concentration of E1 (>10 mg L-1) significantly decreased EPS productivity and metabolic activity due to the excessive accumulation of reactive oxygen species. In addition, the abundance of some sensitive species, such as Pseudanabaenaceae, decreased sharply at this concentration. Overall, this study highlighted the feasibility of periphytic biofilms to adapt to E1 exposure at low concentrations in aquatic environments.


Assuntos
Biofilmes/efeitos dos fármacos , Estrona/toxicidade , Poluentes Químicos da Água/toxicidade , Biofilmes/crescimento & desenvolvimento , Cianobactérias , Matriz Extracelular de Substâncias Poliméricas , Microbiota , Água
6.
Arch Environ Contam Toxicol ; 79(1): 156-166, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32266455

RESUMO

The biological effects of endocrine-active compounds and increasing water temperatures as a result of climate change have been studied extensively and independently, but there is a dearth of research to examine the combined effect of these factors on exposed organisms. Recent data suggest that estrogenic exposure and rising ambient temperatures independently impact predator-prey relationships. However, establishing these connections in natural settings is complex. These obstacles can be circumvented if biomarkers of estrogenic exposure in resident fish can predict changes in predator-prey relationships. To test the effects of estrone and temperature, the piscivore bluegill sunfish (Lepomis macrochirus) was exposed for 30 days to estrone at concentrations (90 ± 17.6 ng/L [mean ± standard deviation] and 414 ± 146 ng/L) previously shown to reduce prey-capture success. Exposures were conducted at four temperatures (15 °C, 18 °C, 21 °C, 24 °C) to simulate breeding season ambient temperatures across the natural range of this species. A suite of morphological and physiological biomarkers previously linked to estrogenic exposures were examined. Biomarkers of estrone exposure were more commonly and severely impacted in male fish than in female fish. Notably, the gonadosomatic index was lower and gonads were less mature in exposed males. Additionally, temperature modulated the effects of estrone similarly in males and females with fish exposed at higher temperatures typically exhibiting a decreased morphological index. This study provides evidence that alterations in hepatic function and gonadal function may cause shifts in metabolism and energy allocation that may lead to declining prey capture performance.


Assuntos
Biomarcadores/metabolismo , Disruptores Endócrinos/toxicidade , Estrona/toxicidade , Água Doce/química , Perciformes/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Comportamento Predatório/efeitos dos fármacos , Temperatura
7.
Bioorg Chem ; 83: 402-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30415021

RESUMO

Heterocyclization of steroids were reported to give biologically active products where ring D modification occured. Estrone (1) was used as a template to develop new heterocyclic compounds. Ring D modification of 1 through its reaction with cyanoacetylhydrazine and elemental sulfur gave the thiophene derivative 3. The latter compound reacted with acetophenone derivatives 4a-c to give the hydrazide-hydrazone derivatives 5a-c, respectively. In addition, compound 3 formed thiazole derivatives through its first reaction with phenylisothiocyanate to give the thiourea derivative 9 followed by the reaction of the later with α-halocarbonyl compounds. In the present work a series of novel estrone derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). The most promising compounds 5b, 5c, 11a, 13c, 15b, 15c, 15d, 17a and 17b were further investigated against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR. Compounds 5b, 15d, 17a and 17b were selected to examine their Pim-1 kinase inhibition activity where compounds 15d and 17b showed high activities. Molecular docking of some of the most potent compounds was demonstrated.


Assuntos
Estrona/análogos & derivados , Estrona/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tiofenos/farmacologia , Anilidas/química , Anilidas/farmacologia , Animais , Artemia/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrona/síntese química , Estrona/toxicidade , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Proteínas Proto-Oncogênicas c-pim-1/química , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/toxicidade
8.
Environ Sci Pollut Res Int ; 25(24): 24003-24012, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29948676

RESUMO

Rivers may receive pharmaceuticals, personal care products, and environment estrogens, which are emerging concerns, from various sources. Understanding the fate of these emerging contaminants (ECs) from the sources to their receiving river is important for assessing their ecosystem risk. Here, the occurrence, seasonal variation, spatial distribution, and ecological risk of 22 ECs in water and sediments from the Jilin Songhua River, as well as in the effluents from the riverside Jilin wastewater treatment plant (WWTP) were investigated. Results indicated that estriol with the highest median concentration of 21.5 ng L-1 in the river water and with the highest median concentration of 481.5 ng g-1 in the sediments, and methylparaben with the highest concentration of 29.6 ± 2.9 ng L-1 in the WWTP effluents were the predominant contaminants. The total concentration of ECs in the river water in the dry season was about 1.5 times higher than that in the wet season. The concentrations of these ECs close to the contaminated tributary and the WWTP were relatively high. Risk assessment showed that the maximum risk quotient value of estrone was 1.07 in the river water and estriol was 2.10 in the effluents. In addition, erythromycin posed generally medium risk in the river water and WWTP effluents. It should be paid attention to the prior control of the three contaminants in the river region.


Assuntos
Rios/química , Poluentes Químicos da Água/análise , China , Cosméticos/análise , Ecossistema , Ecotoxicologia/métodos , Monitoramento Ambiental/métodos , Estrogênios/análise , Estrona/análise , Estrona/toxicidade , Sedimentos Geológicos/análise , Humanos , Preparações Farmacêuticas/análise , Medição de Risco , Estações do Ano , Instalações de Eliminação de Resíduos , Águas Residuárias/análise , Águas Residuárias/química , Poluentes Químicos da Água/toxicidade
9.
Water Res ; 139: 187-197, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29649703

RESUMO

Decades of studies on endocrine disruption have suggested the need to manage the release of key estrogens from municipal wastewater treatment plants (WWTP). However, the proposed thresholds are below the detection limits of most routine chemical analysis, thereby restricting the ability of watershed managers to assess the environmental exposure appropriately. In this study, we demonstrated the utility of a mechanistic model to address the data gaps on estrogen exposure. Concentrations of the prominent estrogenic contaminants in wastewaters (estrone, estradiol, and ethinylestradiol) were simulated in the Grand River in southern Ontario (Canada) for nine years, including a period when major WWTP upgrades occurred. The predicted concentrations expressed as total estrogenicity (E2 equivalent concentrations) were contrasted to a key estrogenic response (i.e., intersex) in rainbow darter (Etheostoma caeruleum), a wild sentinel fish species. A predicted total estrogenicity in the river of ≥10 ng/L E2 equivalents was associated with high intersex incidence and severity, whereas concentrations <0.1 ng/L E2 equivalents were associated with minimal intersex expression. Exposure to a predicted river concentration of 0.4 ng/L E2 equivalents, the environmental quality standard (EQS) proposed by the European Union for estradiol, was associated with 34% (95% CI:30-38) intersex incidence and a very low severity score of 0.6 (95% CI:0.5-0.7). This exposure is not predicted to cause adverse effects in rainbow darter. The analyses completed in this study were only based on the predicted presence of three major estrogens (E1, E2, EE2), so caution must be exercised when interpreting the results. Nevertheless, this study illustrates the use of models for exposure assessment, especially when measured data are not available.


Assuntos
Transtornos do Desenvolvimento Sexual/induzido quimicamente , Disruptores Endócrinos/toxicidade , Estrogênios/toxicidade , Modelos Teóricos , Percas , Poluentes Químicos da Água/toxicidade , Animais , Estradiol/toxicidade , Estrona/toxicidade , Etinilestradiol/toxicidade , Feminino , Masculino , Ontário , Rios , Águas Residuárias
10.
J Water Health ; 16(2): 253-262, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29676761

RESUMO

Potential endocrine disrupting chemicals (EDCs) are present in bottled water from various countries. In South Africa (SA), increased bottled water consumption and concomitant increases in plastic packaging create important consequences for public health. This study aimed to screen SA bottled water for estrogenic activity, selected target chemicals and assessing potential health risks. Ten bottled water brands were exposed to 20 °C and 40 °C over 10 days. Estrogenic activity was assessed using the recombinant yeast estrogen screen (YES) and the T47D-KBluc reporter gene assay. Solid phase extracts of samples were analyzed for bis(2-ethylhexyl) adipate (DEHA), selected phthalates, bisphenol-A (BPA), 4-nonylphenol (4-NP), 17ß-estradiol (E2), estrone (E1), and ethynylestradiol (EE2) using gas chromatography-mass spectrophotometry. Using a scenario-based health risk assessment, human health risks associated with bottled water consumption were evaluated. Estrogenic activity was detected at 20 °C (n = 2) and at 40 °C (n = 8). Estradiol equivalent (EEq) values ranged from 0.001 to 0.003 ng/L. BPA concentrations ranged from 0.9 ng/L to 10.06 ng/L. Although EEqs and BPA concentrations were higher in bottled water stored at 40 °C compared to 20 °C, samples posed an acceptable risk for a lifetime of exposure. Irrespective of temperature, bottled water from SA contained chemicals with acceptable health risks.


Assuntos
Água Potável/química , Estrogênios/toxicidade , Plastificantes/toxicidade , Poluentes Químicos da Água/análise , Exposição Dietética/estatística & dados numéricos , Disruptores Endócrinos/análise , Estrogênios/análise , Estrona/toxicidade , Humanos , Plastificantes/análise , África do Sul
11.
J Appl Toxicol ; 38(5): 705-713, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29277902

RESUMO

Contaminants of emerging concern (CECs) are ubiquitous in aquatic environments with well-established endocrine-disrupting effects. A data matrix of 559 water samples was queried to identify two commonly occurring CECs mixtures in Great Lakes tributaries. One mixture consisted of eight agricultural CECs (AG), while another contained 11 urban CECs (UB). The known estrogenic compounds bisphenol A, estrone and nonylphenol were present in both mixtures. According to the EPA Tox21 in ToxCast database, AG and UB mixture at an environmentally relevant concentration were estimated to account for 6.5% and 3.4% estrogenicity of the model endocrine disruptor estradiol-17ß, respectively. Two isoforms of the estrogen receptor (Esr1 and -2, former Erα and Erß) cloned from fathead minnow, bluegill sunfish, American alligator and human, responded differently to AG and UB mixtures. Human and bluegill Esr1 were the most sensitive to AG and UB mixtures, respectively. Fathead minnow Esr1 and Esr2b were the least sensitive to 10× AG and UB in estrogen dose equivalents, respectively. Even at environmentally documented concentrations, UB significantly activated bluegill Esr1. Moreover, 100× concentrated UB hyperstimulated fathead minnow Esr1 beyond the maximum induction of estradiol-17ß. These results indicate that efficacious receptors and species differ in their response to CEC mixtures. Furthermore, estrogenicity may be present in some CECs not previously considered estrogenic, or, alternatively, estrogenicity of a mixture may be enhanced through chemical interactions. Our study highlights the need for further studies of CECs utilizing a variety of receptors cloned from diverse species.


Assuntos
Receptores de Estrogênio/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Jacarés e Crocodilos/metabolismo , Animais , Compostos Benzidrílicos/toxicidade , Cyprinidae/metabolismo , Disruptores Endócrinos/toxicidade , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/efeitos dos fármacos , Estrona/toxicidade , Humanos , Perciformes/metabolismo , Fenóis/toxicidade
12.
Sci Total Environ ; 610-611: 1262-1270, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28851146

RESUMO

Laboratory exposures indicate that estrogens and their mimics can cause endocrine disruption in male fishes, yet while studies of resident fish populations in estrogen-polluted waters support these findings, biomarker expression associated with field versus laboratory exposure to estrogenic endocrine disruptors (EDs) often differ dramatically. Two of the environmental parameters often found to vary in dynamic aquatic ecosystems were chosen (dissolved oxygen [DO] and sodium chloride concentrations) to assess their potential impact on ED exposure. In separate experiments, male fathead minnows (Pimephales promelas) were exposed to estrone (E1) a natural ED, under either two concentrations of DO, or two concentrations of sodium chloride, in a laboratory flow-through system. Morphological and hematological parameters were assessed. While vitellogenin concentrations were elevated with exposure to estrone (29 to 390ng/L), the effect on other indices were variable. Estrone exposure altered SSC, blood glucose, hematocrit, and hepatic and gonado-somatic index in 1 of 4 experiments, while it decreased body condition factor in 3 of 4 experiments. At the concentrations tested, no main effect differences (P<0.05) were found associated with DO or sodium chloride treatments, except in one experiment low DO resulted in a decrease in secondary sex characteristic score (SSC). The combination of DO or sodium chloride and E1 altered blood glucose in one experiment each. These results indicate the variability of fathead minnow response to estrone, even within the confines of controlled laboratory conditions.


Assuntos
Cyprinidae/fisiologia , Disruptores Endócrinos/toxicidade , Estrona/toxicidade , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Masculino , Oxigênio/metabolismo , Cloreto de Sódio/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-28757214

RESUMO

Pharmaceutical and personal care products (PPCPs) are the environmental pollutants of growing concern. The aim of this study was to indicate the effects of typical PPCPs on the marsh frog Pelophylax ridibundus. We treated male frogs with waterborne ibuprofen (IBU, 250ng·L-1), triclosan (TCS, 500ng·L-1), or estrone (E1, 100ng·L-1) for 14days. Common vulnerability of the frogs was detected from dramatic decrease of Zn, total and metalated metallothionein (MT) concentrations, Zn/Cu ratio, the elevation of activity of glutathione-S-transferase, cathepsin D and DNA instability in the liver, the depletion of cholinesterase in the brain and cortisol in the blood plasma in all exposures. Nevertheless, lipofuscin concentration in the liver was always decreased. The groups were best distinguished by cytochrome P450 (CYP450) activity determined by ELISA. The exposure to IBU caused lesser damage, but elevated the levels of oxyradicals and glutathione (GSH and GSSG) and lysosomal membrane instability. Exposures to TCS and E1 provoked the endocrine disturbance (increased levels of vitellogenin and thyrotropin in blood plasma), decreased lactate dehydrogenase activity and increased level of pyruvate in the liver. TCS caused the increase of GSSG by 7.3 times and lactate levels. Only E1 lead to decrease of deiodinase activity in the liver, activation of CYP450 and caspase-3 and efflux of cathepsin D from lysosomes. Spectrophotometric and ELISA assays of MTs and CYP450 gave distinct results in E1-group. Broad disruption of the hormonal pathways caused by E1 could be of concern for the health status of frogs in their habitats.


Assuntos
Estrona/toxicidade , Ibuprofeno/toxicidade , Ranidae/fisiologia , Triclosan/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Anti-Infecciosos Locais/toxicidade , Anti-Inflamatórios não Esteroides/toxicidade , Biomarcadores/sangue , Estrogênios/toxicidade , Metalotioneína/metabolismo , Estresse Fisiológico/efeitos dos fármacos
14.
Chem Biol Drug Des ; 90(3): 478-484, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28171685

RESUMO

Assembly of cucurbitacin inspired estrone analogs has been previously synthesized and screened against melanoma cell lines. Further synthetic optimization was executed via installation of Azide polar functional moiety across 23, 24 α, ß-unsaturated ketone side chain using Michael addition reaction. This was followed by biological screening against melanoma cell lines employing MTT assay, in-cell-based ELISA assay, and Western blot analysis to monitor the potential of the synthesized analogs to inhibit the phosphorylated ERK levels. This resulted in evolution of MH-4 possessing IC50 of 3.59 µm with significant decrease in the p-ERK and targeting MAPK pathway.


Assuntos
Cucurbitacinas/toxicidade , Estrona/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cucurbitacinas/química , Cucurbitacinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Estrona/análogos & derivados , Estrona/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/análise , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/análise , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Fosforilação , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/metabolismo
15.
Environ Toxicol Chem ; 34(12): 2796-802, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26088724

RESUMO

Endocrine-disrupting chemicals (EDCs) such as 17α-ethynylestradiol, 17ß-estradiol, estrone, and para-nonylphenol have been measured in wastewater-treatment plant effluents, surface waters, sediments, and sludge and have been shown to induce liver-specific vitellogenin (vtg) messenger RNA in male fathead minnows (Pimephales promelas). The purpose of the present study was to establish minimal concentrations of select EDCs necessary to induce transcription of vtg in 48-h static renewal exposures, as measured by quantitative real-time thermal cycle amplification. Adult males were exposed to 17α-ethynylestradiol, 17ß-estradiol, estrone, and para-nonylphenol. Dose-dependent increases in vtg expression were significant with all chemicals tested. The lowest concentrations of these chemicals to induce measurable vtg expression, with significant difference from respective controls, were 17α-ethynylestradiol, 2.2 ng L(-1); para-nonylphenol, 13.9 µg L(-1); 17ß-estradiol, 42.7 ng L(-1); and estrone, 46.7 ng L(-1), measured as 48-h average concentrations. The present experiments were designed to frame a commonly acceptable approach for investigators who conduct static, in-laboratory proxy environmental aquatic exposures. The present study highlights the need for investigators to report in peer-reviewed submissions the observed concentration values for minimal induction levels when measuring molecular responses to chemical exposures by means of real-time polymerase chain reaction, quantitative polymerase chain reaction, or other "omic" technologies.


Assuntos
Cyprinidae/metabolismo , Disruptores Endócrinos/análise , Monitoramento Ambiental/métodos , Vitelogeninas/metabolismo , Poluentes Químicos da Água/análise , Animais , Disruptores Endócrinos/toxicidade , Estradiol/metabolismo , Estradiol/toxicidade , Estrona/análise , Estrona/toxicidade , Etinilestradiol/análise , Etinilestradiol/toxicidade , Masculino , Fenóis/análise , Fenóis/toxicidade , Esgotos/química , Poluentes Químicos da Água/toxicidade
16.
J Appl Toxicol ; 35(1): 11-3, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25580481

RESUMO

The most potent chemicals potentially causing adverse effects on fish species are estrogens in human waste.Sewage is a source of these estrogens and it is difficult to reduce. In particular, although the bioactivity of estrone is estimated to be about half of that of estradiol, multiple studies report that more than 100 ng l(­1) of estrone can be detected in urban rivers, including discharges from sewage treatment works; approximately two times as high as estradiol. Few studies have been conducted to investigate the long-term effects of estrone on wildlife; therefore, we conducted fish multigeneration test using Japanese medaka (Oryzias latipes). Medaka were exposed to estrone for 27 weeks across three generations in environmentally relevant concentrations, being 5.74, 11.4, 24.0, 47.1 and 91.4 ng l(­1). No effects on reproduction were observed in the first generation; however, a decline in egg production and fertility was observed in the second generation exposed to 91.4 ng l(­1) estrone, which is lower than some known environmental concentrations in urban environments. Furthermore, histopathological abnormalities were observed in the third generation exposed to both 47.1 and 91.4 ng l(­1), suggesting that estrone possibly exerts severe effects on the third or later generations. However, appearances of testis­ova were observed in the second and third generation they were not consistent with actual effects on reproduction, notwithstanding the testis-ovais regarded as the key evidence for endocrine disruption. Accordingly, we consider that qualitative measurement of abnormalities using histopathological observations is required for appropriate evaluation of endocrine disruption.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Estrona/toxicidade , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/patologia , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Oryzias , Óvulo/efeitos dos fármacos , Óvulo/patologia , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/patologia , Fatores de Tempo , Testes de Toxicidade
17.
Steroids ; 99(Pt A): 56-60, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25159108

RESUMO

UNLABELLED: Studies in hamsters, mice and rats have demonstrated that estradiol (E2), its interconvertible metabolite estrone (E1) and their catechol metabolites, in particular 4-hydroxy E2/E1, are carcinogenic in the kidney, uterus and mammary gland. Observational studies and clinical trials consistently show that sustained exposure to E2/E1 is associated with the development of sporadic breast cancer. The weight of evidence supports the contribution of two complementary pathways in the initiation, promotion and progression of breast cancer. One pathway involves activation of nuclear and cytoplasmic signaling pathways through the binding of estrogen to nuclear and membrane-bound estrogen receptors leading to increased cell proliferation. The other pathway involves the oxidative metabolism of E2/E1 to catechols and then reactive quinones that can contribute to oxidative DNA damage and form specific, mutagenic depurinating adducts with adenine and guanine which then in turn can serve as biomarkers for the occurrence of these processes. Both pathways can serve as portals to preventive intervention. Antiestrogens are used clinically to block receptor-mediated signaling to block tumor growth. Various chemopreventive agents such as sulforaphane (SFN) and resveratrol have been shown in cell culture to block oxidative metabolism of E2/E1 and thus prevent DNA damage. Pretreatment of MCF-7 and MCF-10F cells with and inhibitor of catechol-O-methyltransferase (COMT) followed by treatment with E2 or 4-OH E2 caused increased oxidative DNA damage (8-oxo-dG) and depurinating DNA adducts showing the importance of E2-catechol O-methylation by COMT as a protective pathway. E2 treatment of MCF-10A cells with E2 or 4-OH E2 caused an increase in E2-adenine and guanine adducts. Treatment with sulforaphane increased NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase A1 (GSTA1) expression without affecting expression of catechol-O-methyltransferase (COMT) or cytochrome P450 1B1. Pretreatment with SFN decreased depurinating DNA adducts while increasing levels of 4-OCH3E1/2 and 4-OHE1/2-glutathione conjugates. Treatment of MCF-10F cells with E2 or 4-OH-E2 also caused increased depurinating DNA adducts and neoplastic transformation while pretreatment with resveratrol caused a reduction in adduct levels and neoplastic transformation. Increased levels of estrogen-quinone conjugates and DNA adducts have also been detected in urine of women at increased risk for and with breast cancer. These observations support the notion that targeting the estrogen/estrone metabolism pathway may be another way to reduce breast cancer risk.


Assuntos
Anticarcinógenos/farmacologia , Carcinógenos/metabolismo , Estrogênios/metabolismo , Estrogênios/toxicidade , Animais , Neoplasias da Mama/etiologia , Carcinógenos/toxicidade , Modelos Animais de Doenças , Estradiol/metabolismo , Estradiol/toxicidade , Estrona/metabolismo , Estrona/toxicidade , Feminino , Humanos , Isotiocianatos/farmacologia , Neoplasias Renais/etiologia , Camundongos , Ratos , Fatores de Risco , Neoplasias Uterinas/etiologia
18.
Bull Environ Contam Toxicol ; 93(2): 215-21, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24849713

RESUMO

This paper investigates the effect of estrone (E1), 17ß-estradiol (E2) and 17α-ethinylestradiol (EE2) individually and mixed at equal proportions (1:1:1) on Desmodesmus subspicatus and Pseudokirchneriella subcapitata in single and combined cultures (S+) at different exposure times based on algal growth (in vivo chlorophyll fluorescence and cell counting) and coenobium formation. EE2 and E2 were more toxic to individual and combined (S+) cultures than was E1. The frequency of coenobium formation by D. subspicatus increased significantly for all estrogens and all concentrations. After 96 h, D. subspicatus prevailed in S+. The results of the exposure to E+ suggested a less-than-additive effect on D. subspicatus and S+ and additive effect on P. subcapitata. Toxic effects occurred for both species exposed to E+ with individual estrogen concentrations below the NOEC of each species. Assays must include changes in response due to the exposure of more than one species to more than one estrogen.


Assuntos
Clorófitas/efeitos dos fármacos , Estradiol/toxicidade , Estrogênios/toxicidade , Estrona/toxicidade , Etinilestradiol/toxicidade , Clorófitas/fisiologia
19.
Environ Toxicol Chem ; 33(1): 134-43, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24115239

RESUMO

To examine effects of municipal wastewater effluent (MWWE) on sentinel organisms, the authors deployed caged freshwater mussels (Lasmigona costata) in the Grand River (ON, Canada) upstream and downstream of an MWWE outfall. Passive sampling devices were deployed alongside caged mussels to confirm exposure. Biomarkers of xenobiotic biotransformation, oxidative stress, estrogenicity, and immunomodulation were investigated. Elevated concentrations of selected pharmaceutical and personal care products (PPCPs) and a natural estrogen (estrone) were found at the downstream sites. Mussels caged downstream of the effluent for 2 wk showed minimal evidence of exposure, while those deployed for 4 wk exhibited significantly higher levels of lipid peroxidation (LPO) and glutathione S-transferase (GST) activity, demonstrating that MWWE-exposed mussels exhibit increased activity in xenobiotic conjugation and oxidative stress. With respect to immune responses, a significant increase in plasma lysozyme activity and hemocyte viability was observed in MWWE-exposed mussels. Vitellogenin (vtg)-like protein in male mussels showed a trend toward induction after 4 wk of deployment at the first downstream site, but mean levels were not significantly different. Discriminant function analysis indicated that mussels deployed for 4 wk upstream and downstream of the MWWE discharge could be discriminated on the basis of LPO, GST, plasma lysozyme, and vtg responses. The physiological stress observed in caged mussels indicates that wild mussels chronically exposed to MWWE in this ecosystem would also be negatively impacted.


Assuntos
Unionidae/efeitos dos fármacos , Águas Residuárias/toxicidade , Poluentes da Água/toxicidade , Animais , Biomarcadores/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Monitoramento Ambiental , Estrona/toxicidade , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Glutationa Transferase/metabolismo , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Hemócitos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Muramidase/metabolismo , Ontário , Rios , Unionidae/metabolismo , Vitelogeninas/metabolismo
20.
Biosens Bioelectron ; 53: 406-13, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24201004

RESUMO

A piezoelectric biosensor for detection of endocrine disrupting chemicals (EDCs) was developed by incorporating chemical/biochemical recognition elements on the ceramic resonator surface for competitive binding assays. A facile electrodeposition was employed to modify the sensor surface with Au nanoparticles, which increased the surface area and enhanced the binding capacity of the immobilized probes. Thiol-labeled long chain hydrocarbon with bisphenol A (BPA) as head group was synthesized and self-assembled on the Au nanoparticle surface as the sensing probes, which showed a linear response upon the binding of estrogen receptor (ER-α) ranging from 1 to 30 nM. Detection of estrone, 17ß-estradiol and BPA was achieved by integrating a competitive binding assay with the piezoelectric sensor. In this detection scheme, different concentrations of EDCs were incubated with 30 nM of ER-α, and the un-bounded ER-α in the solution was captured by the probes immobilized on the ceramic resonator, which resulted in the frequency changes for different EDCs. The biosensor assay exhibited a linear response to EDCs with a low detection limit of 2.4-2.9 nM (S/N=3), and required only a small volume of sample (1.5 µl) with the assay time of 2h. The performance of the biosensor assay was also evaluated for rapid and facile determination of EDCs of environmental relevant concentrations in drinking water and seawater, and the recovery rate was in the range between 94.7% and 109.8%.


Assuntos
Compostos Benzidrílicos/isolamento & purificação , Técnicas Biossensoriais/métodos , Estradiol/isolamento & purificação , Estrona/isolamento & purificação , Fenóis/isolamento & purificação , Cerâmica/química , Disruptores Endócrinos/isolamento & purificação , Disruptores Endócrinos/toxicidade , Monitoramento Ambiental , Estradiol/toxicidade , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Estrona/toxicidade , Ouro/química , Humanos , Nanopartículas Metálicas/química , Água do Mar/análise , Poluentes Químicos da Água/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...