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1.
Sci Total Environ ; 805: 150348, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34818759

RESUMO

A new highly sensitive, selective, and inexpensive electrochemical method has been developed for simultaneously detecting diethylstilbestrol (DES) and 17ß-estradiol (E2) in environmental samples (groundwater and lake water) using a graphite sensor modified by cerium oxide nanoparticles (CPE-CeO2 NPs). The developed sensor and the materials used in its preparation were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The ab initio simulation was used to evaluate the adsorption energies between both DES and E2 with the surface of the sensor. The peak current of oxidation of both hormones showed two regions of linearity. The region of greatest sensitivity was observed for the linear range of 10 nM-100 nM. The detection and quantification limits for this concentration range were 0.8/2.6 nM and 1.3/4.3 nM for DES and E2, respectively. The analytical performance of the developed method showed high sensitivity, precision, repeatability, reproducibility, and selectivity. The CPE-CeO2 NPs sensor was successfully applied to simultaneously detect DES and E2 in real samples with recovery levels above 98%.


Assuntos
Dietilestilbestrol , Técnicas Eletroquímicas , Eletrodos , Estradiol , Limite de Detecção , Reprodutibilidade dos Testes
2.
Anal Chim Acta ; 1187: 339171, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34753561

RESUMO

Nanozyme-mediated 3,3',5,5'-tetramethylbenzidine (TMB) - H2O2 systems have spawned the establishment of multiple colorimetric sensing platforms that are effective but sometimes subject to low sensitivity. Taking temperature as the output signal, photothermal effects lead to new strategies for sensitive detection. In this paper, a colorimetric and photothermal dual-mode immunoassay for diethylstilbestrol (DES) was constructed. It is based on the oxidation reaction of TMB catalyzed by black phosphorus-gold nanoparticle (BP/Au) nanohybrids, and the kinetics as well as catalytic mechanism of the nanohybrids were investigated in detail for the first time. Herein, the nanohybrids playcatalytic and photothermal dual roles. Moreover, the one-electron oxidation product of TMB (oxidized TMB) not only acts as chromogenic agent but also an excellent NIR laser-driven photothermal agent. The temperature (ΔT/°C) was gauged by a portable digital thermometer. Through an indirect competition strategy, a simple, sensitive, and economic immunosensor was proposed. Higher DES content in the sample correlated with less BP/Au nanohybrids conjugated to the surface of ELISA microplate, a weaker color change, and a lower temperature variation when exposed to laser irradiation. This method was applied for DES determination in real samples with gratifying recovery rates, showing great promise in food safety inspection applications.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Colorimetria , Dietilestilbestrol , Ouro , Peróxido de Hidrogênio , Imunoensaio , Peroxidase , Peroxidases , Fósforo
3.
Anal Chem ; 93(40): 13513-13519, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34596384

RESUMO

This paper demonstrates the hierarchical design of functional, fibrous polymer monoliths. The monoliths are composed of conjugated microporous polymers that not only are embedded with heteroatoms but also feature fibrous yet compressible structures due to the in situ self-assembly process that occurs during the polymerization process. Therefore, the doped nitrogen atoms can allow the growth of zeolitic imidazolate framework (ZIF) nanocrystals, which causes the homogeneous encapsulation of individual fibers. The resulting hybrid monoliths exhibit enhanced physical properties as well as catalytic activity, allowing the formation of an additional coating layer via a thiol-epoxy reaction. The deliberate inclusion of template molecules during the reaction forms molecularly imprinted sites on the fibers to afford functional monoliths. As a proof of concept, the hierarchically designed materials are able to show effective recognition properties toward diethylstilbestrol, an endocrine disruptor, taking advantage of the binding sites that selectively capture the analyte molecules and the fibrous morphology that increases the accessibility of these binding sites. We envisage that the incorporation of various heteroatoms or nanocrystals will bring about the bespoke design of advanced monoliths with autonomous functions, leading to smart textile systems.


Assuntos
Nanopartículas , Zeolitas , Dietilestilbestrol , Polimerização , Polímeros
4.
Artigo em Inglês | MEDLINE | ID: mdl-34639263

RESUMO

BACKGROUND: Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on the children born after such treatment and their progeny, focusing particularly on psychiatric disorders. CASE PRESENTATION: We report here an informative family in which one or more psychiatric problems (e.g., bipolarity, suicide attempts and suicide, eating disorders) were detected in all children of second-generation (DES-exposed children; n = 9), but for II-2 who died at the age of 26 years due to rupture of a congenital brain aneurysm, and were associated with non-psychiatric disorders (particularly, endometriosis and hypospadias). In the third generation, 10 out of 19 DES-exposed grandchildren had psychiatric disorders (autism spectrum disorder, bipolar disorder, dyspraxia and learning disabilities, mood and behavioral disorders, and eating disorders), often associated with comorbidities. In the fourth generation (7 DES-exposed great-grandchildren, aged between 0 and 18 years), one child had dyspraxia and autism spectrum disorder. The first daughter of the second generation (not exposed to DES) and her children and grandchildren did not have any psychiatric symptoms or comorbidities. CONCLUSIONS: To our knowledge, the high prevalence of psychiatric disorders of various severities in two, and likely three generations, including DES-free pregnancies and DES-exposed pregnancies from the same family, has never been reported. This work strengthens the hypothesis that in utero exposure to DES contributes to the pathogenesis of psychiatric disorders. It also highlights a multigenerational, and possibly transgenerational, effect of DES in neurodevelopment and psychiatric disorders.


Assuntos
Transtorno do Espectro Autista , Hipospadia , Transtornos Mentais , Efeitos Tardios da Exposição Pré-Natal , Adolescente , Criança , Pré-Escolar , Dietilestilbestrol/toxicidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos Mentais/induzido quimicamente , Transtornos Mentais/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
5.
Artigo em Inglês | MEDLINE | ID: mdl-34639609

RESUMO

Diethylstilbestrol (DES), a transplacental endocrine-disrupting chemical, was prescribed to pregnant women for several decades. The number of women who took DES is hard to know precisely, but it has been estimated that over 10 million people have been exposed around the world. DES was classified in the year 2000 as carcinogenic to humans. The deleterious effects induced by DES are very extensive, such as abnormalities or cancers of the genital tract and breast, neurodevelopmental alterations, problems associated with socio-sexual behavior, and immune, pancreatic and cardiovascular disorders. Not only pregnant women but also their children and grandchildren have been affected. Epigenetic alterations have been detected, and intergenerational effects have been observed. More cohort follow-up studies are needed to establish if DES effects are transgenerational. Even though DES is not currently in use, its effects are still present, and families previously exposed and their later generations deserve the continuity of the research studies.


Assuntos
Disruptores Endócrinos , Efeitos Tardios da Exposição Pré-Natal , Carcinógenos , Criança , Dietilestilbestrol , Disruptores Endócrinos/efeitos adversos , Feminino , Genitália , Humanos , Gravidez
6.
Environ Health ; 20(1): 96, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452632

RESUMO

BACKGROUND: Endometriosis, which affects 10-15 % of women of reproductive age, is an estrogen-driven condition influenced by environmental and genetic factors. Exposition to estrogen-like endocrine-disrupting chemicals (EDCs) has been reported to contribute to the fetal origin of this disease. CASE PRESENTATION: We report here an informative family in which all prenatally DES-exposed daughters and subsequent granddaughters presented endometriosis, whereas the unexposed first daughter and her progeny presented no gynecological disorders. Moreover, the only post-pubertal great-granddaughter, who presents chronic dysmenorrhea that remains resistant to conventional therapy, is at risk of developing endometriosis. The mother (I-2) was prescribed DES (30 mg/day for 3 months) to inhibit lactation after each delivery. CONCLUSIONS: Although a direct causal link between the grandmother's treatment with DES and the development of endometriosis in possibly three exposed generations remains speculative, this report strengthens the suspicion that fetal exposition to DES contributes to the pathogenesis of adult diseases, such as endometriosis. It also highlights a multigenerational and likely transgenerational effect of EDCs.


Assuntos
Dietilestilbestrol/efeitos adversos , Dismenorreia/induzido quimicamente , Disruptores Endócrinos/efeitos adversos , Endometriose/induzido quimicamente , Estrogênios não Esteroides/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Feminino , Humanos , Gravidez
7.
Biomolecules ; 11(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201983

RESUMO

Environmental estrogen is a substance that functions as an endocrine hormone in organisms and can cause endocrine system disruption. A typical environmental estrogen, diethylstilbestrol (DES), can affect normal sexual function and organism development. However, even though the effects of different exposure stages of DES on the endocrine system and gonadal development of zebrafish juveniles are unknown, sex determination is strongly influenced by endocrine-disrupting chemicals (EDCs). From 10-90 days post fertilization (dpf), juvenile zebrafish were exposed to DES (100 and 1000 ng/L) in three different stages (initial development stage (IDS), 10-25 dpf; gonadal differentiation stage (GDS), 25-45 dpf and gonadal maturity stage (GMS), 45-60 dpf). Compared with that of IDS and GMS, the growth indicators (body length, body weight, and others) decreased significantly at GDS, and the proportion of zebrafish females exposed to 100 ng/L DES was significantly higher (by 59.65%) than that of the control; in addition, the zebrafish were biased towards female differentiation. The GDS is a critical period for sex differentiation. Our results show that exposure to environmental estrogen during the critical gonadal differentiation period not only affects the development of zebrafish, but also affects the population development.


Assuntos
Dietilestilbestrol/toxicidade , Disruptores Endócrinos/toxicidade , Estrogênios não Esteroides/toxicidade , Gônadas/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Animais , Tamanho Corporal/efeitos dos fármacos , Tamanho Corporal/fisiologia , Feminino , Masculino , Diferenciação Sexual/fisiologia , Peixe-Zebra
8.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281152

RESUMO

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.


Assuntos
Anoctamina-1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dietilestilbestrol/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Anoctamina-1/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Dietilestilbestrol/metabolismo , Humanos , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Transdução de Sinais
9.
Analyst ; 146(13): 4254-4260, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34100481

RESUMO

In this work, a novel electrochemiluminescence (ECL) aptasensor based on the resonance energy transfer (RET) effect between Ag3PO4-Cu-MOF (ii) and silver nanoparticles (Ag NPs) is proposed. The ECL emission spectra of Ag3PO4-Cu-MOF and the ultraviolet absorption spectra of Ag NPs showed a good spectral overlap. Based on this, we designed an "on-off-on" ECL sensing strategy for the sensitive and specific detection of diethylstilbestrol (DES). Under the optimal conditions, the linear range of the sensor for DES detection was 1.0 × 10-12-1.0 × 10-4 M, with a detection limit of 7.2 × 10-13 M (S/N = 3). The method showed simple and fast operation, high sensitivity and selectivity, a strong anti-interference ability and good stability. More importantly, the developed aptasensor exhibited excellent recognition towards residual DES in actual water samples. The sensor has superior measurement capability and potential application value in the field of environment water quality monitoring.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Dietilestilbestrol , Técnicas Eletroquímicas , Transferência de Energia , Limite de Detecção , Medições Luminescentes , Prata
10.
Front Public Health ; 9: 674357, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34123993

RESUMO

Uterine leiomyoma (UL), common benign tumors in women of child-bearing age, are believed to be caused mainly by Qi stagnation and blood stasis, according to a theory of traditional Chinese medicine. Curcumae Rhizoma and Sparganii Rhizoma (CRSR) is a classical herb pair that activates blood circulation to dissipate blood stasis. The purpose of this study was to explore the prevention and treatment effects of CRSR component compatibility on UL in rats. We randomly assigned adult female non-pregnant rats into three groups: a normal control (NC) group, a UL model group, and a CRSR treatment group. We administered to the UL and CRSR groups oral gavage diethylstilbestrol and injected them with progesterone (P) to establish UL for 5 weeks. The CRSR group received a CRSR medicinal solution after daily modeling. The uterus morphology of the UL group showed significantly more swelling than did that of the NC group, and we found no significant abnormalities in the morphology of the CRSR group. The pathological changes associated with UL were relieved in the CRSR group. CRSR improved the related parameters of the uterus and ovarian coefficients, significantly reducing the concentrations of P in the serum and the concentrations of estradiol, P, estrogen receptor, and P receptor in the uterus and ovary. In addition, CRSR significantly improved the abnormal blood conditions of UL, shown by decreases in plasma viscosity, the erythrocyte sedimentation rate equation K value, and erythrocyte aggregation index. Therefore, CRSR component compatibility may prevent and cure UL through the above ways.


Assuntos
Leiomioma , Medicina Tradicional Chinesa , Animais , Dietilestilbestrol , Feminino , Leiomioma/tratamento farmacológico , Ratos , Rizoma , Útero
11.
Artigo em Inglês | MEDLINE | ID: mdl-34052754

RESUMO

A novel fabric phase sorptive extraction protocol is developed for rapid exposure monitoring of six bisphenol analogues, including bisphenol A, bisphenol S, bisphenol F, bisphenol E, bisphenol B, bisphenol C, and diethylstilbestrol (DES) from human urine prior to high-performance liquid chromatography-photodiode array analysis. FPSE sample pretreatment protocol ensures the harmonization of the proposed method with the principles of Green Analytical Chemistry (GAC). Among eighteen evaluated FPSE membranes, sol-gel poly (ethylene glycol) (PEG) coated cellulose FPSE membrane resulted in the most efficient extraction. This polar FPSE membrane effectively exploits a number of advantageous features inherent to FPSE including sponge-like porous architecture of the sol-gel sorbent coating, favorable surface chemistry, flexibility and built-in permeability of cellulose fabric substrate, high primary contact surface area for rapid sorbent-analyte interaction, expanded pH, solvent and thermal stability as well as reusability of the FPSE membrane. Optimization was centered on the evaluation of critical parameters, namely the size of the FPSE membrane, the elution solvent mixture, the volume of the sample, the extraction time, the elution time, the kind of the external agitation mechanical stimulus, the ionic strength and the pH of the sample. The chromatographic separation was achieved on a Spherisorb C18 column and a gradient elution program with mobile phase consisted of 0.05 ammonium acetate solution and acetonitrile. The total analysis time was 17.4 min. The developed method was validated in terms of linearity, sensitivity, selectivity, precision, accuracy, stability, and ruggedness. The limits of detection and quantification varied from 0.26-0.62 ng/mL and 0.8-1.9 ng/mL, respectively. The relative recoveries were calculated between 90.6 and 108.8%, while the RSD values were <10% in all cases. The effectiveness of the proposed method was confirmed by its successful implementation in the bioanalysis of real urine samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dietilestilbestrol/urina , Fenóis/urina , Feminino , Química Verde , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Têxteis
12.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920546

RESUMO

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8-12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior.


Assuntos
Dibutilftalato/toxicidade , Dietilestilbestrol/toxicidade , Estrogênios não Esteroides/farmacologia , Hipotálamo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Sexual Animal , Animais , Aromatase/genética , Aromatase/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Ocitocina/genética , Ocitocina/metabolismo , Plastificantes/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transcriptoma , Vasopressinas/genética , Vasopressinas/metabolismo
13.
Biomolecules ; 11(2)2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557377

RESUMO

The synthetic estrogen diethylstilbestrol (DES) is used to treat metastatic carcinomas and prostate cancer. We studied its interaction with membranes and its localization to understand its mechanism of action and side-effects. We used differential scanning calorimetry (DSC) showing that DES fluidized the membrane and has poor solubility in DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) in the fluid state. Using small-angle X-ray diffraction (SAXD), it was observed that DES increased the thickness of the water layer between phospholipid membranes, indicating effects on the membrane surface. DSC, X-ray diffraction, and 31P-NMR spectroscopy were used to study the effect of DES on the Lα-to-HII phase transition, and it was observed that negative curvature of the membrane is promoted by DES, and this effect may be significant to understand its action on membrane enzymes. Using the 1H-NOESY-NMR-MAS technique, cross-relaxation rates for different protons of DES with POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) protons were calculated, suggesting that the most likely location of DES in the membrane is with the main axis parallel to the surface and close to the first carbons of the fatty acyl chains of POPC. Molecular dynamics simulations were in close agreements with the experimental results regarding the location of DES in phospholipids bilayers.


Assuntos
Varredura Diferencial de Calorimetria/métodos , Carbono/química , Dietilestilbestrol/química , Ácidos Graxos/química , Membranas Artificiais , Difração de Raios X/métodos , Dietilestilbestrol/análise , Bicamadas Lipídicas/química , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Transição de Fase , Fosfatidilcolinas/química , Fosfolipídeos/química , Radioisótopos de Fósforo/química , Prótons , Solubilidade , Temperatura , Termodinâmica
14.
Reprod Toxicol ; 101: 9-17, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33571642

RESUMO

Developmental exposure to endocrine disrupting chemicals can have negative consequences for reproductive health in both men and women. Our knowledge about how chemicals can cause adverse health outcomes in females is, however, poorer than our knowledge in males. This is possibly due to lack of sensitive endpoints to evaluate endocrine disruption potential in toxicity studies. To address this shortcoming we carried out rat studies with two well-known human endocrine disruptors, diethylstilbestrol (DES) and ketoconazole (KTZ), and evaluated the sensitivity of a series of endocrine related endpoints. Sprague-Dawley rats were exposed orally from gestational day 7 until postnatal day 22. In a range-finding study, disruption of pregnancy-related endpoints was seen from 0.014 mg/kg bw/day for DES and 14 mg/kg bw/day for KTZ, so doses were adjusted to 0.003; 0.006; and 0.0012 mg/kg bw/day DES and 3; 6; or 12 mg/kg bw/day KTZ in the main study. We observed endocrine disrupting effects on sensitive endpoints in male offspring: both DES and KTZ shortened anogenital distance and increased nipple retention. In female offspring, 0.0012 mg/kg bw/day DES caused slightly longer anogenital distance. We did not see effects on puberty onset when comparing average day of vaginal opening; however, we saw a subtle delay after exposure to both chemicals using a time-curve analysis. No effects on estrous cycle were registered. Our study shows a need for more sensitive test methods to protect the reproductive health of girls and women from harmful chemicals.


Assuntos
Dietilestilbestrol/toxicidade , Disruptores Endócrinos/toxicidade , Cetoconazol/toxicidade , Canal Anal/anormalidades , Animais , Feminino , Genitália/anormalidades , Humanos , Masculino , Troca Materno-Fetal , Mamilos/anormalidades , Gravidez , Ratos Sprague-Dawley , Maturidade Sexual , Testes de Toxicidade/métodos
15.
Toxicol In Vitro ; 72: 105088, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33429043

RESUMO

The present study investigated the developmental toxicity of diethylstilbestrol (DES) in the zebrafish embryotoxicity test (ZET). This was done to investigate whether the ZET would better capture the developmental toxicity of DES than the embryonic stem cells test (EST) that was previously shown to underpredict the DES-induced developmental toxicity as compared to in vivo data, potentially because the EST does not capture late events in the developmental process. The ZET results showed DES-induced growth retardation, cumulative mortality and dysmorphisms (i.e. induction of pericardial edema) in zebrafish embryos while the endogenous ERα agonist 17ß-estradiol (E2) showed only growth retardation and cumulative mortality with lower potency compared to DES. Furthermore, the DES-induced pericardial edema formation in zebrafish embryos could be counteracted by co-exposure with ERα antagonist fulvestrant, indicating that the ZET captures the role of ERα in the mode of action underlying the developmental toxicity of DES. Altogether, it is concluded that the ZET differentiates DES from E2 with respect to their developmental toxicity effects, while confirming the role of ERα in mediating the developmental toxicity of DES. Furthermore, comparison to in vivo data revealed that, like the EST, in a quantitative way also the ZET did not capture the relatively high in vivo potency of DES as a developmental toxicant.


Assuntos
Carcinógenos/toxicidade , Dietilestilbestrol/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Estradiol/toxicidade , Estrogênios/toxicidade , Teratógenos/toxicidade , Peixe-Zebra/anormalidades , Animais , Embrião não Mamífero/anormalidades , Feminino , Cabeça/anormalidades , Cardiopatias Congênitas/induzido quimicamente , Masculino , Cauda/anormalidades , Cauda/efeitos dos fármacos , Testes de Toxicidade , Saco Vitelino/anormalidades , Saco Vitelino/efeitos dos fármacos
16.
Eur J Drug Metab Pharmacokinet ; 46(1): 105-118, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33064293

RESUMO

BACKGROUND AND OBJECTIVES: Previous studies have revealed that sulfation, as mediated by the estrogen-sulfating cytosolic sulfotransferase (SULT) SULT1E1, is involved in the metabolism of 17ß-estradiol (E2), 4-hydroxytamoxifen (4OH-tamoxifen), and diethylstilbestrol in humans. It is an interesting question whether the genetic polymorphisms of SULT1E1, the gene that encodes the SULT1E1 enzyme, may impact on the metabolism of E2 and these two drug compounds through sulfation. METHODS: In this study, five missense coding single nucleotide polymorphisms of the SULT1E1 gene were selected to investigate the sulfating activity of the coded SULT1E1 allozymes toward E2, 4OH-tamoxifen, and diethylstilbestrol. Corresponding cDNAs were generated by site-directed mutagenesis, and recombinant SULT1E1 allozymes were bacterially expressed, affinity-purified, and characterized using enzymatic assays. RESULTS: Purified SULT1E1 allozymes were shown to display differential sulfating activities toward E2, 4OH-tamoxifen, and diethylstilbestrol. Kinetic analysis revealed further distinct Km (reflecting substrate affinity) and Vmax (reflecting catalytic activity) values of the five SULT1E1 allozymes with E2, 4OH-tamoxifen, and diethylstilbestrol as substrates. CONCLUSIONS: Taken together, these findings highlighted the significant differences in E2-, as well as the drug-sulfating activities of SULT1E1 allozymes, which may have implications in the differential metabolism of E2, 4OH-tamoxifen, and diethylstilbestrol in individuals with different SULT1E1 genotypes.


Assuntos
Dietilestilbestrol/metabolismo , Estradiol/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Sulfotransferases/genética , Sulfotransferases/metabolismo , Tamoxifeno/análogos & derivados , Dietilestilbestrol/farmacologia , Relação Dose-Resposta a Droga , Estradiol/farmacologia , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Estrogênios/metabolismo , Estrogênios/farmacologia , Estrogênios não Esteroides/metabolismo , Estrogênios não Esteroides/farmacologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Estrutura Secundária de Proteína , Sulfotransferases/química , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia
17.
Hum Reprod ; 36(1): 82-86, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33147330

RESUMO

To date, vaginal/cervical clear cell adenocarcinoma (CCAC) has not been reported in the granddaughters of women treated with diethylstilbestrol (DES) during pregnancy. We present an 8-year-old girl with a history of severe vaginal bleeding who was diagnosed with cervical CCAC. She underwent fertility-sparing surgery and radiotherapy. No sign of recurrence was detected throughout a 10-year follow-up. Her grandmother had received DES therapy during pregnancy with the patient's mother. Although no direct causal link is demonstrated, this case raises for the first time, the hypothesis of multigenerational effects of DES in girls and strongly suggests the need to follow the granddaughters of DES-treated women.


Assuntos
Adenocarcinoma de Células Claras , Disruptores Endócrinos , Efeitos Tardios da Exposição Pré-Natal , Adenocarcinoma de Células Claras/induzido quimicamente , Colo do Útero , Criança , Dietilestilbestrol/efeitos adversos , Feminino , Humanos , Recidiva Local de Neoplasia , Gravidez
19.
J Reprod Dev ; 66(6): 515-522, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-32830152

RESUMO

Cluster of differentiation (CD) 9 and CD81 are closely-related members of the tetraspanin family that consist of four-transmembrane domain proteins. Cd9 and Cd81 are highly expressed in breast cancer cells; however, their expression in healthy mammary glands is unclear. In this study, we performed quantitative real-time PCR to analyze the expression levels of Cd9 and Cd81. Histological techniques were employed to identify Cd9- and Cd81-expressing cells in rat mammary glands during pregnancy and lactation. It was observed that Cd9 and Cd81 were expressed in the mammary glands, and their expression levels correlated with mammary gland development. To identify cells expressing Cd9 and Cd81 in the mammary glands, we performed double immunohistochemical staining for CD9 and CD81, prolactin receptor long form, estrogen receptor alpha, or Ki67. The results showed that CD9 and CD81 were co-expressed in proliferating mammary epithelial cells. Next, we attempted to isolate CD9-positive epithelial cells from the mammary gland using pluriBead cell-separation technology based on antibody-mediated binding of cells to beads of different sizes, followed by isolation using sieves with different mesh sizes. We successfully isolated CD9-positive epithelial cells with 96.8% purity. In addition, we observed that small-interfering RNAs against Cd9 and Cd81 inhibited estrogen-induced proliferation of CD9-positive mammary epithelial cells. Our current findings may provide novel insights into the proliferation of mammary epithelial cells during pregnancy and lactation as well as in pathological processes associated with breast cancer.


Assuntos
Células Epiteliais/citologia , Perfilação da Expressão Gênica , Glândulas Mamárias Animais/metabolismo , Tetraspanina 28/biossíntese , Tetraspanina 29/biossíntese , Animais , Diferenciação Celular , Proliferação de Células , Dietilestilbestrol , Receptor alfa de Estrogênio/biossíntese , Feminino , Antígeno Ki-67/biossíntese , Lactação , Gravidez , Prenhez , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
20.
Artigo em Inglês | MEDLINE | ID: mdl-32710933

RESUMO

Hormonal sex reversal can produce monosex fish stocks and provide insights into their gamity and reproductive physiology. However, paradoxical effects have been reported in several fish species that remain largely ignored as anomalies, particularly those of masculinisation. As a first step, this study examined reproductive viability of paradoxically masculinised Gambusia holbrooki produced following oral administration (20-100 mg/kg feed) of a feminizing hormone diethylstilbestrol (DES). Contrary to expectation, all treatment groups produced 100% male populations. Survival, mating behaviour, gamete production, breeding output as well as expression of anti-Mullerian hormone (amh), ovarian (cyp19a1a) and brain (cyp19a1b) aromatase of masculinised fish were also examined. Survival (≤ 54.1 ± 7.3%) at termination of DES treatment was significantly lower compared with controls (88.6 ± 4.3%) but remained unaffected post treatment. Gonopodium thrusting frequency (33 ± 9.8 per 10 min) was not significantly different to untreated males just as sperm abundance (3.9 ± 1.5 × 108/male) and their motility (88.6 ± 29.1%). Importantly, paradoxically masculinised fish mated with virgin females and produced clutch sizes (22 ± 4) and progeny survival (87.0 ± %) that were comparable to that of untreated males. Masculinised testes showed high amh and low cyp19a1a expression, a pattern resembling those of untreated males. Production of paradoxically sex-reversed males with a capability to produce viable offspring has not been reported previously in this or other fish species. The outcomes support a feed-back regulation of oestrogenic pathways in this viviparous fish and could be useful for ecological applications such as controlling invasive fish populations.


Assuntos
Ciprinodontiformes/fisiologia , Dietilestilbestrol/farmacologia , Ovário/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Hormônio Antimülleriano/metabolismo , Aromatase/genética , Aromatase/metabolismo , Transtornos do Desenvolvimento Sexual/induzido quimicamente , Estrogênios não Esteroides/farmacologia , Feminino , Masculino , Ovário/fisiologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Testículo/fisiologia
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