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1.
Front Immunol ; 12: 599345, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33659001

RESUMO

Exposure to environmental hormones such as di(2-ethylhexyl) phthalate (DEHP) has become a critical human health issue globally. This study aimed to investigate the correlations between DEHP/mono-(2-ethylhexyl) phthalate (MEHP) levels and macrophage-associated immune responses and clinical manifestations in dengue virus (DV)-infected patients. Among 89 DV-infected patients, those with DV infection-related gastrointestinal (GI) bleeding (n = 13, 15% of patients) had significantly higher DEHP exposure than those without GI bleeding (n = 76, 85% of patients), which were 114.2 ng/ml versus 52.5 ng/ml ΣDEHP in urine; p = 0.023). In an in vitro study using cultured human monocyte-derived macrophages (MDMs) to investigate the effects of MEHP, treatment increased IL-1ß and TNF-α release but decreased IL-23 release, with negative correlations observed between urine ΣDEHP and serum IL-23 levels in patients. MEHP-treated MDMs had lower antiviral Th17 response induction activity in mixed T-cell response tests. The in vitro data showed that MEHP increased DV viral load and decreased IL-23 release dose-dependently, and adding IL-23 to MEHP-exposed MDMs significantly reduced the DV viral load. MEHP also suppressed IL-23 expression via the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway. Further, the PPAR-γ antagonist GW9662 significantly reversed MEHP-induced IL-23 suppression and reduced the DV viral load. These study findings help to explain the associations between high MEHP levels and the high global burden of dengue disease.


Assuntos
Antivirais , Vírus da Dengue/imunologia , Dengue/imunologia , Dietilexilftalato/análogos & derivados , Interleucina-23/imunologia , Macrófagos/imunologia , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacologia , Dengue/tratamento farmacológico , Dengue/patologia , Dietilexilftalato/efeitos adversos , Dietilexilftalato/farmacologia , Feminino , Humanos , Interleucina-1beta/imunologia , Macrófagos/fisiologia , Macrófagos/virologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia
2.
Hum Cell ; 34(4): 1153-1162, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33721218

RESUMO

As one of the most prevalent and deadly cancers worldwide, esophageal squamous cell carcinoma (ESCC) can be directly exposed to endocrine-disrupting chemical (EDC). As a potential EDC, diethylhexyl phthalate (DEHP) can trigger the development of various cancers, while the potential effect of DEHP on the ESCC progression was not clear. Our present study revealed that DEHP can trigger the proliferation of ESCC cells and decrease the cisplatin (CDDP) and fluorouracil (5-FU) sensitivity. Mechanistical studies indicated that DEHP can decrease the transcription of PTEN, a well-characterized tumor suppressor, in ESCC cells. Over expression of PTEN can reverse DEHP-regulated ESCC cell proliferation and chemosensitivity. Further, DEHP can increase the expression of HES-1, which can bind with the promoter of PTEN to inhibit its transcription. Collectively, DEHP can increase proliferation while decrease chemosensitivity of ESCC cells via regulation of HES-1/PTEN axis. Further, daily expression of DEHP may be a potent risk factor for ESCC development.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Dietilexilftalato/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Fluoruracila/farmacocinética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Supressores de Tumor , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Transcrição Genética/efeitos dos fármacos , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Ligação Proteica , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Transcrição Genética/genética
3.
Molecules ; 26(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562043

RESUMO

Environmental di(2-Ethylhexyl) phthalate (DEHP) is widely used in various industries as a plasticizer, and has been reported to induce reproductive and developmental toxicities in organisms. The purpose of this study was to evaluate the detoxification capacity of Lycium barbarum polysaccharides (LBP) and wolfberry juice (WJ) against DEHP-induced hepatotoxicity. Two groups of rats were purchased to study two different intervention method experiments: LBP (50, 100, 200 mg/kg·bw) intervention before DEHP (2000 mg/kg·bw) exposure, and LBP (200 mg/kg·bw) or WJ (8 mL/kg·bw) intervention after DEHP (3000 mg/kg·bw) exposure. The rats were exposed to DEHP once, while the intervention lasted for seven days. At the end of the intervention, enzyme-linked immunosorbent assay (ELISA) was used to measure the related index. The LBP intervention before DEHP exposure experiment (the first experimental method) found that LBP group rats showed a strong capacity toward DEHP detoxification, evidenced by the significant upregulation of activities and concentrations of the partner retinoid, X receptor alpha (RXRα), and downstream regulators Cytochrome P4502E1 (CYP2E1), Cytochrome P4503A1 (CYP3A1), Glutathione S-Transferase Pi (GSTpi), and UDP-glucuronosyltransferase 1 (UGT1) in a dose-dependent manner. The LBP and WJ intervention after DEHP exposure experiment (the second intervention experiment) found that WJ could downregulate pregnane X receptor (PXR), and upregulate downstream regulators, CYP2E1, CYP3A1, and Glutathione S-Transferase (GST) with the extension of intervention time, to alleviate the toxicity of DEHP. However, the intervention effect of WJ was more obvious than that of LBP. These results suggested that LBP and WJ might be effective detoxification agents against DEHP-induced toxic effects, by activating PXR and PXR-related detoxifying enzymes.


Assuntos
Citoproteção/efeitos dos fármacos , Dietilexilftalato/efeitos adversos , Sucos de Frutas e Vegetais/análise , Fígado/efeitos dos fármacos , Lycium/química , Polissacarídeos/farmacologia , Receptor de Pregnano X/metabolismo , Animais , Fígado/citologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
4.
J Agric Food Chem ; 68(41): 11468-11479, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-32962341

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is a widespread pollutant that badly affects animals and human health. Lycopene (LYC) has been used as a dietary supplement that has effective antioxidant and antiobesity functions. The present goal was to understand the molecular mechanisms of LYC preventing DEHP-induced lipid metabolism of the liver. The mice were intragastrically administered with LYC (5 mg/kg) and/or DEHP (500 mg/kg or 1000 mg/kg). Here, we found that LYC attenuated DEHP-caused hepatic histopathological lesions including steatosis. Hematological and biochemical analyses revealed that LYC ameliorated DEHP-caused liver function and lipid metabolism disorders. DEHP caused lipid metabolism disorders via activating the peroxisome proliferator activated receptor α/γ (PPARα/γ) signal transducer and Farnesoid X receptor (FXR)/liver X receptor (LXR) signaling pathway. As a major regulator of lipid metabolism, hypoxia-inducible factor-1α (HIF-1α) system was elevated with increased fatty degeneration under DEHP exposure. However, LYC could decrease the levels of HIF-1α/PPARα/PPARγ/FXR/LXR signaling pathway-related factors. Our research indicated that LYC could prevent DEHP-induced lipid metabolism disorders via inhibiting the HIF-1α-mediated PPARα/PPARγ/FXR/LXR system. This study may provide a possible molecular mechanism for fatty liver induced by DEHP.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Receptores X do Fígado/metabolismo , Licopeno/administração & dosagem , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Antioxidantes , Dietilexilftalato/efeitos adversos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Transtornos do Metabolismo dos Lipídeos/genética , Transtornos do Metabolismo dos Lipídeos/metabolismo , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , PPAR alfa/genética , PPAR gama/genética , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais
5.
J Neurol Neurosurg Psychiatry ; 91(9): 968-974, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32636213

RESUMO

BACKGROUND: In neurodegenerative diseases, alongside genetic factors, the possible intervention of environmental factors in the pathogenesis is increasingly being considered. In particular, recent evidence suggests the intervention of a pesticide-like xenobiotic in the initiation of disease with Lewy bodies (DLB). OBJECTIVES: To test for the presence of pesticides or other xenobiotics in the cerebrospinal fluid (CSF) of patients with DLB. METHODS: A total of 45 patients were included in this study: 16 patients with DLB at the prodromal stage, 8 patients with DLB at the demented stage, 8 patients with Alzheimer's disease (AD) at the prodromal stage and 13 patients with AD at the demented stage. CSF was obtained by lumbar puncture and analysed by liquid chromatography-mass spectrometry. RESULTS: Among the compounds detected in greater abundance in the CSF of patients with DLB compared with patients with AD, only one had a xenobiotic profile potentially related to the pathophysiology of DLB. After normalisation and scaling, bis(2-ethylhexyl) phthalate was more abundant in the CSF of patients with DLB (whole cohort: 2.7-fold abundant in DLB, p=0.031; patients with dementia: 3.8-fold abundant in DLB, p=0.001). CONCLUSIONS: This study is the first reported presence of a phthalate in the CSF of patients with DLB. This molecule, which is widely distributed in the environment and enters the body orally, nasally and transdermally, was first introduced in the 1920s as a plasticizer. Thereafter, the first cases of DLB were described in the 1960s and 1970s. These observations suggest that phthalates may be involved in the pathophysiology of DLB.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Dietilexilftalato/efeitos adversos , Dietilexilftalato/líquido cefalorraquidiano , Exposição Ambiental , Doença por Corpos de Lewy/líquido cefalorraquidiano , Metabolômica , Idoso , Doença de Alzheimer/diagnóstico , Feminino , Humanos , Doença por Corpos de Lewy/diagnóstico , Masculino , Pessoa de Meia-Idade , Sintomas Prodrômicos , Xenobióticos/efeitos adversos
6.
J Toxicol Sci ; 45(7): 373-390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612006

RESUMO

DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10-8, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M) for 24 hr. Subsequently, RA (50 µM) was administered for 24 hr before 10-4 M DEHP challenge. We found that DEHP induced thyroid damage and inflammatory infiltration in vivo. In addition, we showed that DEHP triggered inflammatory cell death, which is mediated by multiple inflammasomes. Moreover, RA, pyroptosis inhibitor (Ac-YVAD-cmk) and antioxidant inhibitor (NAC) treatment significantly alleviated DEHP-induced thyrocyte death, suppressing pro-inflammatory cytokine production, inhibiting multiple inflammasomes activation and attenuating thyrocyte death, respectively. Collectively, our results reveal that a critical role of inflammasomes activation in DEHP-induced thyroid injury, and suggest that RA confers protection against DEHP-induced thyroid inflammation, and facilitating control of the effects of DEHP after given pyroptosis inhibitor or antioxidant inhibitor. These results indicate that it should be possible to provide novel insights into toxicologically and pharmacologically targeting this molecule to DEHP-induced inflammation.


Assuntos
Anti-Inflamatórios , Antioxidantes , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Dietilexilftalato/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/tratamento farmacológico , Inflamassomos/metabolismo , Fitoterapia , Animais , Boraginaceae , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Dietilexilftalato/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Hipotireoidismo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Ratos Sprague-Dawley , Células Epiteliais da Tireoide/efeitos dos fármacos
7.
J Clin Res Pediatr Endocrinol ; 12(4): 393-400, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32431137

RESUMO

Objective: We aimed to investigate a possible role of the endocrine disruptors phthalates, di-2-ethylhexyl phthalate (DEHP) and mono (2-ethylhexyl) phthalate (MEHP), in polycystic ovary syndrome (PCOS) aetiopathogenesis. We also wished to evaluate the relationship between phthalates and metabolic disturbances in adolescents with PCOS. Methods: A total of 124 adolescents were included. Serum MEHP and DEHP levels were determined by high-performance liquid chromatography. Insulin resistance was evaluated using homeostasis model assessment-insulin resistance, quantitative Insulin Sensitivity Check Index, fasting glucose/insulin ratio, Matsuda index, and total insulin levels during oral glucose tolerance test. Participants were further subdivided into lean and obese subgroups according to body mass index (BMI). Results: Sixty-three PCOS and 61 controls, (mean age 15.2±1.5; range: 13-19 years) were enrolled. Serum DEHP and MEHP concentrations were not significantly different between PCOS and control groups. The mean (95% confidence interval) values of DEHP and MEHP were 2.62 (2.50-2.75) µg/mL vs 2.71 (2.52-2.90) µg/mL and 0.23 (0.19-0.29) µg/mL vs 0.36 (0.18-0.54) µg/mL in PCOS and the control groups respectively, p>0.05. Correlation analysis, adjusted for BMI, showed that both phthalates significantly correlated with insulin resistance indices and serum triglycerides in adolescents with PCOS. Conclusion: Serum DEHP and MEHP concentrations were not different between adolescents with or without PCOS. However, these phthalates are associated with metabolic disturbances such as dyslipidemia and insulin resistance, independently of obesity, in girls with PCOS.


Assuntos
Biomarcadores/sangue , Dietilexilftalato/análogos & derivados , Dietilexilftalato/sangue , Dislipidemias/epidemiologia , Disruptores Endócrinos/sangue , Resistência à Insulina , Síndrome do Ovário Policístico/fisiopatologia , Adolescente , Adulto , Estudos de Casos e Controles , Estudos Transversais , Dietilexilftalato/efeitos adversos , Dislipidemias/sangue , Dislipidemias/induzido quimicamente , Disruptores Endócrinos/efeitos adversos , Feminino , Seguimentos , Humanos , Plastificantes/efeitos adversos , Plastificantes/metabolismo , Síndrome do Ovário Policístico/sangue , Prognóstico , Turquia/epidemiologia , Adulto Jovem
8.
PLoS One ; 15(1): e0224931, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999712

RESUMO

The plasticizer di(2-ethylhexyl)phthalate (DEHP) is often used for PVC medical devices, that are also largely used for intensive care medical treatments, like extracorporeal membrane oxygenation (ECMO) therapy. Due to the toxicological potential of DEHP, the inner exposure of patients with this plasticizer is a strong matter of concern as many studies have shown a high leaching potential of DEHP into blood. In this study, the inner DEHP exposure of patients undergoing ECMO treatment was investigated. The determined DEHP blood levels of ECMO patients and the patients of the control group ranged from 31.5 to 1009 µg/L (median 156.0 µg/L) and from 19.4 to 75.3 µg/L (median 36.4 µg/L), respectively. MEHP blood levels were determined to range from < LOD to 475 µg/L (median 15.9 µg/L) in ECMO patients and from < LOD to 9.9 µg/L (median 3.7 µg/L) in the control group patients, respectively. Increased DEHP exposure was associated with the number of cannulas and membranes of the ECMO setting, whereas residual diuresis decreased the exposure. Due to the suspected toxicological potential of DEHP, its use in medical devices should be further investigated, in particular for ICU patients with long-term exposure to PVC, like in ECMO therapy.


Assuntos
Dietilexilftalato/sangue , Monitoramento Ambiental , Oxigenação por Membrana Extracorpórea/efeitos adversos , Plastificantes/efeitos adversos , Idoso , Cuidados Críticos , Dietilexilftalato/efeitos adversos , Dietilexilftalato/análogos & derivados , Dietilexilftalato/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plastificantes/uso terapêutico , Cloreto de Polivinila/efeitos adversos , Cloreto de Polivinila/uso terapêutico
9.
Fish Shellfish Immunol ; 96: 26-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794841

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP), a common pollutant in the water environment, has been reported to be associated with immune functions, especially aquatic organisms. However, whether DEHP exposure causes neutrophils toxicity in common carp is still unclear. To investigate the toxic effect of DEHP on immune functions, common carp neutrophils were exposed to DEHP (40 µmol/L and 200 µmol/L) for 2 h. The common carp neutrophils exposed to DEHP showed a decrease in neutrophil phagocytosis rate compared with control group. DEHP exposure induced a significant decrease in mRNA expression levels of inflammatory cytokines-related genes (Interleukin-6, Interleukin-8, transforming growth factor, tumor necrosis factor (TNF)-α, TNF-R1, TNF-T1, Interferon (IFN)-2a, IFN-g2b, IFN-g1) in common carp neutrophils, while the expression levels of IL-1ß and IL-10 were increased compared with control group (P < 0.05). Furthermore, the detection of cytochrome P450 enzyme related genes showed that the mRNA expression levels of CYP (cytochrome P450 proteins)-1A, CYP-1B1, CYP-C1, CYP-2K were significantly decreased, and the mRNA expression level of CYP-3A was significantly reduced (P < 0.05). The results indicated that DEHP could affect the phagocytic ability of neutrophils by regulating the expression of inflammatory cytokines and disrupting cytochrome P450 homeostasis, which caused the immunosuppression in common carp.


Assuntos
Carpas/imunologia , Sistema Enzimático do Citocromo P-450/imunologia , Dietilexilftalato/efeitos adversos , Proteínas de Peixes/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Neutrófilos/imunologia , Poluentes Químicos da Água/efeitos adversos , Animais , Carpas/metabolismo , Homeostase/imunologia , Neutrófilos/efeitos dos fármacos , Plastificantes/efeitos adversos
11.
Artigo em Inglês | MEDLINE | ID: mdl-31297340

RESUMO

Diethylhexylphthalate (DEHP), acting as an endocrine disruptor, disturbed reproductive health. Here, we evaluated the effects of Lactobacillus plantarum TW1-1 (L. plantarum TW1-1) on DEHP-induced testicular damage in adult male mice. Results showed that oral supplementation of L. plantarum TW1-1 significantly increased the serum testosterone concentration, enhanced the semen quality, and attenuated gonad development defects in DEHP-exposed mice. L. plantarum TW1-1 also alleviated DEHP-induced oxidative stress and inflammatory responses by decreasing the mRNA expression and serum protein concentration of different inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1ß and IL-6]. Furthermore, L. plantarum TW1-1 significantly reduced DEHP-induced intestinal hyper-permeability and the increase in the serum lipopolysaccharide level. Gut microbiota diversity analysis revealed that L. plantarum TW1-1 shifted the DEHP-disrupted gut microbiota to that of the control mice. At phylum level, L. plantarum TW1-1 reversed DEHP-induced Bacteroidetes increase and Firmicutes decrease, and restored Deferribacteres in DEHP-exposed mice. Spearman's correlation analysis showed that Bacteroidetes, Deferribacteres, and Firmicutes were associated with DEHP-induced testicular damage. In addition, the ratio of Firmicutes to Bacteroidetes (Firm/Bac ratio) significantly decreased from 0.28 (control group) to 0.13 (DEHP-exposed group), which was restored by L. plantarum TW1-1 treatment. Correlation analysis showed that the Firm/Bac ratio was negatively correlated with testicular damage and inflammation. These findings suggest that L. plantarum TW1-1 prevents DEHP-induced testicular damage via modulating gut microbiota and decreasing inflammation.


Assuntos
Dietilexilftalato/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Inflamação/terapia , Lactobacillus plantarum/fisiologia , Doenças Testiculares/terapia , Testículo/efeitos dos fármacos , Animais , Bactérias/classificação , Modelos Animais de Doenças , Fezes/microbiologia , Expressão Gênica , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Lipopolissacarídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade , Probióticos , RNA Ribossômico 16S/genética , Análise do Sêmen , Doenças Testiculares/induzido quimicamente , Testículo/patologia , Testosterona/sangue , Fator de Necrose Tumoral alfa/metabolismo
12.
Toxicol Appl Pharmacol ; 378: 114612, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175881

RESUMO

Infertility caused by environmental pollution is becoming a global problem, but an effective prevention or treatment is lacking. Icariin (ICA) is a flavonoid used in traditional Chinese medicine. The present study investigated the possible roles of ICA in preventing testicular dysfunction caused by di(2-ethylhexyl) phthalate (DEHP), one of the most studied environmental endocrine disruptors. Cultured mouse Leydig cells were pretreated with ICA and exposed to DEHP to determine ICA effects upon cell proliferation, reactive oxygen species (ROS) levels, mitochondrial membrane potential (Δψm), testosterone levels and the expression of transcription factor SF-1 and steroidogenic enzymes (CYP11, 3ß-HSD and 17ß-HSD), which play critical roles in androgen production. Our results showed that ICA reversed the adverse effect of DEHP on Leydig cell proliferation, and decreased ROS levels and elevated Δψm levels. Also, ICA promoted testosterone production and up-regulated the expression of SF-1 and steroidogenic enzymes. We investigated ICA actions in vivo, using male mice administrated DEHP followed by ICA. Exposure to DEHP decreased epididymal sperm counts and disrupted seminiferous tubules, and both of these effects were reversed by ICA treatment. These results showed that the mechanisms of ICA in protecting mouse testes against DEHP-induced damage involves the prevention of ROS accumulation and promotion of testosterone secretion.


Assuntos
Dietilexilftalato/efeitos adversos , Flavonoides/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Ácidos Ftálicos/efeitos adversos , Substâncias Protetoras/farmacologia , Testosterona/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/metabolismo , Feminino , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo
13.
Chemosphere ; 228: 278-286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31035166

RESUMO

Di(2-etilhexil) phthalate (DEHP) is a compound used in plastic materials, which has endocrine disrupting properties. The human DEHP exposure depend on the use of plastics in toys, medical devices and food and beverage containers. The DEHP effects were studied in some physiological systems; nevertheless, the actions in human arteries were never described. We analysed the DEHP effect on endothelium denuded human umbilical artery (HUA), an important artery to ensure gases and nutrients exchange with fetus. We assessed DEHP short-term effects on contractility, occurring few minutes after DEHP is in contact with HUA in the organ bath receptacles. The long-term effects on HUA, observed after 24 h in presence of DEHP, were assessed in the organ bath system, and also through the analysis of receptors expression (5-HT2A and H1) and of cellular viability, by using HUA smooth muscle cells. DEHP (1 nM-100 µM) induced a short-term relaxing effect on HUA contracted by 5-HT, histamine or KCl. DEHP long-term exposure of arteries (1 nM, 10 µM and 100 µM) reduced its own relaxant effect on HUA contracted by 5-HT and histamine and, precisely, 24 h exposure to DEHP 1 nM reverted the relaxant effect on 5-HT contractility. Long-term exposure at more than 10 nM of DEHP decreased 5HT2A receptors expression. In conclusion, DEHP short-term exposition elicit vasodilation of HUA contracted by different agents. DEHP long-term exposition reduced the expression of 5HT2A receptors. The DEHP long-term exposition decrease the short-term relaxant effect and, at low concentrations can increase the contractile effect of 5-HT.


Assuntos
Dietilexilftalato/efeitos adversos , Artérias Umbilicais/efeitos dos fármacos , Dietilexilftalato/metabolismo , Humanos
14.
J Toxicol Sci ; 44(4): 237-244, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944277

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is widely used in polyvinylchloride-based materials and remains intact in the environment. Lungs are one route of entry of DEHP into the body; however, there is limited information on the effects and mechanism of action of DEHP on non-small cell lung cancer (NSCLC). Here, we addressed this by examining the effect of DEHP on the proliferation of A549 human lung adenocarcinoma cells by MTS assay. The induction of inflammation and epithelial-to-mesenchymal transition (EMT), as well as activation of the mitogen-activated protein kinase (MAPK) and Wnt/ß-catenin signaling pathways, were assessed by western blot and real-time polymerase chain reaction. Although there were discrepancies in the concentration, DEHP treatment enhanced A549 cell viability accompanied by increased mRNA and protein levels of inflammation-related factors, such as matrix metalloproteinase-9 and nuclear factor-κB. Additionally, EMT was activated in cells according to decreased E-cadherin and increased vimentin expression. Furthermore, MAPK pathway components, including phosphorylated p38 and c-Jun N-terminal kinase, and Wnt/ß-catenin pathway components, including phosphorylated glycogen synthase kinase 3ß and ß-catenin, as well as their downstream genes c-Myc and cyclin D1, were upregulated in the presence of DEHP. These results suggest that DEHP promotes NSCLC progression by promoting cell proliferation, inflammation, and EMT via activation of Wnt/ß-catenin signaling.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Dietilexilftalato/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Plastificantes/efeitos adversos , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , Células A549 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Inflamação/genética
15.
Environ Health Perspect ; 127(2): 27003, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30810372

RESUMO

BACKGROUND: Phthalates are environmental contaminants commonly used as plasticizers in polyvinyl chloride (PVC) products. Recently, exposure to phthalates has been associated with preterm birth, low birth weight, and pregnancy loss. There is limited information about the possible mechanisms linking maternal phthalate exposure and placental development, but one such mechanism may be mediated by peroxisome proliferator­activated receptor γ (PPARγ). PPARγ belongs to the nuclear receptor superfamily that regulates, in a ligand-dependent manner, the transcription of target genes. Studies of PPARγ-deficient mice have demonstrated its essential role in lipid metabolism and placental development. In the human placenta, PPARγ is expressed in the villous cytotrophoblast (VCT) and is activated during its differentiation into syncytiotrophoblast. OBJECTIVES: The goal of this study was to investigate the action of mono(2-ethylhexyl) phthalate (MEHP) on PPARγ activity during in vitro differentiation of VCTs. METHODS: We combined immunofluorescence, PPARγ activity/hCG assays, western blotting, and lipidomics analyses to characterize the impacts of physiologically relevant concentrations of MEHP (0.1, 1, and 10 µM) on cultured VCTs isolated from human term placentas. RESULTS: Doses of 0.1 and 1 µM MEHP showed significantly lower PPARγ activity and less VCT differentiation in comparison with controls, whereas, surprisingly, a 10 µM dose had the opposite effect. MEHP exposure inhibited hCG production and significantly altered lipid composition. In addition, MEHP had significant effects on the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: This study suggests that MEHP has a U-shaped dose­response effect on trophoblast differentiation that is mediated by the PPARγ pathway and acts as an endocrine disruptor in the human placenta. https://doi.org/10.1289/EHP3730.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Dietilexilftalato/análogos & derivados , Poluentes Ambientais/efeitos adversos , PPAR gama/genética , Trofoblastos/efeitos dos fármacos , Dietilexilftalato/efeitos adversos , Feminino , Humanos , Masculino , PPAR gama/metabolismo , Placenta/efeitos dos fármacos , Placenta/fisiologia , Gravidez , Trofoblastos/fisiologia
16.
Zhonghua Nan Ke Xue ; 25(12): 1097-1101, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-32251561

RESUMO

Objective: To investigate the relationship between di-(2-ethyl hexyl) phthalate (DEHP) and male infertility by detecting the concentration of DEHP in the seminal plasma of the patient with idiopathic asthenozoospermia (IAS). METHODS: This study included 45 infertile males with diagnosed IAS in the observation group and another 45 men with normal sperm parameters as controls. We obtained the general baseline data on the subjects, determined the concentration of DEHP in the seminal plasma, the ROS level and the sperm DNA fragmentation index (DFI), and compared them between the two groups of males. RESULTS: There were no statistically significant differences between the two groups of subjects in age, living habits and other general in baseline data (P > 0.05). The IAS patients, in comparison with the normal controls, showed significantly increased DEHP concentration in the seminal plasma (ï¼»0.45 ± 0.09ï¼½ vs ï¼»0.23 ± 0.05ï¼½ µg/ml, P < 0.05), ROS level (ï¼»569.4 ± 45.3ï¼½ vs ï¼»317.6 ± 27.8ï¼½ pmol/106 sperm, P < 0.05) and sperm DFI (ï¼»22.1 ± 8.3ï¼½% vs ï¼»10.5 ± 6.7ï¼½%, P < 0.05). The concentration of DEHP in the seminal plasma was correlated positively with the ROS level (r = 0.77, P < 0.05) and sperm DFI (r = 0.75, P < 0.05) but negatively with the percentage of progressively motile sperm (r = -0.81, P < 0.05). CONCLUSIONS: The DEHP level is escalated in the seminal plasma of the IAS patient, which may be responsible for the reduced sperm motility and increased DFI of the patient.


Assuntos
Astenozoospermia/induzido quimicamente , Dietilexilftalato/efeitos adversos , Plastificantes/efeitos adversos , Sêmen/química , Estudos de Casos e Controles , Fragmentação do DNA , Dietilexilftalato/análise , Humanos , Masculino , Plastificantes/análise , Contagem de Espermatozoides , Motilidade Espermática , Espermatozoides/patologia
17.
Thyroid ; 29(2): 183-192, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30588877

RESUMO

BACKGROUND: Diethylhexyl phthalate (DEHP) is widely used in industrial products, particularly as plasticizers and softeners. Because it is used extensively, DEHP has been detected in humans worldwide. Although epidemiological studies suggest that DEHP can disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis, evidence on the association between DEHP exposure and thyroid function remains inconclusive. Therefore, a comprehensive meta-analysis was performed to investigate the association between DEHP exposure and the HPT axis in humans. METHODS: A literature search of the MEDLINE, EMBASE, and Web of Science databases was conducted to search for studies in which the correlation coefficient values or regression coefficient values between three major DEHP metabolites (i.e., monoethylhexyl phthalate [MEHP], mono [2-ethyl-5-hydroxyhexyl] phthalate [MEHHP], and mono [2-ethyl-5-oxohexyl] phthalate) and thyrotropin, free thyroxine (T4), or total T4 were determined. The association between DEHPs and thyroid hormone levels were evaluated using Pearson's correlation coefficients. RESULTS: Thirteen eligible articles were included. Urinary MEHP and MEHHP concentration was negatively correlated with total T4. Pooled correlation coefficients between MEHP/MEHHP and total T4 were -0.02 [confidence interval (CI) -0.05 to 0.00] and -0.03 [CI -0.05 to -0.01], respectively. Urinary mono (2-ethyl-5-oxohexyl) phthalate concentration was positively correlated with thyrotropin, and the pooled correlation coefficient was 0.02 [CI 0.00-0.04]. CONCLUSIONS: The findings of this meta-analysis suggest a significant association between the exposure of DEHP metabolites and the function of the HPT axis.


Assuntos
Dietilexilftalato/efeitos adversos , Dietilexilftalato/metabolismo , Glândula Tireoide/efeitos dos fármacos , Dietilexilftalato/análogos & derivados , Dietilexilftalato/urina , Exposição Ambiental , Humanos , Ácidos Ftálicos/urina , Testes de Função Tireóidea , Tireotropina/sangue , Tiroxina/sangue
18.
Food Chem Toxicol ; 124: 265-272, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30543897

RESUMO

Phthalates are being suggested to be associated with altered thyroid function and proliferative changes, but detailed mechanisms remain unclear. Here, we examined the effects of di-(2-ethylhexyl) phthalate (DEHP) on DNA damage and proliferation in thyroid using thyroid carcinoma cell line, 8505C, in vitro and the rats orally treated with DEHP at 0, 0.3, 3, 30 and 150 mg/kg for 90 days from post-natal day 9 in vivo. Exposure to DHEP (1-50 µM) induced cellular proliferation, as evidenced by increased cell viability and DNA synthesis. Activation of γH2AX, a sensitive biomarker for DNA damage was observed following the exposure to DHEP (from 5 to 50 µM) with increased comet tail moment (5-100 µM) in comet assay, reflecting that DNA damage also occurred. When upstream signaling was examined, both thyrotropin receptor (TSHR)-ERK1/2 axis and TSHR-AKT axis were activated with upregulation of Pax8, a master transcriptional factor for thyroid differentiation and proliferation. Thyroid tissue from juvenile rats orally exposed to DEHP also confirmed DNA damage responses and the activation of TSHR signaling, which was evident from 0.3 to 3 mg/kg respectively. Notably, deletion of TSHR through siRNA attenuated these DEHP-induced events in vitro. Collectively these results suggest that DEHP induces DNA damage and cellular proliferation in thyroid, which appears to be from TSHR activation, providing an important insight into endocrine disrupting activities of phthalates on thyroid.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dietilexilftalato/efeitos adversos , Receptores da Tireotropina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Feminino , Histonas/metabolismo , Humanos , Masculino , Fosfoproteínas/metabolismo , Ratos Sprague-Dawley , Glândula Tireoide/patologia
19.
Ann Thorac Surg ; 107(2): 567-572, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30071236

RESUMO

BACKGROUND: Industrial chemicals are increasingly recognized as potential developmental neurotoxicants. Di(2-ethylhexyl) phthalate (DEHP), used to impart flexibility and temperature tolerance to polyvinylchloride, and bisphenol A (BPA), used to manufacture polycarbonate, are commonly present in medical devices. The magnitude of exposure in neonates during hospitalization for cardiac operations is unknown. METHODS: We quantified urinary concentrations of DEHP metabolites and BPA preoperatively and postoperatively in neonates undergoing cardiac operations and their mothers. Urinary concentrations of these biomarkers reflect recent exposures (half-lives are approximately 6 to 24 hours). Biomarker concentrations in mothers' and infants' preoperative and postoperative samples were compared. RESULTS: Operations were performed in 18 infants (mean age, 5 ± 4 [SD] days). The maternal sample was obtained on postpartum day 4 ± 4. The preoperative urine sample was obtained on day-of-life 4 ± 2 and the postoperative sample on day-of-life 6 ± 4. Mean maternal concentrations for DEHP metabolites and BPA were at the 50th percentile for females in the United States general population. Infant preoperative concentrations of 1 DEHP metabolite and BPA were significantly higher than maternal concentrations. Postoperative concentrations for all DEHP metabolites were significantly greater than preoperative concentrations. CONCLUSIONS: There is considerable perioperative exposure to DEHP and BPA for neonates undergoing cardiac operations. Infant concentrations for both BPA and DEHP metabolites were significantly higher than maternal concentrations, consistent with the infant's exposure to medical devices. Further study is needed to determine the potential role of these suspect neurotoxicants in the etiology of neurodevelopmental disability after cardiac operations.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Dietilexilftalato/efeitos adversos , Exposição Ambiental/efeitos adversos , Equipamentos e Provisões/efeitos adversos , Cardiopatias Congênitas/cirurgia , Neurotoxinas/efeitos adversos , Fenóis/efeitos adversos , Compostos Benzidrílicos/urina , Biomarcadores/urina , Dietilexilftalato/urina , Feminino , Seguimentos , Cardiopatias Congênitas/urina , Humanos , Recém-Nascido , Masculino , Neurotoxinas/urina , Fenóis/urina , Período Pós-Operatório , Período Pré-Operatório , Estudos Prospectivos , Fatores de Risco
20.
Chemosphere ; 214: 812-820, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30300839

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental pollutant with endocrine disrupting properties. As a plasticizer, DEHP can be leach from the plastic to transfer the external environment and thus enters the animal food chain, causing serious damage to the animal organs. The heat-shock response (HSR) comprising heat-shock protein (HSPs) and heat-shock transcription factor (HSFs) plays a pivotal role in various toxic stress conditions. For the sake of investigating the effects of DEHP exposure on cardiac toxicity and the regulation of HSR, male quail were fed the diet with 0, 250, 500 and 750 mg/kg DEHP by gavage administration for 45 days. Histopathological changes including cardiomyocyte swelling and muscle fiber dilatation were observed in the hearts exposed to DEHP. During the DEHP treatment, the mRNA expression of HSP60 and HSP70 were universally reduced, while the expression of other HSPs (HSP10, HSP25, HSP27, HSP40, HSP47, HSP90, HSP110) had different degrees of growth. In addition, the levels of HSF1, HSF2, and HSF3 were significantly increased. Given the facts above, DEHP exposure induced the toxic effects of quail heart. DEHP exposure did great harm to HSR via affecting the synthesis of HSFs to mediate the transcription of the HSPs. Ultimately, this study provided new evidence that DEHP-induced cardiotoxicity in quail was related to activation of HSR and playing a protective role.


Assuntos
Cardiotoxicidade/etiologia , Dietilexilftalato/efeitos adversos , Resposta ao Choque Térmico/genética , Ácidos Ftálicos/efeitos adversos , Animais , Cardiotoxicidade/patologia , Codorniz
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