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1.
Ecotoxicol Environ Saf ; 192: 110309, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061985

RESUMO

In this study, chronic toxicity of three endocrine disrupting chemicals (EDCs) used to make plastic products (i.e., bisphenol A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and nonylphenol (NP)) in a Korean resident fish (Cyprinus carpio), crustacean (Moina macrocopa) and green alga (Pseudokirchneriella subcapitata) species was tested. It was found that M. macrocopa was particularly sensitive to those EDCs, especially DEHP and NP. We exposed M. macrocopa to DEHP (0.0012-0.1 mg/L) and NP (0.00037-0.03 mg/L), and as a result, both chemicals significantly delayed the first day of reproduction. The no observed effect concentrations (NOECs) of DEHP and NP for this endpoint were determined to be 0.0012 and 0.00037 mg/L, respectively, which are far lower than NOECs for any other freshwater species. Existing water quality criteria of various governmental agencies do not consider the toxicity of those EDCs on M. macrocopa, and thus, use of the existing criteria for the risk assessment of the Korean freshwater environment may underestimate the ecological risk. This study recommends using the water quality criteria derived in this study (0.95 µg/L for DEHP and 0.16 µg/L for NP) based on the chronic toxicity data on Korean resident species including M. macrocopa for the aquatic ecological risk assessment in Korea rather than adopting the existing water quality criteria.


Assuntos
Disruptores Endócrinos/toxicidade , Plastificantes/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Compostos Benzidrílicos/toxicidade , Carpas , Clorófitas/efeitos dos fármacos , Cladóceros/efeitos dos fármacos , Dietilexilftalato/toxicidade , Fenômenos Ecológicos e Ambientais , Fenóis/toxicidade , Reprodução/efeitos dos fármacos , República da Coreia , Medição de Risco , Testes de Toxicidade Crônica , Qualidade da Água
2.
Chemosphere ; 246: 125808, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31918107

RESUMO

This study evaluated the acute developmental toxicity of six priority phthalic acid esters (PAEs) including dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), di-n-octyl phthalate (DNOP), and benzyl butyl phthalate (BBP) in zebrafish embryos. A novel alcian blue and alizarin red double staining was performed to detect skeletal development of zebrafish larvae. Results revealed that all six PAEs could induce different developmental abnormalities in zebrafish larvae, including abnormal movement, decreased heart rate, spinal curvature, and pericardial edema. The bone development of zebrafish larvae exposed to PAEs was also affected by PAEs acute exposure. Among PAEs, DBP, and BBP even at low doses can cause mortality in zebrafish, implying their higher toxicity. Contrarily, DEHP and DNOP showed minor effects on the developmental morphology of zebrafish larvae. However, the gene expression levels of skeleton-related genes showed the upregulation of the runx2b and shha genes after DEHP and DBP exposure. Taken together, the strict use and release of PAEs in the environment should be supervised by the government for ecological and environmental safety.


Assuntos
Morfogênese/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Esqueleto/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Animais , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Ésteres/toxicidade , Larva , Ácidos Ftálicos/metabolismo , Esqueleto/efeitos dos fármacos , Peixe-Zebra/fisiologia
3.
PLoS Genet ; 16(1): e1008529, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917788

RESUMO

Exposure to diethylhexyl phthalate (DEHP), the most abundant plasticizer used in the production of polyvinyl-containing plastics, has been associated to adverse reproductive health outcomes in both males and females. While the effects of DEHP on reproductive health have been widely investigated, the molecular mechanisms by which exposure to environmentally-relevant levels of DEHP and its metabolites impact the female germline in the context of a multicellular organism have remained elusive. Using the Caenorhabditis elegans germline as a model for studying reprotoxicity, we show that exposure to environmentally-relevant levels of DEHP and its metabolites results in increased meiotic double-strand breaks (DSBs), altered DSB repair progression, activation of p53/CEP-1-dependent germ cell apoptosis, defects in chromosome remodeling at late prophase I, aberrant chromosome morphology in diakinesis oocytes, increased chromosome non-disjunction and defects during early embryogenesis. Exposure to DEHP results in a subset of nuclei held in a DSB permissive state in mid to late pachytene that exhibit defects in crossover (CO) designation/formation. In addition, these nuclei show reduced Polo-like kinase-1/2 (PLK-1/2)-dependent phosphorylation of SYP-4, a synaptonemal complex (SC) protein. Moreover, DEHP exposure leads to germline-specific change in the expression of prmt-5, which encodes for an arginine methyltransferase, and both increased SC length and altered CO designation levels on the X chromosome. Taken together, our data suggest a model by which impairment of a PLK-1/2-dependent negative feedback loop set in place to shut down meiotic DSBs, together with alterations in chromosome structure, contribute to the formation of an excess number of DSBs and altered CO designation levels, leading to genomic instability.


Assuntos
Troca Genética , Quebras de DNA de Cadeia Dupla , Dietilexilftalato/toxicidade , Oogênese , Oogônios/efeitos dos fármacos , Plastificantes/toxicidade , Animais , Apoptose , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Instabilidade Genômica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oogônios/citologia , Oogônios/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-31927120

RESUMO

The purpose of the present study was to examine the antioxidant and oxidative stress changes in zebrafish liver (ZFL) cells in the presence of mono-(2-ethylhexyl) phthalate (MEHP). When reactive oxygen species (ROS) and antioxidant levels were measured by immunoassay, significant differences were observed between MEHP-treated and control cells, while catalase levels did not change in any group. MEHP-treated cells had higher levels of ROS, glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione, and superoxide dismutase (SOD) than control cells. However, lower levels of lipid peroxidation were observed in MEHP-treated cells compared to control cells. After 24 h of MEHP treatment, ROS, SOD, GPx, and GST activity increased in a dose-dependent manner. Cellular lipid droplet formation and endoplasmic reticulum stress were both induced in the presence of MEHP. These findings demonstrated the potential impacts of the association of MEHP with adverse outcomes in fish liver. Future studies will focus on clarifying the molecular mechanism of phthalate toxicity via oxidative stress and peroxisome proliferator activated receptor as the major mechanistic pathway.


Assuntos
Dietilexilftalato/análogos & derivados , Estresse do Retículo Endoplasmático , Hepatócitos/metabolismo , Gotículas Lipídicas/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Peixe-Zebra/metabolismo , Animais , Células Cultivadas , Dietilexilftalato/toxicidade , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Hepatócitos/citologia , Fígado/citologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
5.
Chemosphere ; 241: 125114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683445

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer. It has neurotoxicity and exposure to it causes impairment of neurodevelopment, behavior and cognition. However, the molecular mechanisms responsible for the DEHP-induced neurotoxicity are not yet clearly defined. Tumor necrosis factor-induced protein 1 (TNFAIP1) was first discovered in umbilical vein endothelial cells and was further found to be important in the progress of Alzheimer's disease. Herein we explore the mechanism of TNFAIP1 in DEHP-induced neurotoxicity with the involvement of cyclic AMP response elements binding protein (CREB) signaling pathway in a mouse neuroblastoma cell line (N2a cells). We found that exposure to DEHP induced apoptosis and downregulated the expression of brain-derived neurotrophic factor (BDNF), synaptic proteins PSD 95 and synapsin-1 while upregulated the expression of TNFAIP1 and decreased the levels of phosphorylated Akt, CaMK Ⅳ, catalytic subunits of PKA and CREB in CREB signaling pathway. Knockdown of TNFAIP1 using TNFAIP1 small interfering RNA (siRNA) expression vector prevented DEHP from inhibiting CREB pathway, thus reduced apoptosis and restored expression of BDNF, PSD 95 and synapsin-1. Our data indicate that downregulation of TNFAIP1 prevents DEHP-induced neurotoxicity via activating CREB pathway. Therefore, TNFAIP1 is a potential target for relieving the DEHP-induced neurotoxicity and related neurological disorders.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dietilexilftalato/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Plastificantes , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Linhagem Celular , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Neuroblastoma/patologia , Síndromes Neurotóxicas/etiologia , Ácidos Ftálicos , Plastificantes/toxicidade
6.
Environ Toxicol ; 35(1): 78-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31486570

RESUMO

Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that gives flexibility to various polyvinyl chloride products. It is a pollutant easily released into the environment and can cause many adverse effects to living organisms including hepatotoxicity. The thioredoxin system is a determining factor in the redox balance maintaining in the liver, which is a vulnerable tissue of reactive oxygen species overproduction because of its high energy needs. In order to determine if the thioredoxin system is a target in the development of DEHP hepatotoxicity, Balb/c mice were administered with DEHP intraperitoneally daily for 30 days. Results demonstrated that after DEHP exposure, biochemical profile changes were observed. This phthalate causes oxidative damage through the induction of lipid peroxydation as well as the increase of superoxide dismutase and catalase activities. As new evidence provided in this study, we demonstrated that the DEHP affected the thioredoxin system by altering the expression and the activity of thioredoxin (Trx) and thioredoxin Reductase (TrxR1). The two enzyme activities of the oxidative phase of the pentose phosphate pathway: Glucose-6-phosphate dehydrogenase and 6-Phosphogluconate dehydrogenase were also affected by this phthalate. This leads to a decrease in the level of nicotinamide adenine dinucleotide phosphate used by the TrxR1 to maintain the regeneration of the reduced Trx. We also demonstrated that such effects can be responsible of DEHP-induced DNA damage.


Assuntos
Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Via de Pentose Fosfato/efeitos dos fármacos , Plastificantes/toxicidade , Tiorredoxinas/metabolismo , Animais , Dano ao DNA , Relação Dose-Resposta a Droga , Glucosefosfato Desidrogenase/metabolismo , Injeções Intraperitoneais , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
7.
Curr Med Sci ; 39(6): 1003-1008, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31845234

RESUMO

Human beings are increasingly exposed to phthalates, which are a group of chemicals used to make plastics more flexible and harder to break, and simultaneously ingesting abundant food emulsifiers via daily diet. The purpose of this study was to investigate the effect of the food emulsifier glycerin monostearate (GMS) on male reproductive toxicity caused by di(2-ethylhexyl) phthalate (DEHP, one of the phthalates) and explore the underlying mechanism. Thirty male Sprague-Dawley rats were randomly divided into control group, DEHP group and DEHP+GMS group. Rats in the DEHP group and DEHP+GMS group were orally administered with 200 mg/kg/d DEHP with or without 20 mg/kg/d GMS. After 30 days of continuous intervention, it was found that the serum testosterone level was significantly lowered in DEHP group and DEHP+GMS group than that in control group (P<0.01). The serum testosterone level and the relative testis weight were significantly decreased in the DEHP+GMS group as compared with those in the DEHP group and control group (P<0.05). More spermatids were observed to be shed off in DEHP+GMS group than in DEHP group. The expression levels of cell cycle checkpoint kinase 1 (Chk1), cell division cycle gene 2 (Cdc2), and cyclin-dependent kinase 2 (CDK2) were down-regulated in DEHP group, and this tendency was more significant in DEHP+GMS group (P<0.05 or P<0.01). There was no significant difference in the P-glycoprotein (P-gp) expression between DEHP group and control group. However, P-gp was markedly down-regulated in DEHP+GMS group (P<0.01). The results indicated that the food emulsifier GMS aggravated the toxicity of DEHP on male reproduction by inhibiting the cell cycle of testicular cells and the expression of P-gp in testis tissues.


Assuntos
Dietilexilftalato/toxicidade , Emulsificantes/toxicidade , Glicerol/toxicidade , Reprodução/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Proteína Quinase CDC2/metabolismo , Quinase 1 do Ponto de Checagem/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Dietilexilftalato/administração & dosagem , Regulação para Baixo , Emulsificantes/administração & dosagem , Glicerol/administração & dosagem , Masculino , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testosterona/sangue
8.
J Environ Pathol Toxicol Oncol ; 38(3): 253-270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679312

RESUMO

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate. DEHP is highly used in PVC floorings and PVC windows and carpeting. The objective of this study was to determine sex hormone levels, oxidative stress parameters, selenium levels, DNA damage, and phthalate levels in plastics workers (n = 24, age = 20-58 years) working in the production of rubber mechanical goods and exposed to DEHP in workplace. The control group (n = 29, age = 25-54, all male) was selected from age-matched healthy adults. Antioxidant parameters and DNA damage were determined by spectrophotometry. Selenium levels were determined by atomic absorption spectroscopy. Plasma hormone levels were measured by chemiluminescence microparticle immunoassay. Plasma phthalate levels were determined by high-pressure liquid chromatography. Plastic workers had lower serum testosterone and free T4 levels and higher follicle-stimulating hormone levels vs. controls. Liver enzyme activities were markedly higher in workers vs. controls. There were also increases in plasma glutathione peroxidase levels and marked decreases in plasma selenium and erythrocyte total glutathione levels in plastics workers (P < 0.05 vs. control). Plasma 8-hydroxy-2'-deoxyguanosine levels were 14-fold higher in plastics workers than in controls. Plasma DEHP and mono(2-ethylhexyl)phthalate were also markedly higher in workers vs. controls. The results of this study show that occupational exposure to DEHP may lead to disturbances in sex hormones, increased liver problems, higher oxidative stress and DNA damage levels, and lower trace element concentrations in workers. More comprehensive and mechanistic studies with higher numbers of subjects are needed to show the unwanted effects of occupational exposure to DEHP.


Assuntos
Dano ao DNA , Dietilexilftalato/análogos & derivados , Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Selênio/metabolismo , Adulto , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Turquia
9.
Artigo em Inglês | MEDLINE | ID: mdl-31493583

RESUMO

The four experimental groups were carried out to test the response of yellow catfish to EE2 and DEHP: control group was exposed to DMSO; EE2 group was exposed to 1.0 µg/L EE2; DEHP group was exposed to 1.0 mg/L DEHP; mix group was exposed to 1.0 µg/L EE2 and 1.0 mg/L DEHP. The experiment continued for 56 days. Fish survival rate was not different among experimental groups. Fish in DEHP and mix groups had the highest weight gain, and lowest value appeared in control group. The highest hepatosomatic index was found in DEHP and mix groups. Serum alanine transaminase of fish in control group was lower than other groups, but the alkaline phosphatase value was the highest. Serum total anti-oxidation capacity, superoxide dismutase and catalase activities of fish in control group were higher than other groups, but malondialdehyde content is opposite. Respiratory burst and phagocytic indices of fish in EE2 group were the lowest. After 96 h of ammonia stress, the survival rate of fish in mix group was significantly lower than control group. This study indicates that EE2 and DEHP exposure can lead to gain weight of yellow catfish, which is related to liver damage and fat accumulation; EE2 and DEHP exerts its toxic effects by inducing ROS generation, leading to lipid peroxidation and immunosuppression.


Assuntos
Antioxidantes/metabolismo , Peixes-Gato , Dietilexilftalato/toxicidade , Etinilestradiol/toxicidade , Fígado/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Peixes-Gato/imunologia , Peixes-Gato/metabolismo , Peroxidação de Lipídeos , Estresse Oxidativo
10.
Ecotoxicol Environ Saf ; 184: 109611, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491605

RESUMO

Mono-2-ethylhexyl phthalate (MEHP), as the major metabolite of Di-(2-ethylhexyl) phthalate (DEHP), can induce lipid accumulation in hepatocytes and further leads to non-alcoholic fatty liver disease (NAFLD), while the underlying mechanism is unclear. We aim to clarify the effects of JAK2/STAT5 pathway on lipid accumulation induced by MEHP and the role of oxidation stress in NAFLD. BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100 and 200 µM) for 24 h and 48 h. Then the lipid droplets in cells were observed by Oil-Red-O staining and quantified by isopropyl alcohol. The levels of TG, SOD, TBARS, AST and ALT were all detected by commercial kits. RT-PCR was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by JAK2/STAT5 pathway genes and lipid metabolism-related genes. As a result, MEHP promoted the lipid synthesis and accumulation in BRL-3A cells. MEHP down-regulated the expression and inhibited the activation of JAK2/STAT5. Moreover, the lipid metabolism-related kinases levels were elevated after MEHP exposure. In addition, the SOD levels were gradually decreased and the TBARS levels were increased in MEHP-treated groups. The lipid metabolism-related proteins levels were correlated with the oxidation stress levels. Furthermore, the ALT and AST levels were elevated after MEHP exposure. Therefore, we concluded that MEHP led to lipid accumulation through inhibiting JAK2/STAT5 pathway, resulted in damaging liver parenchyma and NAFLD by aggravating oxidation stress.


Assuntos
Dietilexilftalato/análogos & derivados , Janus Quinase 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Dietilexilftalato/toxicidade , Regulação para Baixo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Janus Quinase 2/genética , Metabolismo dos Lipídeos/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genética
11.
Environ Pollut ; 255(Pt 1): 113155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31539850

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a prevalent environmental contaminant that severely impacts the health of human and animals. Taxifolin (TAX), a plant flavonoid isolated from yew, exerts protective effects on cardiac diseases. Nevertheless, whether DEHP could induce cardiomyocyte hypertrophy and its mechanism remains unclear. This study aimed to highlight the specific molecular mechanisms of DEHP-induced cardiomyocyte hypertrophy and the protective potential of TAX against it. Chicken primary cardiomyocytes were treated with DEHP (500 µM) and/or TAX (0.5 µM) for 24 h. The levels of glucose and adenosine triphosphate (ATP) were detected, and cardiac hypertrophy-related genes were validated by real-time quantitative PCR (qRT-PCR) and Western blot (WB) in vitro. The results showed that DEHP-induced cardiac hypertrophy was ameliorated by TAX, as indicated by the increased cardiomyocyte area and expression of atrial natriuretic peptide (ANP), natriuretic peptides A-like (BNP) and ß-myosin heavy cardiac muscle (ß-MHC). Furthermore, DEHP induced cardiac hypertrophy via the interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in vitro. In addition, DEHP disrupted mitochondrial function and glycometabolism by activating the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K) pathway and the peroxisome proliferator activated receptors (PPARs)/PPARG coactivator 1 alpha (PGC-1α) pathway to induce cardiac hypertrophy in vitro. Intriguingly, those DEHP-induced changes were obviously alleviated by TAX treatment. Taken together, cardiac hypertrophy was induced by DEHP via activating the IL-6/JAK/STAT3 signaling pathway, triggering glycometabolism disorder and mitochondrial dysfunction in vitro, can be ameliorated by TAX. Our findings may provide a feasible molecular mechanism for the treatment of cardiomyocyte hypertrophy induced by DEHP.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cardiomegalia/prevenção & controle , Dietilexilftalato/toxicidade , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Quercetina/análogos & derivados , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Células Cultivadas , Galinhas/metabolismo , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Quercetina/farmacologia , Miosinas Ventriculares/metabolismo
12.
Reprod Toxicol ; 88: 85-90, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31369804

RESUMO

Endocrine-disrupting compounds (EDCs) are found in the environment due to their use in industrial and manufacturing activities. Exposure of the population to bisphenol A (BPA) and di (2-ethylhexyl) phthalate (DEHP) is significant because they are present in many consumer products. EDCs target the reproductive tract because they express high levels of steroid hormone receptors, which act as transcriptional factors to regulate reproductive development. In the present study, timed-pregnant Long-Evans female rats (n = 8-10) were administered BPA and DEHP by oral gavage at 2.5 or 25 µg/kg body weight and 5 or 50 µg/kg body weight, respectively. Exposures to chemicals were limited to the period between gestational days 12 and 21 followed by assessment of testicular development in male offspring in the postnatal period. Leydig cells and Sertoli cells are the two major somatic cells present in the testis. The 17ß-hydroxysteroid dehydrogenase (17ß-HSD) steroidogenic enzyme is a marker for Leydig cell maturation, whereas transferrin is a marker for Sertoli cell differentiation. At day 10 post-partum, testes were obtained from cohorts of control and chemical-exposed male rats and processed to measure 17ß-HSD and transferrin expression levels in western blots. Compared to control, 17ßHSD enzyme protein was increased in BPA-treated rats but levels were decreased in animals exposed to DEHP (P < 0.05). Transferrin protein was decreased in male rats exposed to both BPA and DEHP compared to control animals (P < 0.05). To assess qualitative cellular changes within the spermatogenic epithelium, testes were obtained from separate cohorts of male rats at 35 days of age and processed for histopathological analysis. Results showed that prenatal exposures of male rats to BPA and DEHP caused disruption of the spermatogenic epithelium evident as disorganization and atrophy of seminiferous tubules as well as desquamation of germ cells into the tubular lumen. Together, results from the present study support the view that developmental exposures to environmentally relevant levels of BPA and DEHP are associated with disruptions of testicular cell development, which have implications for endocrine and exocrine functions of testis.


Assuntos
Compostos Benzidrílicos/toxicidade , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Túbulos Seminíferos/efeitos dos fármacos , Animais , Compostos Benzidrílicos/administração & dosagem , Dietilexilftalato/administração & dosagem , Feminino , Masculino , Fenóis/administração & dosagem , Gravidez , Ratos , Ratos Long-Evans , Receptores Androgênicos/metabolismo , Túbulos Seminíferos/crescimento & desenvolvimento , Túbulos Seminíferos/patologia , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testículo/patologia
13.
Toxicol Ind Health ; 35(8): 520-529, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31462198

RESUMO

Contamination of the aquatic environment by plastic industrial products and their by-products is remarkable. Because of their physical, chemical, and biological degradation resistance, plasticizers can enter the food chain of living organisms, accumulate in the body and generate toxic effects. Here we determined the potential toxic effects of bis(2-ethylhexyl) phthalate (DEHP) plasticizer to larval (72 h post fertilization) zebrafish (Danio rerio) by analyzing changes in expression levels of stress-related genes (p53, rad51, and xrcc5) by the quantitative real-time polymerase chain reaction. Also, possible DNA damage by DEHP in larvae was determined. The concentration of DEHP (0-160 mg/l) that killed 50% of the larval zebrafish within 96 h was 54.02 mg/l. There was a concentration-related increase in DNA damage in cells from larvae exposed (96 h) to DEHP. DNA damage of 31.13% (mean ± standard error of the mean) was observed in larvae at the highest sublethal DEHP concentration (10 mg/l). Some significant differences in the induction of stress-related genes were also observed in larvae exposed to DEHP relative to control (p < 0.05). The conclusion drawn from this ecotoxicological risk assessment is that, under present use and exposure patterns, DEHP presents a small hazard to zebrafish larvae.


Assuntos
Quebras de DNA/efeitos dos fármacos , Dietilexilftalato/toxicidade , Expressão Gênica/efeitos dos fármacos , Animais , Ensaio Cometa , Relação Dose-Resposta a Droga , Larva , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
14.
Ecotoxicol Environ Saf ; 183: 109582, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442803

RESUMO

Di-2-ethylhexyl phthalate (DEHP), widely used as a plasticizer, is a ubiquitous artificial pollutant. DEHP can induce biological toxicity in various organs, with an especially high potential for toxicity to the cardiovascular system. Taxifolin (TAX) is used in the treatment of cardiovascular diseases due to its antioxidative capacities. However, it is not clear whether TAX can alleviate apoptosis induced by DEHP exposure through the cytochrome P450 (CYP) pathway in cardiomyocytes. To understand the role of TAX in attenuating cardiomyocyte toxicity induced by DEHP, primary cardiomyocytes were divided into 4 groups (control group, DEHP group, TAX group and DEHP + TAX group). The results showed that in the cardiomyocytes, DEHP initiated apoptosis by increasing the expression of caspase-3, caspase-9, cyt c, and Bax at both the mRNA and protein levels and by decreasing the Bcl-2 levels compared with that of the control group. In addition, the activities of catalase (CAT), superoxide dismutase (SOD), and total antioxidative capacity (T-AOC) were clearly decreased (P < 0.05), while in the DEHP group, the malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels were observably increased (P < 0.05), compared with those in control group. Furthermore, compared with the control group, the DEHP group demonstrated a clear partial decrease in the expression of the mRNA levels of CYP1B1 and CYP2C18 (P < 0.05), and DEHP/TAX cotreatment partially prevented apoptosis and oxidative stress damage (P < 0.05). These results showed that exposure to DEHP induced apoptosis in chicken cardiomyocytes, while TAX could antagonize the toxicity of DEHP on cardiomyocytes by attenuating oxidative stress responses and modulating CYPs.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dietilexilftalato/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Plastificantes/toxicidade , Quercetina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Galinhas , Homeostase , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia
15.
Environ Toxicol ; 34(11): 1191-1198, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31313480

RESUMO

The phthalate plasticizer, di(2-ethyl-hexyl) phthalate (DEHP), and its derived metabolites are common anthropogenic environmental toxins, which are known to act as endocrine disruptors. Numerous studies have associated DEHP with disruption of sex hormones, abnormal development of reproductive organs, allergies, and inflammation. Its role in promoting inflammation has been reported by both human epidemiological and animal studies. In stomach tissue, chronic inflammation is known to accompany mucosal damage, and pave the way to gastritis, stomach ulcers, and ultimately gastric cancer. Eastern Asian populations possess the highest gastric cancer incidences in the world. Coincidentally, East Asia is one of the world's major sites for plastics manufacture and export. Thus, possible correlations between DEHP, a common plasticizer, and gastric cancer are of great interest. Our study revealed several critical findings. First, even at very low dosage, mimicking the residual plasticizer exposure, detrimental effects of DEHP on gastric cells can be detected. Second, gastric cells treated with DEHP increased cyclooxygenase-2 (COX-2) in a time-dependent manner. Third, promoter deletion studies revealed a critical role of nuclear factor-kappa B (NF-κB) for COX-2 gene responses. Finally, our results indicated that a low concentration of DEHP is able to trigger COX-2 activation via the extracellular signal-regulated kinase (ERK1/2) and NF-κB signaling pathway. Taken together, we demonstrate that very low doses of DEHP enhance the expression of the prototypical inflammatory gene, COX-2, in gastric cancer cells via ERK1/2 and NF-κB activation. This study provides important insights into the inflammatory process and damages associated with phthalate plasticizers exposure.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Dietilexilftalato/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Plastificantes/toxicidade , Adenocarcinoma , Animais , Linhagem Celular Tumoral , Dietilexilftalato/metabolismo , Poluentes Ambientais/química , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Plastificantes/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas
16.
J Toxicol Sci ; 44(7): 459-469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270302

RESUMO

Phenobarbital (PB) and Di (2-ethylhexyl) phthalate (DEHP), an anti-epileptic drug and a plasticizer used in flexible polyvinylchloride formulations, respectively, are well-known typical hepatotoxicants. This study investigated the effects of PB (100 mg/kg/day) or DEHP (500 mg/kg/day) on the endocrine system in intact juvenile/peripubertal male rats exposed for 31 days beginning on postnatal day 23. Slight hormone level changes, histopathological changes in thyroid gland or induction of UDP-glucuronosyltransferase in liver were observed in both the PB and DEHP groups. One of the assumed mechanisms inducing thyroid effects is predictable to be secondary changes based on the enhancement in thyroid hormone metabolism via the induction of hepatic microsomal enzymes. No reproductive system-related changes in organ weights, histopathology, and sexual maturation were observed in both groups. Lower testosterone level was observed in the PB group. CYP2B and CYP3A, which are involved in testosterone metabolism, were induced in liver of the PB group. There was no change of 17ß-hydroxysteroid dehydrogenase activity in testis of both groups. Lower testosterone level in the PB-treated male rats was attributed to an indirect, hepatotoxicity-associated effect on the reproductive system and not to direct effects on testis such as the antiandrogenic activity and the inhibition of steroidogenesis. These results did not indicate that PB or DEHP exposure affects the endocrine system directly.


Assuntos
Anticonvulsivantes/toxicidade , Dietilexilftalato/toxicidade , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/patologia , Fenobarbital/toxicidade , Plastificantes/toxicidade , Animais , Animais Recém-Nascidos , Anticonvulsivantes/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Fígado/enzimologia , Masculino , Fenobarbital/administração & dosagem , Ratos Sprague-Dawley , Testosterona/metabolismo , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Fatores de Tempo
17.
Biomed Environ Sci ; 32(6): 406-418, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262386

RESUMO

OBJECTIVE: Previous studies have indicated that the plasticizer di (2-ethylhexyl) phthalate (DEHP) affects lipid accumulation; however, its underlying mechanism remains unclear. We aim to clarify the effect of DEHP on lipid metabolism and the role of TYK2/STAT1 and autophagy. METHODS: In total, 160 Wistar rats were exposed to DEHP [0, 5, 50, 500 mg/(kg•d)] for 8 weeks. Lipid levels, as well as mRNA and protein levels of TYK2, STAT1, PPARγ, AOX, FAS, LPL, and LC3 were detected. RESULTS: The results indicate that DEHP exposure may lead to increased weight gain and altered serum lipids. We observed that DEHP exposure affected liver parenchyma and increased the volume or number of fat cells. In adipose tissue, decreased TYK2 and STAT1 promoted the expression of PPARγ and FAS. The mRNA and protein expression of LC3 in 50 and 500 mg/(kg•d) groups was increased significantly. In the liver, TYK2 and STAT1 increased compensatorily; however, the expression of FAS and AOX increased, while LPL expression decreased. Joint exposure to both a high-fat diet and DEHP led to complete disorder of lipid metabolism. CONCLUSION: It is suggested that DEHP induces lipid metabolism disorder by regulating TYK2/STAT1. Autophagy may play a potential role in this process as well. High-fat diet, in combination with DEHP exposure, may jointly have an effect on lipid metabolism disorder.


Assuntos
Autofagia/efeitos dos fármacos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos Wistar , Fator de Transcrição STAT1/metabolismo , TYK2 Quinase/metabolismo
18.
Zygote ; 27(4): 203-213, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296276

RESUMO

The present study investigated if the presence of encircling granulosa cells protected against di(2-ethylhexyl)phthalate (DEHP)-induced oxidative stress in rat oocytes cultured in vitro. Denuded oocytes and cumulus-oocyte complexes (COCs) were treated with or without various doses of DEHP (0.0, 25.0, 50.0, 100, 200, 400 and 800 µM) in vitro. Morphological apoptotic changes, levels of oxidative stress and reactive oxygen species (ROS), mitochondrial membrane potential, and expression levels of apoptotic markers (Bcl2, Bax, cytochrome c) were analyzed. Our results showed that DEHP induced morphological apoptotic changes in a dose-dependent manner in denuded oocytes cultured in vitro. The effective dose of DEHP (400 µg) significantly (P>0.05) increased oxidative stress by elevating ROS levels and the mitochondrial membrane potential with higher mRNA expression and protein levels of apoptotic markers (Bax, cytochrome c). Encircling granulosa cells protected oocytes from DEHP-induced morphological changes, increased oxidative stress and ROS levels, as well as increased expression of apoptotic markers. Taken together our data suggested that encircling granulosa cells protected oocytes against DEHP-induced apoptosis and that the presence of granulosa cells could act positively towards the survival of oocytes under in vitro culture conditions and may be helpful during assisted reproductive technique programmes.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/fisiologia , Células da Granulosa/fisiologia , Oócitos/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Células Cultivadas , Dietilexilftalato/toxicidade , Feminino , Expressão Gênica/efeitos dos fármacos , Células da Granulosa/citologia , Potencial da Membrana Mitocondrial/fisiologia , Oócitos/citologia , Oócitos/metabolismo , Estresse Oxidativo/fisiologia , Plastificantes/toxicidade , Ratos , Espécies Reativas de Oxigênio/metabolismo
19.
Environ Health Prev Med ; 24(1): 47, 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31279339

RESUMO

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.


Assuntos
Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , PPAR alfa/genética , Plastificantes/toxicidade , Animais , Haplorrinos , Humanos , Camundongos , PPAR alfa/metabolismo , Ratos
20.
Toxicol Mech Methods ; 29(9): 633-643, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31354016

RESUMO

In this study, we aimed to investigate whether bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) exposure have any association with Hashimoto's thyroiditis (HT) and its biomarkers and to determine whether oxidative stress biomarkers and trace element levels showed any alterations in children with HT. We found that superoxide dismutase and glutathione peroxidase activities are lower in HT group from control (24% and 46%, respectively, p < 0.05). Zinc levels were significantly lower in HT group vs. control. In addition, the levels of mono-(2-ethylhexyl) phthalate (MEHP) which is the primary metabolite for DEHP, were markedly higher in HT group compared to control (p < 0.05). A negative correlation was observed between urinary BPA levels and fT4. In children with HT, oxidant/antioxidant balance is changed and these differences may be related by EDC exposure, the importance of which should be elucidated with further studies.


Assuntos
Compostos Benzidrílicos/sangue , Dietilexilftalato/sangue , Disruptores Endócrinos/sangue , Doença de Hashimoto/sangue , Estresse Oxidativo/efeitos dos fármacos , Fenóis/sangue , Oligoelementos/sangue , Adolescente , Compostos Benzidrílicos/toxicidade , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Feminino , Doença de Hashimoto/epidemiologia , Humanos , Masculino , Fenóis/toxicidade , Turquia/epidemiologia
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