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1.
Food Chem Toxicol ; 188: 114666, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38621509

RESUMO

This work was designed to investigate the neurotoxic effects of the typical plasticizer dibutyl phthalate (DBP) using zebrafish larvae as a model. The results of exhibited that zebrafish larvae exposed to DBP at concentrations of 5 µg/L and 10 µg/L exhibited brain malformations (24 h) and behavioral abnormalities (72 h). After 72 h of exposure to DBP, microglia in the brain were over-activated, reactive oxygen species (ROS) formation was increased, and apoptosis was observed. Meanwhile, it was found that neurons exhibited impaired mitochondrial structure, absent mitochondrial membrane potential and up-regulated autophagy. Further comprehensive biochemical analyses and RNA-Seq, validated by RT-qPCR, glutamate metabolism and PPAR signaling pathway were significantly enriched in the DBP stress group, this may be the main reason for the disruption of glycolysis/gluconeogenesis processes and the reduction of energy substrates for the astrocyte-neuron lactate shuttle (ANLS). In addition, the DBP-exposed group showed aberrant activation of endoplasmic reticulum (ER) stress signaling pathway, which may be related to ROS as well as neuronal apoptosis and autophagy. In conclusion, DBP-induced neurotoxicity may be the combined result of insufficient neuronal energy acquisition, damage to mitochondrial structure, apoptosis and autophagy. These results provide a theoretical basis for understanding the neurotoxic effects of DBP.


Assuntos
Apoptose , Dibutilftalato , Larva , Neurônios , Peixe-Zebra , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dibutilftalato/toxicidade , Larva/efeitos dos fármacos , Larva/metabolismo , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Autofagia/efeitos dos fármacos , Plastificantes/toxicidade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos
2.
Food Chem Toxicol ; 188: 114663, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38631435

RESUMO

The effect of endothelial cells' exposure to dibutyl phthalate (DBP) on monocyte adhesion is largely unknown. We evaluated monocyte adhesion to DBP-exposed endothelial cells by combining three approaches: short-term exposure (24 h) of EA.hy926 cells to 10-6, 10-5, and 10-4 M DBP, long-term exposure (12 weeks) of EA.hy926 cells to 10-9, 10-8, and 10-7 M DBP, and exposure of rats (28 and 90 days) to 100, 500, and 5000 mg DBP/kg food. Monocyte adhesion to human EA.hy926 and rat aortic endothelial cells, expression of selected cellular adhesion molecules and chemokines, and the involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) were analyzed. We observed increased monocyte adhesion to DBP-exposed EA.hy926 cells in vitro and to rat aortic endothelium ex vivo. ERK1/2 inhibitor prevented monocyte adhesion to DBP-exposed EA.hy926 cells in short-term exposure experiments. Increased ERK1/2 phosphorylation in rat aortic endothelium and transient decrease in ERK1/2 activation following long-term exposure of EA.hy926 cells to DBP were also observed. In summary, exposure of endothelial cells to DBP promotes monocyte adhesion, thus suggesting a possible role for this phthalate in the development of atherosclerosis. ERK1/2 signaling could be the mediator of monocyte adhesion to DBP-exposed endothelial cells, but only after short-term high-level exposure.


Assuntos
Adesão Celular , Dibutilftalato , Células Endoteliais , Monócitos , Dibutilftalato/toxicidade , Animais , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Adesão Celular/efeitos dos fármacos , Humanos , Ratos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Masculino , Aorta/efeitos dos fármacos , Aorta/citologia , Linhagem Celular , Fosforilação/efeitos dos fármacos
3.
Food Chem Toxicol ; 188: 114686, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663762

RESUMO

Dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP), two common types of phthalates, are known to cause reproductive and developmental toxicity in animals and humans. The reference doses (RfD) of DBP and DEHP should be determined by sensitive endpoints. We here aimed to identify sensitive endpoints for DBP- and DEHP-induced such toxicity using published literatures. By examining the impacts of maternal exposure to DBP or DEHP on anogenital distance (AGD) and semen quality of offspring, we discovered that DBP or DEHP caused AGD decline in boys but increase in girls with DBP being more potent and the first 14weeks of pregnancy being more susceptible, suggesting a chemical- and time-dependent phenomenon. We also identified AGD shortening and total sperm count reduction as two sensitive endpoints for DBP- or DEHP-induced reproductive and developmental toxicity, respectively. Based upon these two endpoints and the employment of the Bayesian benchmark dose approach with an uncertainty factor of 3,000, we estimated the RfD values of DBP and DEHP were 15 µg/kg/day and 36 µg/kg/day, respectively. Thus, we uncover previously unrecognized phenomena of DBP- or DEHP-induced reproductive and developmental toxicity and establish new and comparable or more conservative RfDs for the risk assessment of phthalates exposure in humans.


Assuntos
Dibutilftalato , Reprodução , Masculino , Humanos , Reprodução/efeitos dos fármacos , Feminino , Animais , Dibutilftalato/toxicidade , Gravidez , Dietilexilftalato/toxicidade , Ácidos Ftálicos/toxicidade , Exposição Materna/efeitos adversos
4.
Toxicol Appl Pharmacol ; 486: 116933, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38631520

RESUMO

"White pollution" has a significant impact on male reproduction. Di-n-butyl phthalate (DBP) is one of the most important factors in this type of pollution. Currently, research from international sources has demonstrated the significant reproductive toxicity of DBP. However, most of these studies have focused mainly on hormones expression at the protein and mRNA levels and the specific molecular targets of DBP and its mechanisms of action remain unclear. In this study, we established a Sprague Dawley pregnant mouse model exposed to DBP, and all male offspring were immediately euthanized at birth and bilateral testes were collected. We found through transcriptome sequencing that cell apoptosis and MAPK signaling pathway are the main potential pathways for DBP induced reproductive toxicity. Molecular biology analyses revealed a significant increase in the protein levels of JNK1(MAPK8) and BAX, as well as a significant increase in the BAX/BCL2 ratio after DBP exposure. Therefore, we propose that DBP induces reproductive toxicity by regulating JNK1 expression to activate the MAPK signaling pathway and induce reproductive cell apoptosis. In conclusion, our study provides the first evidence that the MAPK signaling pathway is involved in DBP-induced reproductive toxicity and highlights the importance of JNK1 as a potential target of DBP in inducing reproductive toxicity.


Assuntos
Apoptose , Dibutilftalato , Sistema de Sinalização das MAP Quinases , Testículo , Animais , Masculino , Dibutilftalato/toxicidade , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Feminino , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Gravidez , Apoptose/efeitos dos fármacos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/genética
5.
Environ Sci Technol ; 58(18): 7731-7742, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38662601

RESUMO

Plastics contaminations are found globally and fit the exposure profile of the planetary boundary threat. The plasticizer of dibutyl phthalate (DBP) leaching has occurred and poses a great threat to human health and the ecosystem for decades, and its toxic mechanism needs further comprehensive elucidation. In this study, environmentally relevant levels of DBP were used for exposure, and the developmental process, oxidative stress, mitochondrial ultrastructure and function, mitochondrial DNA (mtDNA) instability and release, and mtDNA-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway with inflammatory responses were measured in zebrafish at early life stage. Results showed that DBP exposure caused developmental impairments of heart rate, hatching rate, body length, and mortality in zebrafish embryo. Additionally, the elevated oxidative stress damaged mitochondrial ultrastructure and function and induced oxidative damage to the mtDNA with mutations and instability of replication, transcription, and DNA methylation. The stressed mtDNA leaked into the cytosol and activated the cGAS-STING signaling pathway and inflammation, which were ameliorated by co-treatment with DBP and mitochondrial reactive oxygen species (ROS) scavenger, inhibitors of cGAS or STING. Furthermore, the larval results suggest that DBP-induced mitochondrial toxicity of energy disorder and inflammation were involved in the developmental defects of impaired swimming capability. These results enhance the interpretation of mtDNA stress-mediated health risk to environmental contaminants and contribute to the scrutiny of mitochondrial toxicants.


Assuntos
DNA Mitocondrial , Dibutilftalato , Peixe-Zebra , Animais , DNA Mitocondrial/efeitos dos fármacos , Dibutilftalato/toxicidade , Estresse Oxidativo/efeitos dos fármacos
6.
Ecotoxicol Environ Saf ; 277: 116338, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38640799

RESUMO

Various phthalic acid esters (PAEs) such as dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) co-exist with nanopollutants in aquatic environment. In this study, Daphnia magna was exposed to nano-CuO and DBP or BBP at environmental relevant concentrations for 21-days to investigate these combined toxic effects. Acute EC50 values (48 h) of nano-CuO, DBP, and BBP were 12.572 mg/L, 8.978 mg/L, and 4.785 mg/L, respectively. Results showed that co-exposure with nano-CuO (500 µg/L) for 21 days significantly enhanced the toxicity of DBP (100 µg/L) and BBP (100 µg/L) to Daphnia magna by 18.37% and 18.11%, respectively. The activities of superoxide dismutase, catalase, and glutathione S-transferase were enhanced by 10.95% and 14.07%, 25.63% and 25.91%, and 39.93% and 35.01% in nano-CuO+DBP and nano-CuO+BBP treatments as compared to the individual exposure groups, verifying that antioxidative defense responses were activated. Furthermore, the co-exposure of nano-CuO and PAEs decreased the population richness and diversity microbiota, and changed the microbial community composition in Daphnia magna. Metabolomic analysis elucidated that nano-CuO + PAEs exposure induced stronger disturbance on metabolic network and molecular function, including amino acid, nucleotides, and lipid metabolism-related metabolic pathways, as comparison to PAEs single exposure treatments. In summary, the integration of physiological, microflora, and untargeted metabolomics analysis offers a fresh perspective into the potential ecological risk associated with nanopollutants and phthalate pollution in aquatic ecosystems.


Assuntos
Cobre , Daphnia , Dibutilftalato , Ácidos Ftálicos , Poluentes Químicos da Água , Animais , Daphnia/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Poluentes Químicos da Água/toxicidade , Cobre/toxicidade , Dibutilftalato/toxicidade , Nanopartículas Metálicas/toxicidade , Ésteres/toxicidade , Microbiota/efeitos dos fármacos , Glutationa Transferase/metabolismo , Metabolômica , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Metaboloma/efeitos dos fármacos , Daphnia magna
7.
Environ Pollut ; 348: 123846, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38548160

RESUMO

Dibutyl phthalate (DBP) contamination has raised global concern for decades, while its health risk with toxic mechanisms requires further elaboration. This study used zebrafish ZF4 cells to investigate the toxicity of ferroptosis with underlying mechanisms in response to DBP exposure. Results showed that DBP induced ferroptosis, characterized by accumulation of ferrous iron, lipid peroxidation, and decrease of glutathione peroxidase 4 levels in a time-dependent manner, subsequently reduced cell viability. Transcriptome analysis revealed that voltage-dependent anion-selective channel (VDAC) in mitochondrial outer membrane was upregulated in ferroptosis signaling pathways. Protecting mitochondria with a VDAC2 inhibitor or siRNAs attenuated the accumulation of mitochondrial superoxide and lipid peroxides, the opening of mitochondrial permeability transition pore (mPTP), and the overload of iron levels, suggesting VDAC2 oligomerization mediated the influx of iron into mitochondria that is predominant and responsible for mitochondria-dependent ferroptosis under DBP exposure. Furthermore, the pivotal role of activating transcription factor 4 (ATF4) was identified in the transcriptional regulation of vdac2 by ChIP assay. And the intervention of atf4b inhibited DBP-induced VDAC2 upregulation and oligomerization. Taken together, this study reveals that ATF4-VDAC2 signaling pathway is involved in the DBP-induced ferroptosis in zebrafish ZF4 cells, contributing to the in-depth understanding of biotoxicity and the ecological risk assessment of phthalates.


Assuntos
Ferroptose , Peixe-Zebra , Animais , Dibutilftalato/toxicidade , Dibutilftalato/metabolismo , Mitocôndrias/metabolismo , Ferro/metabolismo
8.
Environ Pollut ; 347: 123722, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38460589

RESUMO

An understanding of the risk of gene deletion and mutation posed by endocrine-disrupting chemicals (EDCs) is necessary for the identification of etiological reagents for many human diseases. Therefore, the characterization of the genetic traits caused by developmental exposure to EDCs is an important research subject. A new regenerative approach using embryonic stem cells (ESCs) holds promise for the development of stem-cell-based therapies and the identification of novel therapeutic agents against human diseases. Here, we focused on the characterization of the genetic traits and alterations in pluripotency/stemness triggered by phthalate ester derivatives. Regarding their in vitro effects, we reported the abilities of ESCs regarding proliferation, cell-cycle control, and neural ectoderm differentiation. The expression of their stemness-related genes and their genetic changes toward neural differentiation were examined, which led to the observation that the tumor suppressor gene product p53/retinoblastoma protein 1 and its related cascades play critical functions in cell-cycle progression, cell death, and neural differentiation. In addition, the expression of neurogenic differentiation 1 was affected by exposure to di-n-butyl phthalate in the context of cell differentiation into neural lineages. The nervous system is one of the most sensitive tissues to exposure to phthalate ester derivatives. The present screening system provides a good tool for studying the mechanisms underlying the effects of EDCs on the developmental regulation of humans and rodents, especially on the neuronal development of ESCs.


Assuntos
Dibutilftalato , Células-Tronco Embrionárias Murinas , Ácidos Ftálicos , Animais , Humanos , Camundongos , Dibutilftalato/toxicidade , Diferenciação Celular , Ésteres
9.
Ecotoxicol Environ Saf ; 274: 116124, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38503108

RESUMO

OBJECTIVE: The primary objective of this study was to investigate the toxicological impact of Dibutyl phthalate (DBP) on the process of liver fibrosis transitioning into cirrhosis and the subsequent development of portal hypertension (PHT) through the mechanism of epithelial-mesenchymal transition (EMT) mediated by the ROS/TGF-ß/Snail-1 signaling pathway. METHOD: Carbon tetrachloride (CCl4) (1 mg/kg) was introduced in adult rats by oral feeding in CCl4 and CCl4+DBP groups twice a week for 8 weeks, and twice for another 8 week in CCl4 group. DBP was introduced by oral feeding in the CCl4+DBP group twice over the following 8 weeks. We subsequently analyzed hemodynamics measurements and liver cirrhosis degree, hepatic inflammation and liver function in the different groups. EMT related genes expression in rats in the groups of Control, DBP, CCl4 and CCl4+DBP were measured by immunohistochemistry (IHC). Enzyme-linked immunosorbent Assay (ELISA), qRT-PCR, western blot were used to detect the EMT related proteins and mRNA gene expression levels in rats and primary hepatocytes (PHCs). Reactive oxygen species (ROS) were examined with a ROS detection kit. RESULTS: The results showed that the CCl4+DBP group had higher portal pressure (PP) and lower mean arterial pressure (MAP) than the other groups. Elevated collagen deposition, profibrotic factor, inflammation, EMT levels were detected in DBP and CCl4+DBP groups. ROS, TGF-ß1 and Snail-1 were highly expressed after DBP exposure in vitro. TGF-ß1 had the potential to regulate Snail-1, and both of them were subject to regulation by ROS. CONCLUSION: DBP could influence the progression of EMT through its toxicological effect by ROS/TGF-ß1/Snail-1 signalling pathway, causing cirrhosis and PHT in final. The findings of this research might contribute to a novel comprehension of the underlying toxicological mechanisms and animal model involved in the progression of cirrhosis and PHT, and potentially offered a promising therapeutic target for the treatment of the disease.


Assuntos
Dibutilftalato , Transição Epitelial-Mesenquimal , Hipertensão Portal , Fator de Crescimento Transformador beta1 , Animais , Ratos , Dibutilftalato/toxicidade , Fibrose , Hipertensão Portal/induzido quimicamente , Inflamação , Cirrose Hepática/induzido quimicamente , Espécies Reativas de Oxigênio , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
10.
Environ Sci Pollut Res Int ; 31(16): 23680-23696, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38427170

RESUMO

Plastics, especially polystyrene nanoplastic particles (PSNPs), are known for their durability and absorption properties, allowing them to interact with environmental pollutants such as di-n-butyl phthalate (DBP). Previous research has highlighted the potential of these particles as carriers for various pollutants, emphasizing the need to understand their environmental impact comprehensively. This study focuses on the subchronic exposure of male Swiss albino mice to PSNP and DBP, aiming to investigate their reproductive toxicity between these pollutants in mammalian models. The primary objective of this study is to examine the reproductive toxicity resulting from simultaneous exposure to PSNP and DBP in male Swiss albino mice. The study aims to analyze sperm parameters, measure antioxidant enzyme activity, and conduct histopathological and morphometric examinations of the testis. By investigating the individual and combined effects of PSNP and DBP, the study seeks to gain insights into their impact on the reproductive profile of male mice, emphasizing potential synergistic interactions between these environmental pollutants. Male Swiss albino mice were subjected to subchronic exposure (60 days) of PSNP (0.2 mg/m, 50 nm size) and DBP (900 mg/kg bw), both individually and in combination. Various parameters, including sperm parameters, antioxidant enzyme activity, histopathological changes, and morphometric characteristics of the testis, were evaluated. The Johnsen scoring system and histomorphometric parameters were employed for a comprehensive assessment of spermatogenesis and testicular structure. The study revealed non-lethal effects within the tested doses of PSNP and DBP alone and in combination, showing reductions in body weight gain and testis weight compared to the control. Individual exposures and the combination group exhibited adverse effects on sperm parameters, with the combination exposure demonstrating more severe outcomes. Structural abnormalities, including vascular congestion, Leydig cell hyperplasia, and the extensive congestion in tunica albuginea along with both ST and Leydig cell damage, were observed in the testis, underscoring the reproductive toxicity potential of PSNP and DBP. The Johnsen scoring system and histomorphometric parameters confirmed these findings, providing interconnected results aligning with observed structural abnormalities. The study concludes that simultaneous exposure to PSNP and DBP induces reproductive toxicity in male Swiss albino mice. The combination of these environmental pollutants leads to more severe disruptions in sperm parameters, testicular structure, and antioxidant defense mechanisms compared to individual exposures. The findings emphasize the importance of understanding the interactive mechanisms between different environmental pollutants and their collective impact on male reproductive health. The use of the Johnsen scoring system and histomorphometric parameters provides a comprehensive evaluation of spermatogenesis and testicular structure, contributing valuable insights to the field of environmental toxicology.


Assuntos
Poluentes Ambientais , Testículo , Masculino , Camundongos , Animais , Dibutilftalato/toxicidade , Poliestirenos/toxicidade , Microplásticos , Antioxidantes/farmacologia , Sêmen , Espermatozoides , Poluentes Ambientais/toxicidade , Mamíferos
11.
Aquat Toxicol ; 269: 106881, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430782

RESUMO

Dibutyl phthalate (DBP) is a commonly used plasticizer that is frequently detected in water samples due to its widespread use. Titanium dioxide nanoparticles (n-TiO2) have been found to enhance the harmful effects of organic contaminants by increasing their bioavailability in aquatic environments. However, the combined toxic effects of DBP and n-TiO2 on aquatic organisms remain unclear. This study aimed to investigate the neurotoxicity of DBP and n-TiO2 synergistic exposure during the early life stage of zebrafish. The results of the study revealed that co-exposure of DBP and n-TiO2 led to an increase in deformities and a significant reduction in the active duration of zebrafish larvae. Furthermore, the co-exposure of DBP and n-TiO2 resulted in elevated levels of oxidative stress and altered gene expression related to neurodevelopment and apoptosis. Notably, n-TiO2 exacerbated the oxidative damage and apoptosis induced by DBP alone exposure. Additionally, co-exposure of the 1.0 mg/L DBP and n-TiO2 significantly affected the expression of genes associated with neurodevelopment. Moreover, disturbances in amino acid metabolism and interference with lipid metabolism were observed as a result of DBP and n-TiO2 co-exposure. In general, n-TiO2 aggravated the neurotoxicity of DBP in the early life stage of zebrafish by increasing oxidative stress, apoptosis, and disrupting amino acid synthesis and lipid metabolism. Therefore, it is essential to consider the potential risks caused by DBP and nanomaterials co-existence in the aquatic environment.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Dibutilftalato/toxicidade , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo , Titânio/toxicidade , Aminoácidos/metabolismo
12.
J Hazard Mater ; 467: 133642, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38330644

RESUMO

Due to their endocrine-disrupting effects and the risks posed in surface waters, in particular by chronic low-dose exposure to aquatic organisms, phthalate esters (PAEs) have received significant attention. However, most assessments of risks posed by PAEs were performed at a selection level, and thus limited by empirical data on toxic effects and potencies. A quantitative structure activity relationship (QSAR) and interspecies correlation estimation (ICE) model was constructed to estimate hazardous concentrations (HCs) of selected PAEs to aquatic organisms, then they were used to conduct a multiple-level environmental risk assessment for PAEs in surface waters of China. Values of hazardous concentration for 5% of species (HC5s), based on acute lethality, estimated by use of the QSAR-ICE model were within 1.25-fold of HC5 values derived from empirical data on toxic potency, indicating that the QSAR-ICE model predicts the toxicity of these three PAEs with sufficient accuracy. The five selected PAEs may be commonly measured in China surface waters at concentrations between ng/L and µg/L. Risk quotients according to median concentrations of the five PAEs ranged from 3.24 for di(2-ethylhexhyl) phthalate (DEHP) to 4.10 × 10-3 for dimethyl phthalate (DMP). DEHP and dibutyl phthalate (DBP) had risks to the most vulnerable aquatic biota, with the frequency of exceedances of the predicted no-effect concentration (PNECs) of 75.5% and 38.0%, respectively. DEHP and DBP were identified as having "high" or "moderate" risks. Results of the joint probability curves (JPC) method indicated DEHP posed "intermediate" risk to freshwater species with a maximum risk product of 5.98%. The multiple level system introduced in this study can be used to prioritize chemicals and other new pollutant in the aquatic ecological.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Poluentes Químicos da Água , Dietilexilftalato/toxicidade , Relação Quantitativa Estrutura-Atividade , Rios/química , Ésteres/toxicidade , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Ácidos Ftálicos/toxicidade , Dibutilftalato/toxicidade , Medição de Risco , China
13.
Environ Sci Pollut Res Int ; 31(14): 21399-21414, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38393557

RESUMO

The phthalate ester, dibutyl phthalate (DBP), is one of the endocrine-disrupting chemicals detected in various aquatic environments. Previous research has found multiple toxic effects of DBP in aquatic organisms; however, the neurotoxic effects of the compound are surprisingly scanty. The purpose of this study was aimed to evaluate the role of oxidative stress in the induction of neurotoxicity in the brain tissue of the fish Pseudetroplus maculatus. The fish were exposed to the sublethal concentration of DBP (200 µg L-1) for 1, 4, 7, and 15 days along with control and vehicle control groups. The induction of oxidative stress in the brain subcellular fractions was proved by alterations in the activities of superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase along with the reduction in the total antioxidant capacity. Meanwhile, the levels of hydrogen peroxide and lipid peroxidation were increased. Neurotransmitters such as acetylcholine, dopamine, adrenaline, noradrenaline, and serotonin were altered in all subcellular fractions suggesting the disruption of the neurotransmitter system in the fish brain. These results indicate that DBP induces oxidative stress, which correlates with neurotoxicity in Pseudetroplus maculatus brain tissue.


Assuntos
Dibutilftalato , Plastificantes , Animais , Dibutilftalato/toxicidade , Plastificantes/toxicidade , Estresse Oxidativo , Antioxidantes/metabolismo , Encéfalo
14.
J Hazard Mater ; 466: 133534, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38241835

RESUMO

Phthalate esters (PAEs) have received widespread attentions due to their ubiquity in various kinds of matrices and potential biotoxicity. This study systematically compared the concentrations, bioaccumulation, trophodynamics and health risk of PAEs in 25 species (n = 225) collected from a marine (Bohai Bay, BHB) and freshwater environment (Songhua River, SHR), China. Results showed that di-(2-ethylhexyl) phthalate and di-n-butyl phthalate were the predominant PAEs in the organisms from the two aquatic environments. The total concentrations of 6 PAEs in algae and fish from SHR were significantly higher than those from BHB. Two food webs were constructed in BHB and SHR based on the abundance of 15N in the organisms. All the PAEs except dimethyl phthalate exhibited trophic dilution with the trophic magnification factors less than 1. Moreover, an obvious biodilution of PAEs was observed in marine food web compared to freshwater food web. A low health risk of PAEs was found in organisms from both BHB and SHR. However, di-(2-ethylhexyl) phthalate exhibited a potential carcinogenic risk by consumption of some benthos in BHB and fish in SHR. This study provides a valuable perspective for understanding the trophodynamics and health risk of PAEs in marine and freshwater environments.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Animais , Cadeia Alimentar , Bioacumulação , Ésteres , Ácidos Ftálicos/toxicidade , Dibutilftalato/toxicidade , Rios , Peixes , China
15.
Ecotoxicol Environ Saf ; 270: 115941, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38184977

RESUMO

Early exposure to dibutyl phthalate (DBP) can cause hypospadias in newborn foetuses. However, the underlying molecular mechanism is not well defined. Aberrant angiogenesis is associated with various dysplasias including urogenital deficits. In vivo and in vitro angiogenesis assays showed reduced angiogenesis in the hypospadias group and DBP exposed group. RNA-sequencing analysis of DBP-treated HUVECs revealed decreased expression of transforming growth factor beta 1-induced transcript 1 (TGFB1I1) and a significantly enriched angiogenesis-associated pathway. Further experiments revealed that decreased TGFB1I1 expression was associated with disrupted tube formation and migration, which resulted in decreased angiogenesis. Functional assays revealed that the overexpression of TGFB1I1 promoted tube formation and migration of HUVECs in the DBP-treated group. Moreover, we showed that the transcription factor AR was regulated by TGFB1I1 through inhibiting its translocation from the cytoplasm to the nucleus. Together, our results identified TGFB1I1 as a component of aberrant angiogenesis in hypospadias rats and its interaction with AR might be a potential target for hypospadias development.


Assuntos
Dibutilftalato , Hipospadia , Masculino , Humanos , Feminino , Ratos , Animais , Dibutilftalato/toxicidade , Exposição Materna , Hipospadia/induzido quimicamente , Hipospadia/metabolismo , Plastificantes/toxicidade , Angiogênese , Ratos Sprague-Dawley
16.
Ecotoxicol Environ Saf ; 271: 115977, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38242044

RESUMO

To unravel the toxic mechanism of phthalate ester plasticizer endocrine disruptor in spermatozoa, we examined the effect of dibutyl phthalate (DBP) on the stability and inhibitory phosphorylation of glycogen synthase kinase 3α (GSK3α), a protein kinase crucial for sperm motility in mice. In DBP-treated spermatozoa, reactive oxygen species (ROS) and lipid peroxide were significantly increased. In computer-assisted sperm analysis, DBP at concentrations of 10 - 100 µg/mL significantly decreased total motility and progressive motility of spermatozoa. On western blots, DBP decreased p-GSK3α(Ser21) and increased p-GSK3α(Tyr279) in spermatozoa. Similarly, hydrogen peroxide decreased p-GSK3α(Ser21) but not p-GSK3α(Tyr279) in spermatozoa. Immunofluorescent labeling demonstrated that DBP markedly decreased immunoreactivities of GSK3α and p-GSK3α(Ser21) but increased immunoreactivity of p-GSK3α(Tyr279) in spermatozoa. DBP at a concentration of 100 µg/mL significantly increased phosphatase activity in spermatozoa. Calyculin A, a protein phosphatase 1 and 2 A inhibitor, markedly increased p-GSK3α(Ser21) and sperm motility and attenuated a DBP-induced decrease of p-GSK3α(Ser21) and sperm motility. On western blot, 1-100 µg/mL DBP decreased GSK3α in spermatozoa. On immunoprecipitation western blot, DBP at 10 - 100 µg/mL increased polyubiquitinated sperm proteins including GSK3α. The MG115, proteasome inhibitor attenuated degradation of GSK3α in DBP-treated spermatozoa. Hydrogen peroxide at 10 µM increased polyubiquitinated sperm proteins, suggesting that DBP may increase ubiquitination of GSK3α via ROS induction. Together, DBP may decrease the cellular amount of GSK3α through the ubiquitin-proteasome pathway and p-GSK3α(Ser21) through ROS generation and activation of protein phosphatases, impairing sperm motility.


Assuntos
Dibutilftalato , Motilidade dos Espermatozoides , Masculino , Camundongos , Animais , Dibutilftalato/toxicidade , Dibutilftalato/metabolismo , Proteínas do Espermatozoide , Peróxido de Hidrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sêmen , Espermatozoides
17.
Toxicol Ind Health ; 40(4): 167-175, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38285958

RESUMO

Phthalic acid esters (PAEs) and carbon nanotubes (CNTs) are common environmental pollutants and may degrade differently with different resulting biotoxicity, when present together. This study investigated the toxicological effects of singular or combined exposure to dibutyl phthalate (DBP) and multi-walled carbon nanotubes (MWCNTs) in KM mice. Results indicated that combined exposure led to slower weight gain and an increased leukocyte count in the blood, as well as liver tissue lesions and downregulation of organ coefficients. Additionally, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated in the liver, and glucose, pyruvate, triglyceride (TG), and total cholesterol (T-CHO) were significantly reduced, suggesting compromised liver function. Furthermore, mRNA levels of genes related to hepatic glucose and lipid metabolism were significantly altered. These findings suggest that combined exposure to DBP and MWCNTs can have severe impacts on liver function in mice, highlighting the importance of considering interactions between multiple contaminants in environmental risk assessments.


Assuntos
Poluentes Ambientais , Nanotubos de Carbono , Ácidos Ftálicos , Animais , Camundongos , Dibutilftalato/toxicidade , Glucose/metabolismo , Fígado , Ácidos Ftálicos/toxicidade
18.
Environ Res ; 247: 118221, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38246300

RESUMO

As one of the endocrine-disrupting chemicals (EDCs), dibutyl phthalate (DBP) has been extensively used in industry. DBP has been shown to cause damage to Leydig cells, yet its underlying mechanism remains elusive. In this study, we show that DBP induces ferroptosis of mouse Leydig cells via upregulating the expression of Sp2, a transcription factor. Also, Sp2 is identified to promote the transcription of Vdac2 gene by binding to its promoter and subsequently involved in DBP-induced ferroptosis of Leydig cells. In addition, DBP is proved to induce ferroptosis via inducing oxidative stress, while inhibition of oxidative stress by melatonin alleviates DBP-induced ferroptosis and upregulation of Sp2 and VDAC2. Taken together, our findings demonstrate that melatonin can alleviate DBP-induced ferroptosis of mouse Leydig cells via inhibiting oxidative stress-triggered Sp2/VDAC2 signals.


Assuntos
Ferroptose , Melatonina , Camundongos , Masculino , Animais , Dibutilftalato/toxicidade , Células Intersticiais do Testículo/metabolismo , Testículo/metabolismo , Melatonina/farmacologia , Melatonina/metabolismo
19.
Food Chem Toxicol ; 184: 114387, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38123059

RESUMO

Diisobutyl phthalate (DiBP) is a commonly used plasticizer in manufacturing consumer and industrial products to improve flexibility and durability. Despite of the numerous studies, however, the direct mechanism underlying the male reproductive damage of DiBP is poorly understood. In this study, we investigated the male germ cell toxicity of DiBP using GC-1 spermatogonia (spg) cells. Our results indicated that DiBP exposure causes oxidative stress and apoptosis in GC-1 spg cells. In addition, DiBP-derived autophagy activation and down-regulation of phosphoinositide 3-kinase (PI3K)-AKT and extracellular signal-regulated kinase (ERK) pathways further inhibited GC-1 spg cell proliferation, indicating that DiBP can instigate male germ cell toxicity by targeting several pathways. Importantly, a combined treatment of parthenolide, N-acetylcysteine, and 3-methyladenine significantly reduced DiBP-induced male germ cell toxicity and restored proliferation. Taken together, the results of this study can provide valuable information to the existing literature by enhancing the understanding of single phthalate DiBP-derived male germ cell toxicity and the therapeutic interventions that can mitigate DiBP damage.


Assuntos
Acetatos , Dibutilftalato , Fenóis , Fosfatidilinositol 3-Quinases , Humanos , Masculino , Dibutilftalato/toxicidade , Células Germinativas
20.
J Hazard Mater ; 465: 133360, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38157815

RESUMO

BACKGROUND: Dibutyl phthalate (DBP), a commonly used plasticizer, has been found to be strongly linked to a consistently high prevalence of allergic diseases, particularly allergic asthma. Previous animal experiments have demonstrated that exposure to DBP can worsen asthma by triggering the production of calcitonin gene-related peptide (CGRP), a neuropeptide in the lung tissue. However, the precise neuroimmune mechanism and pathophysiology of DBP-exacerbated allergic asthma with the assistance of CGRP remain unclear. OBJECTIVE: The present study was to investigate the potential pathophysiological mechanism in DBP-exacerbated asthma from the perspective of neural-immune interactions. METHODS AND RESULTS: C57BL/6 mice were orally exposed to different concentrations (0.4, 4, 40 mg/kg) of DBP for 28 days. They were then sensitized with OVA and nebulized with OVA for 7 consecutive excitations. To investigate whether DBP exacerbates allergic asthma in OVA induced mice, we analyzed airway hyperresponsiveness and lung histopathology. To investigate the activation of JNC and TRPV1 neurons and the release of CGRP by JNC cells, we measured the levels of TRPV1 channels, calcium inward flow, and downstream neuropeptide CGRP. Results showed that TRPV1 expression, inward calcium flux, and CGRP levels were significantly elevated in the lung tissues of the 40DBP + OVA group, suggesting the release of CGRP by JNC cells. To counteract the detrimental effects of DBP mediated by CGRP, we employed olcegepant (also known as BIBN-4096), a CGRP receptor specific antagonist. Results revealed that 40DBP + OVA + olcegepant led to notable decreases in TRPV1, calcium inward flow, and CGRP expression in lung tissues compare with 40DBP + OVA, further supporting the efficacy of olcegepant. Additionally, we also conducted ILC2 flow sorting and observed that neuropeptide CGRP-activated ILC2 cells have a crucial role as key effector cells in DBP-induced neuroimmune positive feedback regulation. Finally, we examined the protein expression of CGRP, GATA3 and P-GATA3, and found that significant upregulations of CGRP and P-GATA3 in the 40DBP + OVA group, suggest that GATA3 acted as a key regulator of CGRP-activated ILC2. CONCLUSION: The aforementioned studies indicate that exposure to DBP can exacerbate allergic asthma, leading to airway inflammation. This exacerbation occurs through the activation of TRPV1 in JNC, resulting in the release of CGRP. The excessive release of CGRP further promotes the release of Th2 cytokines by inducing the activation of ILC2 through GATA phosphorylation. Consequently, this process contributes to the development of airway inflammation and allergic asthma. The increased production of Th2 cytokines also triggers the production of IgE, which interacts with FcεRI on JNC neurons, thereby mediating neuro-immune positive feedback regulation.


Assuntos
Asma , Hipersensibilidade , Neuropeptídeos , Camundongos , Animais , Peptídeo Relacionado com Gene de Calcitonina/toxicidade , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Imunidade Inata , Retroalimentação , Dibutilftalato/toxicidade , Neuroimunomodulação , Cálcio , Linfócitos , Camundongos Endogâmicos C57BL , Asma/induzido quimicamente , Asma/metabolismo , Pulmão/patologia , Citocinas , Neuropeptídeos/toxicidade , Inflamação/patologia , Camundongos Endogâmicos BALB C , Ovalbumina
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