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1.
Sci Total Environ ; 783: 147038, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34088158

RESUMO

People are constantly exposed to phthalates, due to their common use in the production of plastics, pharmaceuticals, cosmetics and skin care products. The ability of phthalates to disrupt endocrine signaling, leading to developmental, reproductive and metabolic defects, has been studied, yet how phthalates interfere with these biological functions is still unclear. To uncover DBP interacting molecular pathways, we raised Drosophila melanogaster on food containing dibutyl phthalate (DBP) at various concentrations. Whole transcriptome analysis of adult Drosophila reveals that DBP exposure throughout development disrupts the expression of genes central to circadian rhythm regulation, including increased expression of vrille (vri, human NFIL3), timeless (tim, human TIMELESS) and period (per, human PER3), with decreased expression of Pigment-dispersing factor (Pdf). DBP exposure also alters the expression of the evolutionarily conserved nuclear receptor Hormone receptor-like in 38 (Hr38, human NR4A2), which is known to regulate Pdf expression. Furthermore, behavioral assays determined that exposing Drosophila to DBP throughout development modifies the circadian rhythm of adults. Although DBP inhibits the expression of signaling systems regulating vision, including Rh5 and Rh6, two light-sensing G-protein coupled receptors involved in the daily resetting of circadian rhythm, it does not influence eye development. Circadian rhythm genes are well conserved from flies to humans; therefore, we tested the effect of DBP exposure on human breast cells (MCF10A) and demonstrate that, similar to the fruit fly model, this exposure disrupts circadian rhythm (BMAL1 expression) at doses that promote the proliferation and migration ability of MCF10A cells. Our results are the first to provide comprehensive evidence that DBP interferes with circadian rhythm in both adult Drosophila and human cells, which may help to explain the broad physiological action of phthalates.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Ritmo Circadiano , Dibutilftalato/toxicidade , Drosophila melanogaster/genética , Humanos , Receptores Citoplasmáticos e Nucleares
2.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920546

RESUMO

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


Assuntos
Dibutilftalato/toxicidade , Dietilestilbestrol/toxicidade , Estrogênios não Esteroides/farmacologia , Hipotálamo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Sexual Animal , Animais , Aromatase/genética , Aromatase/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Ocitocina/genética , Ocitocina/metabolismo , Plastificantes/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transcriptoma , Vasopressinas/genética , Vasopressinas/metabolismo
3.
Aquat Toxicol ; 235: 105838, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33910148

RESUMO

Dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) have been reported to exhibit reproductive toxicity in vertebrates. However, the combined effect of DBP and DiBP on offspring of exposed parents remains unclear, especially for aquatic organisms such as fish. The aims of this study were to assess the effects of parental co-exposure to DBP and DiBP on early development of zebrafish offspring, and to explore the potential molecular mechanisms involved. The early developmental indicators and transcriptomic profiles of F1 larvae were examined after parental exposure to DBP, DiBP and their mixtures (Mix) for 30 days. Results showed that parental exposure to DBP and DiBP, alone or in combination, resulted in increased hatchability at 48 hpf and heart rate at 96 hpf, and increased the prevalence of malformations and mortality in F1 larvae. Generalized linear model (GLM) suggested an antagonistic interactive effect between DBP and DiBP on mortality and malformations of F1 larvae. The transcriptomic analysis revealed that the molecular mechanisms of parental co-exposure were different from those of either chemical alone. Disruption of molecular functions involved unfolded protein binding, E-box binding and photoreceptor activity in F1 larvae. These findings provide initial insights in the potential mechanism of action of parental co-exposure to DBP and DiBP.


Assuntos
Dibutilftalato/análogos & derivados , Dibutilftalato/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Perfilação da Expressão Gênica , Reprodução/efeitos dos fármacos , Transcriptoma , Peixe-Zebra/genética , Peixe-Zebra/fisiologia
4.
Sci Total Environ ; 778: 146281, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33721639

RESUMO

The widespread presence of phthalate esters (PAEs) in a variety of agricultural inputs has led to PAE contamination in soils and farm products. The endocrine disruption and carcinogenicity of PAEs have attracted much attention. Our research investigated the characteristics of PAE pollution in the soils of vegetable fields and adjacent stable crop fields in four provinces/municipalities across a major agricultural production area in China. We found that the concentrations of PAEs in vegetable soils were not significantly higher than those in stable crop soils. The noncarcinogenic and carcinogenic risks from bis (2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) to humans were calculated to represent the risk posed by PAEs. The results showed that diet was the main route for noncarcinogenic risks from PAEs in crop soil and vegetable soils. Because of the combined effect of the population dietary structure and the concentration of PAEs in soils, the noncarcinogenic risks from PAEs in crop soils were similar to or higher than those in vegetable soils. The same pattern was also applicable to the carcinogenic risk from DEHP. Low noncarcinogenic and carcinogenic risks posed by DEHP and DBP indicated that the current level of PAEs in soils did not decrease the safety of agricultural products in the Huang-Huai-Hai region. Stable crop soil, as a non-negligibly phthalate-polluted area, is worthy of as much attention as vegetable soil. This study provides scientific support for food safety risk assessment and control of PAE pollution in the main agricultural production areas in China.


Assuntos
Ácidos Ftálicos , Poluentes do Solo , China , Cidades , Dibutilftalato/análise , Dibutilftalato/toxicidade , Ésteres/análise , Humanos , Ácidos Ftálicos/análise , Solo , Poluentes do Solo/análise , Verduras
5.
Environ Pollut ; 278: 116871, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33714058

RESUMO

Microplastics, an emerging pollutant in the environment, have attracted extensive attention in recent years for their possible negative impact on organisms. However, direct and indirect effects of polystyrene (PS) microplastics on vegetables are still not completely known. In this study, we used red lettuce (Lactuca sativa L. Red Sails) in a hydroponic system to investigate the effects of nano- and micro-sized PS and dibutyl phthalate (DBP) on the photosynthesis and red lettuce quality. The results clearly indicated that PS reduced the bioavailability of DBP while causing a decrease in the photosynthetic parameters as well as the total chorophyll content compared to DBP alone by affecting the crystalline structure of the water-soluble chlorophyll protein. Compared with DBP monotherapy, the presence of PS significantly increased hydrogen peroxide and malondialdehyde content in the lettuce treated with DBP, indicating serious oxidative damage. Furthermore, the soluble protein and sugar content in lettuce leaves decreased with higher PS concentration and smaller PS size. It may be due to PS inhibited lettuce root and ribulose-1,5-bisphosphate carboxylase/oxygenase activities. In contrast, nitrite content increased significantly with the induction of the glutathione-ascorbic acid cycle, indicating that the presence of PS reduced the quality of DBP-treated-red lettuce. Additionally, the nano-sized PS greatly inhibited lettuce growth and quality more than the micro-sized PS. This study described the interactions between microplastics and phthalates using molecular simulation and experimental validation to highlight the potential risks of microplastics on vegetable crop production.


Assuntos
Dibutilftalato , Alface , Dibutilftalato/toxicidade , Fotossíntese , Plásticos , Poliestirenos
6.
Ecotoxicol Environ Saf ; 213: 112041, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33601174

RESUMO

Awareness of risks posed by widespread presence of nanoplastics (NPs) and bioavailability and potential to interact with organic pollutants has been increasing. Inhalation is one of the more important pathways of exposure of humans to NPs. In this study, combined toxicity of concentrations of polystyrene NPs and various phthalate esters (PAEs), some of the most common plasticizers, including dibutyl phthalate (DBP) and di-(2-ethyl hexyl) phthalate (DEHP) on human lung epithelial A549 cells were investigated. When co-exposed, 20 µg NPs/mL increased viabilities of cells exposed to either DBP or DEHP and the modulation of toxic potency of DEHP was greater than that of DBP, while the 200 µg NPs/mL resulted in lesser viability of cells. PAEs sorbed to NPs decreased free phase concentrations (Cfree) of PAEs, which resulted in a corresponding lesser bioavailability and joint toxicity at the lesser concentration of NPs. The opposite effect was observed at the greater concentration of NPs, which may result from the dominated role of NPs in the combined toxicity. Furthermore, our data showed that oxidative stress and inflammatory reactions were mechanisms for combined cytotoxicities of PAEs and NPs on A549 cells. Results of this study emphasized the combined toxic effects and mechanisms on human lung cells, which are helpful for assessing the risk of the co-exposure of NPs and organic contaminants in humans.


Assuntos
Poluentes Ambientais/toxicidade , Microplásticos/toxicidade , Ácidos Ftálicos/toxicidade , Poliestirenos/toxicidade , Células A549 , China , Dibutilftalato/toxicidade , Dietilexilftalato , Ésteres , Humanos , Pulmão , Estresse Oxidativo , Plastificantes
7.
J Hazard Mater ; 402: 123527, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-32712359

RESUMO

The wide application of plastics led to the wide exposure of plasticizers to the environment. As a new environmental pollutant, plasticizers' toxicity researches were far from enough in fish. To further explore these mechanisms, we used two common plasticizers (Diethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP) expose to grass carp hepatocytes (L8824). The results showed that the mRNA levels of NOD2-RIP2-NF-κB signal pathway and its downstream inflammatory genes were significantly increased compared to those in control group. Then, the levels of mRNAs and proteins of apoptosis markers were changed, and hepatocytes apoptosis was induced. After DBP and DEHP exposure together, there were higher levels of inflammatory factors and the proportion of apoptotic cells. After NOD2 inhibitor treatment, the phenomena mentioned above were obviously alleviated. We conclude that DBP and DEHP exposure at least partially activated the NOD2-RIP2-NF-κB signal pathway in grass carp hepatocytes, and caused inflammation and apoptosis. In terms of hepatotoxicity, there was synergistic relationship between DBP and DEHP. In addition, we put forward new views on the use of plasticizers: select low toxicity plasticizers, then reduce the types of plasticizers used and reduce the high toxicity level of mixed plasticizers.


Assuntos
Carpas , Dietilexilftalato , Animais , Apoptose , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Hepatócitos , NF-kappa B/genética , Plastificantes/toxicidade
8.
J Hazard Mater ; 401: 123422, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33113715

RESUMO

The effects of dibutyl phthalate (DBP) on the toxicity and edible quality (e.g., soluble proteins, soluble sugars, and vitamin C) of green and purple lettuce in the presence of polyethylene (PE) fragments were evaluated. The results revealed that PE treatment for 28 days decreased DBP and monobutyl phthalate content in lettuce roots and leaves, but enhanced the inhibitory effects of DBP on root growth and activity, reduced soluble protein and sugar content in lettuce leaves, and increased vitamin C content in lettuce leaves. Scanning and transmission electron microscopies revealed that PE only adhered to the root surface and did not enter the lettuce roots. Moreover, separation of the cell wall was aggravated in lettuce roots treated with DBP+PE, but not in lettuce treated with individual DBP or PE, and even led to the expansion of endoplasmic reticulum vesicles and cell rupture. Gaussian analysis indicated that PE interacted with DBP molecules through van der Waals interactions, which decreased DBP transport from the culture solution into the lettuce roots. In addition, purple lettuce was more sensitive to exogenous pollutants than green lettuce. This study provides new insights for food safety related to DBP fate and toxicity under PE stress.


Assuntos
Dibutilftalato , Poluentes Ambientais , Dibutilftalato/toxicidade , Alface , Folhas de Planta , Polietileno/toxicidade
9.
J Hazard Mater ; 408: 124891, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33360700

RESUMO

This study was to investigate the occurrence, migration and health risk of phthalic acid esters (PAEs) in tap water, barreled water and bottled water in Tianjin, China. Six priority controlled PAEs were measured, among which the detection frequency of butyl benzyl phthalate (BBP), dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) was 100%, while the others were not detected. The concentration of DEHP was higher than BBP and DBP in all the samples. The initial ∑3PAEs concentrations in tap water, barreled water and bottled water were 2.409 ± 0.391 µg/L, 1.495 ± 0.213 µg/L and 1.963 ± 0.160 µg/L, respectively. Boiling tap water could reduce the PAEs content to an extent, but they increased significantly in hot tap water contacting with disposable plastic cups. The migration of PAEs in barreled water and bottled water were positively correlated with storage time and temperature, which could be described by exponential models. The hazard indexes of PAEs in different types of drinking water were very low. However, the human carcinogenic risks of DEHP will reach the maximum acceptable risk level of 10-6 when bottled water is stored for 8.8 days at 40 °C, 7.7 days at 50 °C, or 6.1 days at 60 °C.


Assuntos
Água Potável , Ácidos Ftálicos , China , Dibutilftalato/toxicidade , Água Potável/análise , Ésteres/análise , Humanos , Ácidos Ftálicos/análise
10.
Environ Toxicol ; 36(5): 821-830, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33336902

RESUMO

Dibutyl phthalate (DBP), a typical representative of phthalate esters (PAEs), is used as a plasticizer in various industrial applications and has been reported to be responsible for neurobehavioral changes. Despite mounting evidence showing that nimodipine (Nim) palys a neuropharmacological and psychopharmacological role in neurons, the attenuating effects of Nim on learning and memory impairment induced by DBP exposure remain unknown. Based on bioinformatics analysis we found that the biological processes affected by both DBP and Nim may involve the calcium signaling pathway, the MAPK signaling pathway and the apoptosis pathway. The results of an in vivo study confirmed that DBP affects the levels of Ca2+ -related proteins, up-regulates phosphorylated -ERK1/2 expression and results in hippocampal neuronal damage and apoptosis, whereas Nim as a Ca2+ antagonist, has a certain neuroprotective role to avoid these adverse effects. Our data suggest that Nim could be used to attenuate the learning and memory impairment in DBP-exposed mice, to down-regulate intracellular Ca2+ levels, subordinate the ERK1/2 pathway and attenuate apoptosis in hippocampal tissue.


Assuntos
Dibutilftalato , Nimodipina , Animais , Biologia Computacional , Dibutilftalato/toxicidade , Transtornos da Memória/induzido quimicamente , Camundongos , Nimodipina/toxicidade , Plastificantes
11.
Ecotoxicol Environ Saf ; 205: 111154, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810643

RESUMO

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Gestacional/induzido quimicamente , Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Proteína Forkhead Box M1/metabolismo , Exposição Materna/efeitos adversos , Fator de Transcrição STAT1/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Proteína Forkhead Box M1/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Fosforilação , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT1/genética , Transdução de Sinais
12.
Chemosphere ; 258: 127408, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32782161

RESUMO

This study investigates the impacts of exposure to an environment Ca2+ challenge and the mechanism of action of dibutyl phthalate (DBP) on Ca2+ influx in the gills of Danio rerio. In vitro profile of 45Ca2+ influx in gills was verified through the basal time-course. Fish were exposed to low, normal and high Ca2+ concentrations (0.02, 0.7 and 2 mM) for 12 h. So, gills were morphologically analysed and ex vivo45Ca2+ influx at 30 and 60 min was determined. For the in vitro studies, gills were treated for 60 min with DBP (1 pM, 1 nM and 1 µM) with/without blockers/activators of ionic channels, Ca2+ chelator, inhibitors of ATPases, ionic exchangers and protein kinase C to study the mechanism of DBP-induced 45Ca2+ influx. Exposure to high environmental Ca2+ augmented 45Ca2+ influx when compared to fish exposed to normal and low Ca2+ concentrations. Additionally, histopathological changes were observed in the gills of fish maintained for 12 h in low and high Ca2+. In vitro exposure of gills to DBP (1 pM) disturbed Ca2+ homeostasis. DBP stimulated 45Ca2+ influx in gills through the transitory receptor potential vanilloid 1 (TRPV1), and reverse-mode Na+/Ca2+ exchanger (NCX) activation, protein kinase C and K+ channels and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). These data suggest that in vivo short-term exposure of gills to low and high Ca2+ leads to 45Ca2+ influx and histopathological changes. Additionally, the DBP-induced rapid 45Ca2+ influx is mediated by TRPV1, NCX activation with the involvement of PKC, K+-channels and SERCA, thereby altering Ca2+ homeostasis.


Assuntos
Radioisótopos de Cálcio/metabolismo , Cálcio/metabolismo , Dibutilftalato/toxicidade , Brânquias/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Cálcio/toxicidade , Dibutilftalato/metabolismo , Retículo Endoplasmático/metabolismo , Brânquias/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Canais de Cátion TRPV/metabolismo , Poluentes Químicos da Água/metabolismo
13.
Chemosphere ; 261: 127711, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32731021

RESUMO

Dibutyl phthalate (DBP) is a commonly used additive in plastic products, so it may potentially coexist with microplastics (MPs) in marine environment. The ingestion of MPs might affect the accumulation of DBP in marine organisms. In this study, the marine copepod Tigriopus japonicus was applied to study the combined effect of DBP and polystyrene microplastics (mPS) on the copepod through both acute mortality tests and chronic reproduction tests. The LC50 of DBP was 1.23 mg L-1 (95% CI: 1.11-1.35 mg L-1), while exposure to mPS didn't have significant lethal effect on the copepods. Adsorption to MPs led to decreased bioavailability of DBP, resulting in decreased toxicity of DBP. In contrast to the results of acute toxicity tests, DBP didn't affect the reproduction of the copepods at lower exposure concentrations, while mPS reduced the number of nauplii and extended the time to hatch. Similar as acute toxicity tests, antagonistic interaction was observed for mPS and DBP in chronic reproduction tests, which might be attributed to promoted aggregation of mPS at presence of DBP. Overall, antagonistic toxicity effect between the two pollutants was observed for both acute and chronic tests, but the mechanisms of the interaction between DBP and mPS were different. Results of the present study highlighted the importance of long-term exposure when evaluating the toxic effect of MPs and their combined effect with other chemicals.


Assuntos
Copépodes/fisiologia , Dibutilftalato/toxicidade , Microplásticos/toxicidade , Poliestirenos/toxicidade , Poluentes Químicos da Água/toxicidade , Adsorção , Animais , Organismos Aquáticos/efeitos dos fármacos , Copépodes/efeitos dos fármacos , Dose Letal Mediana , Plásticos/farmacologia , Reprodução/efeitos dos fármacos , Testes de Toxicidade Aguda , Poluentes Químicos da Água/química
14.
Chem Biol Interact ; 328: 109189, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32622864

RESUMO

Di-n-butyl phthalate (DBP) is a pollutant that is widely present in the environment. We have previously demonstrated that maternal exposure to DBP resulted in renal fibrosis in offspring, but the underlying mechanism was not well elucidated. Therefore, the current study aims to understand the underlying molecular mechanisms in these sex-specific developmental alterations. Here, we used RNA-seq analysis to explore the underlying molecular mechanisms of DBP-associated renal fibrosis. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14-18. Upregulated autophagy in renal tubules in offspring was confirmed in the DBP-treated group via accessing LC3Ⅱ/Ⅰ protein expression. Increased expression of the HhIP gene was found in the DBP-treated group via RNA-seq analysis. Immunohistochemistry (IHC) staining and Western blot analysis confirmed increased expression of HhIP protein and inhibited hedgehog signaling. Increased HhIP expression further leaded to impaired activation of hedgehog signaling, which is critical for normal embryonic development. Additional in vitro experiments on renal tubular cells suggest that inactivation of hedgehog signaling induced autophagy in renal tubular cells. Taken together, our findings show that maternal exposure to DBP induced autophagy through regulation of hedgehog signaling via overexpression of HhIP in foetal renal tubular cells, which may be essential for renal fibrosis development.


Assuntos
Autofagia , Dibutilftalato/toxicidade , Proteínas Hedgehog/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Linhagem Celular , Feminino , Túbulos Renais/efeitos dos fármacos , Exposição Materna , Gravidez , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
Chemosphere ; 258: 127238, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32563064

RESUMO

Dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) are phthalate compounds frequently detected in the environment. Despite increasing awareness of their toxicity in human and animals, the male reproductive toxicity of their combined exposure remains elusive. The purposes of this study were to investigate whether combined exposure to DBP and DiBP could induce male reproductive toxicity, and to explore the potential toxicological mechanisms. Adult male zebrafish were exposed to DBP (11, 113 and 1133 µg L-1), DiBP (10, 103 and 1038 µg L-1) and their mixtures (Mix) (11 + 10, 113 + 103, 1133 + 1038 µg L-1) for 30 days, and their effects on plasma hormone secretion, testis histology and transcriptomics were examined. Highest concentrations of Mix exposure caused greater imbalance ratio of T/E2 and more severe structural damage to testis than single exposure. These effects were consistent with the testis transcriptome analysis for which 4570 genes were differentially expressed in Mix exposure, while 2795 and 1613 genes were differentially expressed in DBP and DiBP, respectively. KEGG pathway analysis showed that both single and combined exposure of DBP and DiBP could affect cytokine-cytokine receptor interaction. The difference was that combined exposure could also affect steroid hormone synthesis, extracellular matrix receptor interaction, retinol metabolism, and PPAR signaling pathways. These results demonstrated that combined exposure to DBP and DiBP could disrupt spermatogenesis and elicit male reproductive toxicity in zebrafish.


Assuntos
Dibutilftalato/análogos & derivados , Dibutilftalato/toxicidade , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Teóricos , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Testículo/metabolismo
16.
Environ Sci Technol ; 54(13): 8245-8258, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32525310

RESUMO

Previous studies demonstrated that maternal exposure to di-n-butyl phthalate (DBP) resulted in developmental disorder of the male reproductive organ; however, the underlying mechanism has not been thoroughly elucidated to date. The present study was aimed to investigate the effects of maternal exposure to DBP on the formation of the Sertoli cell (SC)-based tight junctions (TJs) in the testes of male offspring mice and the underlying molecular mechanism. By observing the pathological structure and ultrastructure, permeability analysis of the testis of 22 day male offspring in vivo, and transepithelial electrical resistance measurement of inter-SCs in vitro, we found that the formation of TJs between SCs in offspring mice was accelerated, which was paralleled by the accumulation of TJ protein occludin at 50 mg/kg/day DBP exposure in utero and 0.1 mM monobutyl phthalate (MBP, the active metabolite of DBP) in vitro. Our in vitro results demonstrated that 0.1 mM MBP downregulated the expression of matrix metalloproteinase-2 (MMP-2) by inhibiting the activation of nuclear factor-κB (NF-κB)/cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) cascades via attenuated binding of NF-κB to both the MMP-2 promoter and COX-2 promoter. Taken together, the data confirmed that maternal exposure to a relatively low dose of DBP promoted the formation of testicular TJs through downregulation of NF-κB/COX-2/PGE2/MMP-2, which might promote the development of the testis during puberty. Our findings may provide new perspectives for prenatal DBP exposure, which is a potential environmental contributor, leading to earlier puberty in male offspring mice.


Assuntos
Dibutilftalato , Dinoprostona , Animais , Ciclo-Oxigenase 2/genética , Dibutilftalato/toxicidade , Regulação para Baixo , Feminino , Humanos , Masculino , Exposição Materna , Metaloproteinase 2 da Matriz , Camundongos , NF-kappa B/metabolismo , Gravidez , Maturidade Sexual , Testículo/metabolismo , Junções Íntimas/metabolismo
17.
Ecotoxicol Environ Saf ; 199: 110740, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446102

RESUMO

Dibutyl phthalate (DBP) is one of the most ubiquitous phthalate esters found in everyday products, and is receiving increased attention as an immunologic adjuvant. However, information regarding DBP-aggravated allergic asthma is still limited. This study used a mouse model sensitized with ovalbumin (OVA) to determine any adverse effects of DBP on allergic asthma. Our results reveal that allergic asthmatic mice exposed to DBP for an extended period had a significant increase in inflammatory cell infiltration; a significant increase in levels of serum immunoglobulin and T helper 2 cell (Th2) and T helper 17 cell (Th17) cytokines in lung tissue; and significant changes in lung histology and AHR, all of which are typical asthmatic symptoms. The levels of oxidative stress and levels of the neuropeptide, calcitonin gene related peptide (CGRP), were also elevated after DBP exposure. Interestingly, blocking oxidative stress by administering melatonin (MT) not only reduced oxidative stress and CGRP levels, but also ameliorated the asthmatic symptoms. Collectively, these results show that DBP exacerbates asthma-like pathologies by increasing the expression of CGRP mediated by oxidative stress.


Assuntos
Asma/induzido quimicamente , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Dibutilftalato/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
18.
Ecotoxicol Environ Saf ; 194: 110378, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146194

RESUMO

The primary purpose of this study was to systematically explore the complete metabolic pathway and tolerance mechanism of strain DNB-S1 to dibutyl phthalate (DBP), and the effect of DBP on energy metabolism of DNB-S1. Here, DNB-S1, a strain of Pseudomonas sp. that was highly effective in degrading DBP, was identified, and differentially expressed metabolites and metabolic networks of DBP were studied. The results showed that the differentially expressed metabolites were mainly aromatic compounds and lipid compounds, with only a few toxic intermediate metabolites. It speculated that phthalic acid, salicylic acid, 3-hydroxybenzoate acid, 3-Carboxy-cis, cis-muconate, fumarypyravate were intermediate metabolites of DBP. Their up-regulation indicated that there were two metabolic pathways in the degradation of DBP (protocatechuate pathway and gentisate pathway), which had been verified by peak changes at 290 nm, 320 nm, 330 nm, and 375 nm in the enzymatic method. Also, aspartate, GSH, and other metabolites were up-regulation, indicating that DNB-S1 had a high tolerance to DBP and maintained cell homeostasis, which was also one of the essential reasons to ensure the efficient degradation of DBP. Altogether, this study firstly proposed two pathways to degrade DBP and comprehensively explored the effect of DBP on the metabolic function of DNB-S1, which enriched the study of microbial metabolism of organic pollutants, and which provided a basis for the application of metabolomics.


Assuntos
Dibutilftalato/metabolismo , Poluentes Ambientais/metabolismo , Pseudomonas/metabolismo , Adaptação Fisiológica/efeitos dos fármacos , Biodegradação Ambiental , Dibutilftalato/toxicidade , Metabolismo Energético/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Pseudomonas/efeitos dos fármacos , Pseudomonas/crescimento & desenvolvimento
19.
Ecotoxicol Environ Saf ; 192: 110201, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32028152

RESUMO

OBJECTIVE: This study focused on the oxidative stress effect of di-n-butyl phthalate (DBP) on development of the urinary system. METHODS: We examined the mRNA expression of genital tubercle (GT) in control and DBP induced hypospadias group by Affymetrix Rat 230 2.0 Array. Real-time PCR and Western Blot were used to detect the protein and mRNA expression levels of inositol-1,4,5-triphate-receptor (IP3R) and epithelial-mesenchymal-transition (EMT)-related molecular markers, such as E-cadherin, ß-Catenin, Snail, N-cadherin, in the GT of hypospadiac male rats and controls. The results of array were further confirmed in vitro. The changes of intracellular calcium concentration in urethral epithelial cells were detected by Fluo-3-AM before and after DBP treatment. The levels of reactive oxygen species (ROS) in urethral epithelial cells were measured by DCFH-DA with different concentrations of DBP (0, 1, 10, 100 µmol/L) treatment. RESULTS: The mRNA expression profiles of GT in control and DBP induced hypospadias group showed high expression of IP3R and the abnormalities of EMT. Compared to the control group, the expression levels of IP3R, E-cadherin and ß-Catenin increased at both the protein and mRNA levels. However the expression levels of Snail and N-cadherin decreased. The intracellular calcium concentration increased significantly after DBP treatment. The effect of DBP on urethral epithelial cells was linked to the generation of oxidative stress. CONCLUSION: DBP can influence the development of GT through its oxidative stress effect, which significantly increases the concentration of calcium and inhibits EMT in urethral epithelial cells, and block the fusion process of urethral groove, causing the occurrence of hypospadias. This study provides a new understanding of DBP's molecular mechanisms on hypospadias and may lead to new treatment strategies for the disease.


Assuntos
Dibutilftalato/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hipospadia/induzido quimicamente , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Estresse Oxidativo , Plastificantes/toxicidade , Animais , Caderinas/genética , Caderinas/metabolismo , Cálcio/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Hipospadia/genética , Hipospadia/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Masculino , Exposição Materna , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Uretra/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
20.
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
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