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1.
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
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.
Artigo em Inglês | MEDLINE | ID: mdl-31546793

RESUMO

Phthalate acid esters (PAEs) are the most frequently utilized synthetic chemical compounds worldwide. They are typical emergent contaminants and are currently attracting considerable concern due to their risks to plants, animals, and public health. Determining the vital environmental factors that affect the toxicity of target pollutants in soil is important for vegetable production and the maintenance and control of soil productivity. We investigated the influence of di-n-butyl phthalate (DBP) and bis(2-ethylhexyl) phthalate (DEHP) under different soil conditions on physiological changes in water spinach (Ipomoea aquatic Forsk.) seedlings and the rhizosphere soil microbial community. Supported by our former experiments in which we determined the representative concentrations that caused the most pronounced toxic effects, three experimental concentrations were studied including control soils without PAEs and spiked soils with either 20 mg DBP or DEHP kg-1 soil. The soil at all the three PAE concentrations was then adjusted to test two soil pH values, three levels of soil organic matter (SOM) content, and three levels of soil moisture content; thus, we completed 12 treatments or conditions simulating different soil environment conditions in greenhouses. After 30 days of cultivation, we analyzed the toxicity effects of two target PAEs on plant growth and physiological factors, and on soil microbial community characteristics. The toxicity of soil DBP and DEHP to the physiology of water spinach was found to be most affected by the soil pH value, then by SOM content, and least of all by soil moisture. The results of the 454 high-throughput sequencing analysis of the soil microbial community indicated that the toxicity of target PAEs to soil microorganisms was most affected by SOM content and then by soil moisture, and no clear relationship was found with soil pH. Under different soil conditions, declines in leaf biomass, chlorophyll a content, and carotenoid content-as well as increases in free amino acid (FAA) content, superoxide anion free radical activity, and hydroxyl radical activity-occurred in response to DBP or DEHP. Heavy use of chemical fertilizer, organic fertilizer, and high humidity led to the special environmental conditions of greenhouse soil, constituting the main conditions considered in this study. The results indicate that under the special highly intensive production systems of greenhouses, soil conditions may directly influence the effects of pollutant phytotoxicity and may thus endanger the yield, nutrient content, and food safety of vegetables. The combined studies of the impacts on plants and rhizosphere microorganisms give a more detailed picture of the toxic effects of the pollutants under different soil conditions.


Assuntos
Dibutilftalato/toxicidade , Ipomoea/efeitos dos fármacos , Microbiota , Plastificantes/toxicidade , Plântula/efeitos dos fármacos , Poluentes do Solo/toxicidade , Verduras/efeitos dos fármacos , Produção Agrícola , Fertilizantes/toxicidade , Microbiologia do Solo
4.
Aquat Toxicol ; 216: 105290, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518775

RESUMO

Phthalate esters (PAEs), which are notable plasticizers, can be prolific contaminants in aquatic environments, and have been shown to induce reproductive toxicity. However, the studies concerning their toxicity towards aquatic species are based on individual chemicals, and the combined toxicity of PAEs to aquatic organisms remains unclear. The aim of this study was to explore the potential toxicity mechanisms associated with combined exposure to dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) in adult female zebrafish ovaries. Zebrafish were exposed to DBP, DiBP and their mixtures for 30 days, and their effects on ovarian histology, plasma sex hormones and ovarian transcriptomics were investigated. Plasma estradiol (E2) levels were significantly decreased by 38.9% in the DBP-1133 exposure group and 41.0% in the DiBP-1038 exposure group. The percentage of late/mature oocytes was also significantly decreased by 17.3% under DBP-1133 exposure and 16.2% under DiBP-1038 exposure, while that under combined exposure was not significantly affected. Nevertheless, transcriptome sequencing revealed 2564 differentially expressed genes (DEGs) in zebrafish ovaries after exposure to the mixtures. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were involved in the neuroactive ligand-receptor interaction, GnRH, progesterone-mediated oocyte maturation, oocyte meiosis and steroid hormone biosynthesis signaling pathways. These results revealed that combined exposure exerts potential reproductive toxicity at the molecular level.


Assuntos
Dibutilftalato/análogos & derivados , Dibutilftalato/toxicidade , Exposição Ambiental , Perfilação da Expressão Gênica , Ovário/metabolismo , Transcriptoma/genética , Peixe-Zebra/genética , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Hormônios Esteroides Gonadais/sangue , Ovário/efeitos dos fármacos , Ovário/patologia , Reprodutibilidade dos Testes , Reprodução/efeitos dos fármacos , Reprodução/genética , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/sangue
5.
Food Chem Toxicol ; 133: 110750, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31390533

RESUMO

Human peripheral blood mononuclear cells (PBMCs) are one of the main cell models used in studies concerning the exposure of humans (in vitro) to various chemical substances. Changes in PBMCs may reflect the general reaction of the organism regarding the effect of xenobiotics. The aim of this work was to evaluate the effect of di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP) and their metabolites: mono-n-butylphthalate (MBP), mono-benzylphthalate (MBzP) upon the induction of apoptosis in human peripheral blood mononuclear cells in vitro. PBMCs were incubated with the studied compounds at concentrations from 1 to 100 µg/mL for 12 h and/or 24 h. In order to clarify the mechanism of phthalates-induced programmed cell death, the changes in the calcium ions (Ca2+) level, alterations in the transmembrane mitochondrial potential (ΔÑ°m) and caspase-8, -9, -3 activity as well as externalization of phosphatidylserine have been determined. An increased Ca2+ level and a reduction of the ΔÑ°m were observed in PBMCs incubated with all of the studied compounds, and particularly with DBP and BBP. Phthalates caused an increase of caspases activity. The most pronounced increase was observed for caspase -9. The most pronounced pro-apoptotic changes were caused by DBP followed by BBP and then by their metabolites.


Assuntos
Apoptose/efeitos dos fármacos , Dibutilftalato/toxicidade , Linfócitos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Cálcio/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Necrose/induzido quimicamente , Plastificantes/toxicidade
6.
Chemosphere ; 237: 124482, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31398608

RESUMO

The increase in the proportion of microplastics in the environment has intensified the interest in phthalate and microplastic contamination in recent years. In this study, we investigated the response of photosynthetic parameters and the antioxidant system of lettuce to di-n-butyl phthalate (DBP) stress and exposure to various concentrations of microplastic polyethylene (MP) for different durations (14 d and 28 d). Lettuce growth, photosynthetic parameters, and chlorophyll content were reduced significantly after MP- and DBP-only treatments and after the combined (MP + DBP) treatments with both pollutants (P < 0.05), when compared with the control. Our findings indicated that the exposure to MP can inhibit growth, hinder photosynthesis, and interfere with the antioxidant defense system in lettuce. Specifically, compared with the DBP-only treatment group, in all MP + DBP treatment groups, the lettuce growth parameters (dry and fresh weights of the leaves and roots and the number of leaves) decreased (P < 0.05). Moreover, the photosynthetic rate, stomatal conductance, transient transpiration rate, fluorescence parameters, chlorophyll content of leaves, and activity of Rubisco decreased, but the intercellular CO2 concentration increased in all MP + DBP treatment groups. The reduction in photosynthesis was attributed to the limitation of non-porosity and inhibition of the photoelectron flow, and the increase in exogenous MP content aggravated the effect of DBP on photosynthesis in lettuce. Compared with the DBP-only group, in all MP + DBP treatment groups, the content of superoxide radicals and hydrogen peroxide in lettuce leaves and roots increased. Antioxidant levels increased with the increase in MP content, except in the 1.0 mg mL-1 MP treatment after 14 d. Although the antioxidant system exhibited certain protective effects in the latter treatment, the cell membranes were still damaged. The degree of damage to cells decreased with the growth of lettuce, but the damage to root tissue always remained higher than that of the leaves. In conclusion, exposure to exogenous MP exacerbated the damage to lettuce by DBP.


Assuntos
Dibutilftalato/toxicidade , Alface/efeitos dos fármacos , Polietileno/toxicidade , Antioxidantes/metabolismo , Clorofila/metabolismo , Peróxido de Hidrogênio/metabolismo , Alface/fisiologia , Fotossíntese/efeitos dos fármacos , Ácidos Ftálicos , Folhas de Planta/metabolismo , Plásticos/metabolismo , Polietileno/metabolismo , Plântula/efeitos dos fármacos
7.
Environ Sci Pollut Res Int ; 26(29): 29763-29779, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407264

RESUMO

Dibutyl phthalate (DBP), a persistent environmental pollutant, can induce neural tube abnormal development in animals. The possible effects of DBP exposure on human neural tube defects (NTDs) remain elusive. In this study, the distribution of DBP in the body fluid of human NTDs was detected by GC-MS. Then, chick embryos were used to investigate the effects of DBP on early embryonic development. Oxidative stress indicators in chick embryos and the body fluid of human NTDs were detected by ELISA. The cell apoptosis and total reactive oxygen species (ROS) level in chick embryos were detected by whole-mount TUNEL and oxidized DCFDA, respectively. The study found that the detection ratio of positive DBP and its metabolites in maternal urine was higher in the NTD population than that in normal controls. 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA) were evidently upregulated and superoxide dismutase (SOD) was observably downregulated in amniotic fluid and urine. Animal experiments indicated that DBP treatment induced developmental toxicity in chick embryos by enhancing the levels of oxidative stress and cell apoptosis. MDA was increased and SOD was decreased in DBP-treated embryos. Interestingly, the supplement of high-dose choline (100 µg/µL), not folic acid, could partially restore the teratogenic effects of DBP. Our data collectively suggest that the incidence of NTDs is closely associated with DBP exposure. This study may provide new insight for NTD prevention.


Assuntos
Galinhas/metabolismo , Colina/metabolismo , Dibutilftalato/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Defeitos do Tubo Neural/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Líquidos Corporais/metabolismo , Embrião de Galinha , Galinhas/crescimento & desenvolvimento , Dibutilftalato/urina , Poluentes Ambientais/urina , Feminino , Ácido Fólico/metabolismo , Humanos , Exposição Materna/efeitos adversos , Teratogênese/efeitos dos fármacos
8.
Aquat Toxicol ; 215: 105281, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446302

RESUMO

Phthalate esters are highly present in aquatic plastic litter, which can interfere with the biological processes in the wildlife. In this work, the commonly found freshwater microalga Scenedesmus sp. was exposed to environmental concentrations (0.02, 1 and 100 µg L-1) and to a higher concentration (500 µg L-1) of dibutyl phthalate (DBP), which is an environmental pollutant. The growth, pH variation, production of photosynthetic pigments, proteins and carbohydrates were evaluated. The main inhibition effect of DBP on the microalgal growth was observed in the first 48 h of the exposure (EC50: 41.88 µg L-1). A reduction in the photosynthetic pigment concentration was observed for the 0.02, 1 and 100 µg L-1 conditions indicating that the DBP downregulated the growth rate and affected the photosynthetic process. A significant increase in protein production was only observed under 500 µg L-1 DBP exposure. The extracellular carbohydrates production slightly decreased with the presence of DBP, with a stronger decrease occurring in the 500 µg L-1 condition. These results highlight the environmental risk evaluation and ecotoxicological effects of DBP on the production of biovaluable compounds by microalgae. The results also emphasize the importance of assessing the consequences of the environmental concentrations exposure as a result of the DBP dose-dependent correlation effects.


Assuntos
Dibutilftalato/toxicidade , Ecotoxicologia , Plásticos/toxicidade , Scenedesmus/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Proteínas de Algas/biossíntese , Carboidratos/biossíntese , Concentração de Íons de Hidrogênio , Fotossíntese/efeitos dos fármacos , Pigmentos Biológicos/biossíntese , Scenedesmus/crescimento & desenvolvimento
9.
Environ Pollut ; 252(Pt A): 388-398, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158667

RESUMO

Dibutyl phthalate (DBP), one of the most widely used plasticizers, is a known environmental endocrine disruptor that impairs male and female fertility. In this study, oral administration of DBP was given to pregnant mice on 14.5 days post coitus (dpc) for 3 days; and additionally, DBP was added into the culture of 14.5 dpc fetal ovaries for 3 days. DBP exposure during gestation disturbed the progression of meiotic prophase I of mouse oocytes, specifically from the zygotene to pachytene stages. Meanwhile, the DBP-exposed pachytene oocytes showed increased homologous recombination sites and unrepaired DNA damage. Furthermore, DBP caused DNA damage by increasing oxidative stress, decreased the expression of multiple critical meiotic regulators, and consequently induced oocyte apoptosis. Moreover, the effect of DBP on meiosis I prophase involved estrogen receptors α and ß. Collectively, these results demonstrated a set of meiotic defects in DBP-exposed fetal oocytes. As aberrations in homologous recombination can result in aneuploid gametes and embryos, this study provides new support for the deleterious effects of phthalates.


Assuntos
Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Recombinação Homóloga/efeitos dos fármacos , Prófase Meiótica I/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Plastificantes/toxicidade , Aneuploidia , Animais , Apoptose/efeitos dos fármacos , Feminino , Masculino , Prófase Meiótica I/genética , Camundongos , Oócitos/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Gravidez
10.
Endocrinology ; 160(7): 1613-1630, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125050

RESUMO

Developmental exposures to phthalates are suspected to contribute to risk of metabolic syndrome. However, findings from human studies are inconsistent, and long-term metabolic impacts of early-life phthalate and phthalate mixture exposures are not fully understood. Furthermore, most animal studies investigating metabolic impacts of developmental phthalate exposures have focused on diethylhexyl phthalate (DEHP), whereas newer phthalates, such as diisononyl phthalate (DINP), are understudied. We used a longitudinal mouse model to evaluate long-term metabolic impacts of perinatal exposures to three individual phthalates, DEHP, DINP, and dibutyl phthalate (DBP), as well as two mixtures (DEHP+DINP and DEHP+DINP+DBP). Phthalates were administered to pregnant and lactating females through phytoestrogen-free chow at the following exposure levels: 25 mg of DEHP/kg of chow, 25 mg of DBP/kg of chow, and 75 mg of DINP/kg of chow. One male and female per litter (n = 9 to 13 per sex per group) were weaned onto control chow and followed until 10 months of age. They underwent metabolic phenotyping at 2 and 8 months, and adipokines were measured in plasma collected at 10 months. Longitudinally, females perinatally exposed to DEHP only had increased body fat percentage and decreased lean mass percentage, whereas females perinatally exposed to DINP only had impaired glucose tolerance. Perinatal phthalate exposures also modified the relationship between body fat percentage and plasma adipokine levels at 10 months in females. Phthalate-exposed males did not exhibit statistically significant differences in the measured longitudinal metabolic outcomes. Surprisingly, perinatal phthalate mixture exposures were statistically significantly associated with few metabolic effects and were not associated with larger effects than single exposures, revealing complexities in metabolic effects of developmental phthalate mixture exposures.


Assuntos
Composição Corporal/efeitos dos fármacos , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Intolerância à Glucose/metabolismo , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Adipocinas/sangue , Animais , Proteínas de Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Lipase/efeitos dos fármacos , Lipase/metabolismo , Masculino , Camundongos , Gravidez
11.
Toxicol Mech Methods ; 29(7): 488-498, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31050326

RESUMO

The increased incidence of testicular disorders in young men and the possible influence of environmental chemicals, such as dibutyl phthalate (DBP) and acrylamide (AA), requires experimental models for identifying modes of action. Most published reproductive toxicologic studies use RNA samples from the total testis to evaluate testicular gene expression; however, analyses of isolated cell types could provide a more specific tool. Among testicular germ cells, spermatogonia are critical since they represent the onset of spermatogenesis. This study aimed, (1) to establish a technique for spermatogonia isolation; (2) to apply this isolation technique to verify possible gene expression alterations (Pou5f1, Kitlg, Mki-67, Bak1 and Spry4) in prepubertal post-natal day, (PND24) and pubertal (PND45) testes after in utero and postnatal exposure to DBP or AA. The technique was efficient for isolation of a majority of spermatogonia. In utero DBP exposure led to reduced litter body weight at birth, reduced anogenital distance of male pups on PND4, and increased frequency of male nipple retention on PND14 compared to controls. DBP-exposed relative testes weights were reduced only at PND24 compared to control but they did not differ at PND45. DBP-exposed animals showed reduced expression levels of Pou5f1 and Mki67 on PND24, and reduced expression of Pou5f1 and Spry4 on PND45. AA exposure reduced expression of Pou5f1, Mki67, and Spry4 at PND45 although not significantly. Our results suggest that DBP acts by reducing cell proliferation and impairing differentiation in prepubertal and pubertal testes.


Assuntos
Acrilamida/toxicidade , Dibutilftalato/toxicidade , Poluentes Ambientais/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Espermatogônias/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Peso Corporal , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos Sprague-Dawley , Espermatogônias/patologia , Testículo/embriologia , Testículo/crescimento & desenvolvimento , Testículo/patologia
12.
Hum Exp Toxicol ; 38(8): 899-913, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30995857

RESUMO

Cryptorchidism (CPT), the most common male congenital abnormality, is variably associated with other male reproductive tract problems. We evaluated if cryptorchid rats develop enhanced testicular susceptibility to dibutyl phthalate (DBP) or acrylamide (AA) after extended exposure. Three studies with rats were performed: (1) in utero and postnatal exposure to DBP or AA; (2) establishment of CPT and orchiopexy; and (3) in utero and postnatal exposures to DBP or AA associated with CPT/orchiopexy. Seminiferous tubules were histologically scored according to the severity of lesions: (1) Rats exposed to DBP (score 1.5) or AA (score 1.1) presented mostly preserved spermatogenesis. Some seminiferous tubules showed vacuolated germinative epithelium, germ cell apoptosis, and a Sertoli cell-only (SCO) pattern. (2) CPT (score 3.3) resulted in decreased absolute testes weights, degenerated and SCO tubules, and spermatogenesis arrest that were reversed by orchiopexy (score 1.1). (3) Exposure to DBP or AA with CPT/orchiopexy led to atrophic testes, spermatogenesis arrest, germ cell exfoliation/multinucleation, and SCO tubules (both chemicals score 2.5). Exposure to chemicals such as DBP or AA prevented the recovery of cryptorchid testes by orchiopexy. The possible role of environmental contaminants should be considered when looking for factors that modulate human testicular disorders associated with CPT.


Assuntos
Acrilamida/toxicidade , Criptorquidismo/cirurgia , Dibutilftalato/toxicidade , Testículo/efeitos dos fármacos , Animais , Criptorquidismo/patologia , Modelos Animais de Doenças , Feminino , Masculino , Troca Materno-Fetal , Orquidopexia , Gravidez , Ratos Sprague-Dawley , Testículo/patologia
13.
Food Chem Toxicol ; 129: 239-248, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029726

RESUMO

Dibutyl phthalate (DBP) is commonly used plasticizer and a known endocrine disruptor that can cause birth defects and developmental disorders. Although several studies have reported that DBP has neurotoxic effects on neurite outgrowth and on learning and memory, its neurotoxic effects on neural progenitor cells (NPCs) have not been investigated. The present study was undertaken to determine the effects of DBP on NPCs and hippocampal neurogenesis. At high concentration DBP (500 µM) retarded NPC proliferation without affecting cell viability by arresting the cell cycle at G1 but did not cause cell death. DNA damage was observed by examining p53 expression and by γH2AX staining. DBP-treated cells had elevated ROS levels and exhibited mitochondrial dysfunction, which can cause DNA damage. Adult hippocampal neurogenesis was investigated using BrdU immunohistochemistry in young C57BL/6 mice intraperitoneally administrated with vehicle or DBP (10 or 50 mg/kg) for 2 weeks. DBP administered mice were found to have significantly fewer newly generated neurons in hippocampi, and the Morris water maze test revealed that DBP (50 mg/kg) impaired spatial learning and memory. Taken together, these findings suggest that DBP has harmful effects on NPCs and hippocampal neurogenesis and that DBP exposure could lead to learning and memory dysfunctions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dibutilftalato/toxicidade , Hipocampo/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Plastificantes/toxicidade , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Hipocampo/citologia , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células-Tronco Neurais/citologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
14.
Hum Exp Toxicol ; 38(8): 938-950, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31014133

RESUMO

Dibutyl phthalate (DBP), a ubiquitous environmental contaminant, has been reported to be involved in hepatic and renal tissue damage. However, the role of DBP in oxidative stress and in extracellular signal-regulated kinase (ERK1/2) pathways remains unclear. To investigate the underlying mechanism, Kunming (KM) mice received daily doses of combinations of 50 mg/kg DBP, 50 mg/kg vitamin E (VitE), and 1 mg/kg PD98059 for 28 consecutive days. Any changes in reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as any histopathological alterations in tissues, were observed to assess oxidative stress. In addition, the levels of alanine aminotransferase, aspartate aminotransferase, and albumin in serum were used to evaluate liver function. The levels of creatinine and urea nitrogen in serum were measured to evaluate kidney function. We found that DBP significantly increased oxidative damage and the expression of phosphorylated ERK1/2. Furthermore, pretreatment with the ERK inhibitor PD98059 followed by the antioxidant VitE attenuated the levels of ROS, MDA, ERK1/2 phosphorylation, and DBP-mediated disorders, indicating that the oxidative stress and the ERK1/2 pathways are associated with DBP-induced hepatic and renal dysfunction in KM mice.


Assuntos
Dibutilftalato/toxicidade , Poluentes Ambientais/toxicidade , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Plastificantes/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
15.
Ann Clin Lab Sci ; 49(2): 175-182, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31028061

RESUMO

In recent years, environmental endocrine disruptors (EEDs) have received extensive attention because of their hormone-like or anti-hormone effects. Dibutyl phthalate (DBP) is not only one of the most widely-used phthalates but also a member of EEDs with the estrogenic property. Although some studies have revealed the negative effect of DBP on the reproductive system, the underlying mechanisms are still elusive. Here the effect of DBP on P450 aromatase, a rate-limiting enzyme stimulated by FSH in the estradiol synthesis, was investigated in human granulosa cell line KGN. Cultured cells were treated with FSH and various doses of DBP (0.1µM, 1µM, 10µM, 50µM, or 100µM) for 24hr. Then the expression of aromatase was assessed, and the synthesis of estradiol was detected to reflect aromatase activity. As shown by the results, all concentrations of DBP could up-regulate the mRNA as well as protein levels of aromatase, and 0.1µM DBP increased the production of estradiol significantly. Furthermore, the ovary-specific promoter of aromatase, promoter II, was activated by 0.1µM DBP, and the expression of FSH receptor (FSHR) was increased by DBP from 0.1µM to 100µM. The study results show that DBP can affect aromatase from both quantitative and functional aspects, and this process may involve the activation of aromatase promoter II and upregulation of FSHR in KGN. Additionally, low-concentration DBP, near human serum concentration, has a more robust effect. This study suggests that DBP may affect the steroidogenic capacity in human ovaries and contributes to our understanding of the effects of DBP on the female reproductive system.


Assuntos
Aromatase/genética , Dibutilftalato/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/metabolismo , Aromatase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células da Granulosa/efeitos dos fármacos , Humanos , PPAR alfa/genética , PPAR alfa/metabolismo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do FSH/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
Environ Pollut ; 250: 357-365, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31009929

RESUMO

Herein, we investigated the effects of di-n-butyl phthalate (DBP) on photosynthesis, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) content, oxidative damage, and biomass accumulation of different tissues in wheat (Triticum aestivum L) planted in cinnamon soils. The photosynthetic or fluorescence parameters (except for the intercellular carbon dioxide concentration), chlorophyll content, RuBisCO content, and biomass of roots, stems, and leaves decreased at the seedling, jointing, and booting stages under the stress of DBP. Compared with the control, the content of superoxide anions and hydrogen peroxide in the roots, stems, and leaves increased with increasing DBP concentrations at the seedling, jointing, and booting stages. The activities of superoxide dismutase (SOD) and catalase (CAT) in the roots, stems, and leaves increased under the 10 and 20 mg kg-1 DBP treatments; however, no significant changes were observed under the 40 mg kg-1 DBP treatment at the seedling stage (except for the SOD activity in roots). The increase in SOD and CAT activities in the roots, stems, and leaves with increasing DBP concentration at the jointing and booting stages suggested that an increase in the activities of these antioxidant enzymes may play an important role in defending against excess reactive oxygen species under DBP stress. The biomass of wheat roots, stems, and leaves decreased with an increase in DBP concentration, which was presumably caused by a decrease in photosynthesis and RuBisCO. The effect of DBP on wheat roots, stems, and leaves decreased with wheat growth.


Assuntos
Dibutilftalato/toxicidade , Fotossíntese/efeitos dos fármacos , Poluentes do Solo/toxicidade , Triticum/fisiologia , Antioxidantes/metabolismo , Catalase/metabolismo , Clorofila/metabolismo , Cinnamomum zeylanicum , Peróxido de Hidrogênio/farmacologia , Oxirredução , Estresse Oxidativo/fisiologia , Folhas de Planta/química , Raízes de Plantas/metabolismo , Espécies Reativas de Oxigênio , Ribulose-Bifosfato Carboxilase/metabolismo , Plântula/metabolismo , Solo/química , Poluentes do Solo/análise , Superóxido Dismutase/metabolismo , Triticum/efeitos dos fármacos , Triticum/metabolismo
17.
Toxicol Lett ; 308: 24-33, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30910607

RESUMO

Dibutyl phthalate (DBP)-induced germ cell apoptosis contributes to male reproductive toxicity, however, the primary target organelle of DBP or the molecular events triggered by DBP to initiate germ cell apoptosis remain unclear. Our previous studies demonstrated DBP could stimulate the production of intracellular reactive oxygen species (ROS), which served as an upstream mediator of activation of endoplasmic reticulum (ER) stress in mouse spermatocyte-derived GC-2 cells. In the present study, the impacts of DBP-induced ROS generation on the mitochondria-related damage and the associations between ER stress and mitochondrial-related damage were investigated in GC-2 cells. We observed significant decreases of mitochondrial mass, mtDNA copy number, COX IV protein level, and ATP level in DBP-treated GC-2 cells in a dose-dependent manner. And DBP activated mitochondrial-related apoptosis, indicated by the elevation of cytoplasmic cytochrome C (Cyt C) and the activation of caspase-9/3 cascade. Pretreatment with antioxidant melatonin obviously attenuated DBP-induced mitochondrial damage and mitochondrial-dependent apoptosis in GC-2 cells, indicating the role of ROS in DBP-caused testicular toxicity. In response to oxidative stress, the Nrf2/ARE axis was activated in DBP-treated GC-2 cells to counteract ROS overproduction and subsequent mitochondrial damage. Further experiments showed DBP treatment increased the phosphorylated expression of ER stress-related protein PERK. GSK2606414, a specific inhibitor of PERK, partly attenuated the expression of Nrf2. And both DBP-induced mitochondrial damage in GC-2 cells and mitochondrial-dependent apoptosis of the germ cells in rat testes were further aggravated by PERK inhibition. Taken together, our data suggest that PERK regulates the Nrf2/ARE antioxidant pathway functioning as a self-defense mechanism against ROS-related mitochondrial damage induced by DBP in male germ cells.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Dibutilftalato/toxicidade , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Espermatócitos/efeitos dos fármacos , eIF-2 Quinase/metabolismo , Animais , Linhagem Celular , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Espermatócitos/metabolismo , Espermatócitos/patologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia
18.
Food Chem Toxicol ; 127: 163-172, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30904481

RESUMO

To estimate realistic exposure to a chemical, the aggregate exposure from multiple consumer products should be considered. A receptor-based aggregate exposure assessment was conducted according to individuals' exposure factors and simultaneous use patterns including co-use and non-use. A product-based aggregate exposure assessment was conducted by product usage rates of population and users' exposure factors. Two aggregate exposure assessments were compared. Exposure factors for 31 cosmetic products were collected by face-to-face interviews with 1001 members of the Korean population through national representative sampling. The concentrations of phthalates in 214 cosmetic products were analyzed by GC-MS-MS. The average aggregate exposure dose (AED) determined by the receptor-based method for di(2-ethylhexyl)phthalate (DEHP), di-n-butyl phthalate (DnBP), and diethyl phthalate (DEP) were 0.68 ±â€¯0.87, 1.08 ±â€¯5.71, and 2.47 ±â€¯9.05 µg/kg/day, respectively. The cosmetics that contributed most to the receptor-based AED were skin care and body care products for DEHP, nail care products for DnBP, and fragrance and hair care products for DEP. The young female group showed the highest exposure. The product-based aggregate exposure assessment method underestimated high exposure but overestimated average exposure for DnBP and DEP. The receptor-based aggregate exposure assessment method would be used to determine high exposure groups.


Assuntos
Cosméticos/química , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Exposição Ambiental/análise , Ácidos Ftálicos/toxicidade , Adulto , Dibutilftalato/análise , Dietilexilftalato/análise , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Ftálicos/análise , República da Coreia , Adulto Jovem
19.
Ecotoxicol Environ Saf ; 174: 75-82, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822670

RESUMO

Epidemiological studies have shown that high molecular weight phthalates (HMW) such as diethylhexyl phthalate (DEHP), are associated with hypertension in humans, while low molecular weight phthalates (LMW) such as dibutyl phthalate (DBP), have hardly any impact on the elevation of blood pressure. However, the molecular mechanisms responsible for this difference are not completely understood. In this experiment, mice were exposed to 0.1/1/10 mg/kg/day DEHP and 0.1/1/10 mg/kg/day DBP for 6 weeks, and their blood pressure was monitored using the tail pressure method. The results showed that exposure to DEHP dosages of 1 or 10 mg/kg/day resulted in a sharp increase in blood pressure, while exposure to DBP did not induce any significant changes in blood pressure. Investigating the renin-angiotensin-aldosterone system (RAAS) and NO pathway in mice exposed to DEHP, we found that levels of angiotensin-converting enzyme (ACE) and angiotensin II (AngII) increased with increasing exposure to DEHP, and the expression of nitric oxide synthase (eNOS) and the level of NO decreased. Treatment with ACE inhibitor (ACEI) to block the ACE pathway inhibited the enhancement of RAAS expression, inhibited the increase in blood pressure, and inhibited the decrease in NO levels induced by DEHP. However, the expression of ACE, AngII, AT1R, and eNOS in the DBP treatment groups showed no significant changes. When examining estradiol in vivo, we found that exposure to DBP resulted in a significant increase in the level of estradiol, while exposure to DEHP did not lead to a significant change. When ICI182780 was used to block the estradiol receptors, any increase in the level of NO induced by DBP exposure, was inhibited. These results indicate that exposure to DEHP induces an increase in mouse blood pressure through RAAS, and the different effects of DEHP and DBP on blood pressure are partly due to the different estradiol levels induced by DEHP and DBP.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Hipertensão/induzido quimicamente , Angiotensina II/metabolismo , Animais , Estradiol/metabolismo , Hipertensão/fisiopatologia , Masculino , Camundongos , Óxido Nítrico Sintase Tipo III/metabolismo , Peptidil Dipeptidase A/metabolismo
20.
Ecotoxicol Environ Saf ; 174: 658-666, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875559

RESUMO

The potential effects of dibutyl phthalate (DBP) on soil ecosystems and biological processes have recently aroused great concern because of the ubiquitous nature of this pollutant. However, the effects of DBP-associated disturbance on rhizosphere and non-rhizosphere soil microbial communities remain poorly understood. In the present study, we investigated the effects of DBP contamination on microbial function and soil enzyme activities in rhizosphere and non-rhizosphere soils throughout the growing season of wheat. We conducted pot experiments under glasshouse conditions and used different concentrations of DBP: 10, 20, and 40 mg kg-1. We found that the average well color development value and McIntosh index in rhizosphere and non-rhizosphere soils increased in the 10 and 20 mg kg-1 DBP treatments, but declined in the 40 mg kg-1 DBP treatment at the seedling and tillering stages, particularly, in the non-rhizosphere soil. DBP addition enhanced the Shannon-Wiener and Simpson indexes in rhizosphere and non-rhizosphere soils throughout the growing period of wheat. A principal component analysis clearly differentiated the treatments from the control, indicating that DBP led to different patterns of potential carbon utilization in rhizosphere and non-rhizosphere soils. The microbial use of amino acids was significantly increased in rhizosphere and non-rhizosphere soils after DBP addition, while the use of carbohydrates was significantly declined (p < 0.05). The dehydrogenase, urease, and acid phosphatase activities were significantly stimulated (p < 0.05) at the seedling stage, while the phenol oxidase and ß-glucosidase activities were inhibited. The 40 mg kg-1 DBP treatment significantly decreased the phenol oxidase and ß-glucosidase activities in rhizosphere and non-rhizosphere soils at the seedling stage, particularly in non-rhizosphere soil (p < 0.05). The microbial function and soil enzymatic activities were gradually restored following the wheat growing stage. These results offer a better understanding of the effects of DBP on the activities and functional diversity of microbial communities in farmland soils.


Assuntos
Dibutilftalato/toxicidade , Microbiota/efeitos dos fármacos , Microbiologia do Solo , Poluentes do Solo/toxicidade , Triticum/crescimento & desenvolvimento , Biodiversidade , Carbono/metabolismo , Dibutilftalato/química , Relação Dose-Resposta a Droga , Rizosfera , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Poluentes do Solo/química , Triticum/metabolismo
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