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1.
Chemosphere ; 249: 126153, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32058129

RESUMEN

In this study, we determined DNA damage and chromosome breakage (indicators of genotoxicity) and cell viability (an indicator of cytotoxicity) in human lymphoblastoid TK6 and Chinese hamster ovary (CHO) cells treated with 33 e-liquids using in vitro single cell gel (comet), micronucleus (MN), and trypan blue assays, respectively. We also measured the contents of nicotine, five phthalate esters, and DL-menthol in the e-liquids to examine their effects on DNA damage, chromosome breakage, and cell viability. Our chemical analyses showed that: (1) six e-liquids had nicotine ≥2-fold higher than the manufacture's label claim (2-3.5 mg); (2) both dimethyl- and dibutyl-phthalate levels were >0.1 µg/g, i.e., their threshold limits as additives in cosmetics; and (3) the DL-menthol contents ranged from 0.0003 to 85757.2 µg/g, with those of two e-liquids being >1 mg/g, the threshold limit for trigging sensory irritation. Though all the e-liquids induced DNA damage in TK6 cells, 20 resulted in cell viabilities ≤75%, indicating cytotoxicity, yet the inverse relationship between cell viability and DNA damage (r = -0.628, p = 0.003) might reflect their role as pro-apoptotic and DNA damage inducers. Fifteen e-liquids induced MN% in TK6 cells ≥3-fold that of untreated cells. Some of the increase in %MN might be false due to high cytotoxicity, yet six brands showed acceptable cell viabilities (59-71%), indicating chromosome damage. DNA damage and %MN increased when the TK6 cells were exposed to metabolic activation. The CHO cells were less sensitive to the genotoxic effects of the e-liquids than the TK6 cells. DL-menthol was found to be associated with decreased cell viability and increased DNA damage, even at low levels. We cannot dismiss the presence of other ingredients in e-liquids with cytotoxic/genotoxic properties since out of the 63 different flavors, 47 induced DNA damage (≥3-folds), and 26 reduced cell viability (≤75%) in TK6 cells.


Asunto(s)
Cigarrillo Electrónico a Vapor/química , Ácidos Ftálicos/química , Animales , Células CHO , Supervivencia Celular/efectos de los fármacos , Cricetinae , Cricetulus , Daño del ADN , Dibutil Ftalato/farmacología , Cigarrillo Electrónico a Vapor/análisis , Cigarrillo Electrónico a Vapor/toxicidad , Ésteres/química , Humanos , Mentol/química , Mentol/toxicidad , Pruebas de Micronúcleos/métodos , Nicotina/química , Nicotina/toxicidad
2.
Environ Toxicol ; 35(3): 377-384, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31705742

RESUMEN

Sterol is synthesized from cholesterol which is from the hydrolysis of stored cholesteryl esters. The process of maintaining cholesterol homeostasis is regulated by SREBP2-STARD4. Lots of researches demonstrated that male steroidogenesis could be interfered by di-n-butyl phthalate (DBP) or monobutyl phthalate (MBP). However, mechanisms of MBP exposure in this process have not been uncovered clearly. The objectiveof this study was to explore roles of SREBP2 and STARD4 in cholesteryl estersynthesis stimulated by MBP in mouse Leydig tumor cells (MLTC-1). MLTC-1 exposedto 10-8, 10-7, 10-6, 10-5 M MBP showed that levels of cholestery ester were increased significantly at 10-7 M MBP. Besides, cholesteryl ester synthesis stimulated by MBP was down-regulate when STARD4 or SREBP2 were inhibited. Activity of SREBP2 binding to the promoter of STARD4 was increased after MBP exposure. This study suggests that MBP can increase cholesteryl ester synthesis through SREBP2-STARD4 signal pathway in MLTC-1 cells.


Asunto(s)
Ésteres del Colesterol/biosíntesis , Proteínas de Transporte de Membrana/metabolismo , Ácidos Ftálicos/farmacología , Transducción de Señal/efectos de los fármacos , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Animales , Línea Celular Tumoral , Dibutil Ftalato/farmacología , Regulación hacia Abajo/efectos de los fármacos , Masculino , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/genética , Ratones , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética
3.
Biol Res ; 52(1): 41, 2019 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-31387634

RESUMEN

BACKGROUND: Di-N-butyl-phthalate (DBP) is an endocrine disrupting substance. We investigated the adverse effect of DBP on testis of male rat and reveal its potential mechanism of MAPK signaling pathway involved this effect in vivo and in vitro. Gonadal hormone, sperm quality, morphological change and the activation status of JNK, ERK1/2 and p38 was determined in vivo. Primary Sertoli cell was established and cultivated with JNK, ERK1/2 inhibitors, then determine the cell viability, apoptosis and the expression of p-JNK, p-ERK1/2. Data in this study were presented as mean ± SD and determined by one-way analysis of variance (ANOVA) followed by Bonferroni's test. Difference was considered statistically significant at P < 0.05. RESULTS: In vivo experiment, DBP impaired the normal structure of testicular tissue, reduced testosterone levels in blood serum, decreased sperm count and increased sperm abnormality, p-ERK1/2 and p-JNK in rat testicular tissue increased in a dose-dependent manner. In vitro studies, DBP could decrease the viability of Sertoli cells and increase p-ERK1/2 and p-JNK. Cell apoptosis in SP600125 + DBP group was significantly lower than in DBP group (P < 0.05). p-JNK was not significantly decreased in SP600125 + DBP group, while p-ERK1/2 was significantly decreased in U0126 + DBP group. CONCLUSIONS: These results suggest that DBP can lead to testicular damage and the activation of ERK1/2 and JNK pathways, the JNK signaling pathway may be primarily associated with its effect.


Asunto(s)
Dibutil Ftalato/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Transducción de Señal/fisiología , Testículo/lesiones , Testículo/metabolismo , Animales , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Masculino , Proteínas Quinasas Activadas por Mitógenos/fisiología , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos
4.
Reproduction ; 158(3): 281-290, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31437814

RESUMEN

Epidemiological studies reported a negative relationship between concentrations of heavy metals and phthalates in seminal fluid and semen quality, likely compromising male fertility potential. The aim of this study was to investigate the in vitro effects of cadmium chloride (CdCl2), a common heavy metal, and diisobutyl phthalate (DIBP), a common phthalate ester, on human sperm functions necessary for fertilization. After in vitro incubation of spermatozoa with 10 µM CdCl2 or 100 and 200 µM DIBP for 24 h, a significant decrease of sperm progressive and hyperactivated motility was observed. The exposure to each of the two toxic agents also induced spontaneous sperm acrosome reaction and blunted the physiological response to progesterone. Both agents induced an increase of caspase activity suggesting triggering of an apoptotic pathway. Our results suggest that acute exposure of spermatozoa to these pollutants may impair sperm ability to reach and fertilize the oocyte.


Asunto(s)
Reacción Acrosómica/efectos de los fármacos , Cloruro de Cadmio/farmacología , Dibutil Ftalato/análogos & derivados , Motilidad Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Dibutil Ftalato/farmacología , Humanos , Masculino , Progesterona/farmacología , Análisis de Semen , Espermatozoides/metabolismo
5.
Biol Reprod ; 101(4): 854-867, 2019 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-31318015

RESUMEN

Phthalates have a history of reproductive toxicity in animal models and associations with adverse reproductive outcomes in women. Human exposure to dibutyl phthalate (DBP) occurs via consumer products (7-10 µg/kg/day) and medications (1-233 µg/kg/day). Most DBP toxicity studies have focused on high supraphysiological exposure levels; thus, very little is known about exposures occurring at environmentally relevant levels. CD-1 female mice (80 days old) were treated with tocopherol-stripped corn oil (vehicle control) or DBP dissolved in oil at environmentally relevant (10 and 100 µg/kg/day) or higher (1000 µg/kg/day) levels for 30 days to evaluate effects on DNA damage response (DDR) pathway genes and folliculogenesis. DBP exposure caused dose-dependent effects on folliculogenesis and gene expression. Specifically, animals exposed to the high dose of DBP had more atretic follicles in their ovaries, while in those treated with environmentally relevant doses, follicle numbers were no different from vehicle-treated controls. DBP exposure significantly reduced the expression of DDR genes including those involved in homologous recombination (Atm, Brca1, Mre11a, Rad50), mismatch repair (Msh3, Msh6), and nucleotide excision repair (Xpc, Pcna) in a dose-specific manner. Interestingly, staining for the DNA damage marker, γH2AX, was similar between treatments. DBP exposure did not result in differential DNA methylation in the Brca1 promoter but significantly reduced transcript levels for the maintenance DNA methyltransferase, Dnmt1, in the ovary. Collectively, these findings show that oral exposure to environmentally relevant levels of DBP for 30 days does not significantly impact folliculogenesis in adult mice but leads to aberrant ovarian expression of DDR genes.


Asunto(s)
Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Dibutil Ftalato/farmacología , Disruptores Endocrinos/farmacología , Contaminantes Ambientales/farmacología , Ovario/efectos de los fármacos , Animales , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Ciclo Estral/efectos de los fármacos , Ciclo Estral/fisiología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Proteína 3 Homóloga de MutS/genética , Proteína 3 Homóloga de MutS/metabolismo , Ovario/metabolismo
6.
Toxicol In Vitro ; 54: 168-177, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30218697

RESUMEN

The present study examined the effects of di-n-butyl phthalate (DBP) on phorbol myristate acetate (PMA)-induced macrophage differentiation of THP-1 monocytes, determined by morphological classification and flow cytometry. Focusing on the expression of the surface marker CD36, the potential role of peroxisome proliferator-activated receptor gamma (PPARγ) was examined using various PPARγ agonists and antagonists. As the PPARγ ligand-binding domain contains multiple ligand-binding sites (LBS), agonist and antagonists targeting the different sites were used. DBP accelerated PMA-induced morphological changes and increased expression of CD36, although to a lesser degree than the PPARγ agonists rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). A proteomics screening revealed that DBP enhanced the expression of PPARγ-regulated proteins. During combined exposures, DBP partly attenuated the effect of rosiglitazone, an agonist binding reversibly to PPARγ's canonical LBS. In contrast, DBP increased expression of CD36 in combination with 15d-PGJ2 which binds irreversibly to the canonical LBS. Thus, DBP appears to interact with both the canonical and alternative LBS. Accordingly, the antagonist GW9662, which binds to the canonical LBS, only partly reduced the DBP-induced CD36 expression, while the dual-site antagonist SR16832 completely blocked the effects of DBP. Overall, the results show that DBP modifies PMA-induced differentiation of THP-1 cells through interaction with PPARγ.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Dibutil Ftalato/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , PPAR gamma/metabolismo , Antígenos CD36/metabolismo , Humanos , Macrófagos/citología , Macrófagos/metabolismo , Monocitos/citología , Monocitos/metabolismo , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidores , Células THP-1 , Acetato de Tetradecanoilforbol
7.
Biomed Pharmacother ; 109: 1437-1444, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30551395

RESUMEN

CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD.


Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Dibutil Ftalato/farmacología , Hidrogeles/farmacología , Ovalbúmina/farmacología , Receptores CCR4/antagonistas & inhibidores , Piel/efectos de los fármacos , Animales , Quimiocina CCL17/metabolismo , Quimiocina CCL22/metabolismo , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Inmunoglobulina E/metabolismo , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Piel/metabolismo , Células Th2/efectos de los fármacos , Células Th2/metabolismo
8.
Environ Pollut ; 244: 774-782, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30388681

RESUMEN

Di (2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) are important pollutants that contaminate agricultural soils. We determined the effects of di (2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) on the production of reactive oxygen species, photosynthesis, and activity of antioxidant enzymes in wheat planted in fluvo-aquic soils. DBP- and DEHP-induced oxidative stress decreased the values of the photosynthetic/fluorescence parameters (except for intercellular carbon dioxide concentration) and chlorophyll content at the seedling, jointing, and booting stages. Moreover, the non-stomatal factor responsible for the net decrease in photosynthetic efficiency was identified as the decrease in fluorescence resulting from the decreased amount of chlorophyll a returning from the excited to the ground energy state. The content of superoxide anions and hydrogen peroxide in wheat leaves and roots increased with increasing DBP and DEHP supplementation, compared to the control. Antioxidant enzyme activities in the leaves and roots at the seedling stage increased at DBP and DEHP levels of 10 and 20 mg kg-1, respectively, and the enzyme activities at the jointing and booting stages increased with increasing concentrations of the chemicals, compared to the control. These results demonstrated that increased levels of antioxidant enzymes play a significant role in protecting plant growth under DBP and DEHP stress.


Asunto(s)
Dibutil Ftalato/farmacología , Dietilhexil Ftalato/farmacología , Contaminantes Ambientales/farmacología , Estrés Oxidativo/efectos de los fármacos , Ácidos Ftálicos/farmacología , Plastificantes/farmacología , Suelo/química , Triticum/crecimiento & desarrollo , Agricultura , Antioxidantes/metabolismo , Dióxido de Carbono/análisis , Clorofila A/análisis , Peróxido de Hidrógeno/metabolismo , Fotosíntesis/efectos de los fármacos , Hojas de la Planta/química , Raíces de Plantas/química , Plantones/efectos de los fármacos , Triticum/efectos de los fármacos
9.
Metab Brain Dis ; 34(1): 235-244, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30446882

RESUMEN

Due to its ability to cross blood brain barrier and placenta, dibutyl phthalate (di-n-butyl phthalate, DBP) is expected to cause severe side effects to the central nervous system of animals and humans. A little data is available about the potential DBP neurotoxicity; therefore, this work was designed to investigate the brain tissue injury induced by DBP exposure. Forty Wister albino rats were allocated randomly into 4 groups (10 rats each). Group 1 served as control and the rats administered with physiological saline (0.9% NaCl) orally for 12 weeks. Groups 2, 3 and 4 were orally treated with DPB (100, 250 and 500 mg/kg) respectively for 12 weeks. DBP-intoxicated rats showed a disturbance in the oxidative status in cerebral cortex, striatum and brainstem, as represented by the elevated oxidants [malondialdehyde (MDA), nitric oxide (NO), 8-hydroxy-2-deoxyguanosine (8-OHdG)] and the decreased antioxidant molecules [reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)]. DBP also enhanced a pro-inflammatory state through increasing the release of tumor necrosis factor- α (TNF-α) and interleukin-1ß (IL-1ß). The increase of these cytokines was associated with the increase of pro-apoptotic proteins [Bcl-2 associated X protein (Bax) and caspase-3] and the decrease of the anti-apoptotic protein, B cell lymphoma 2 (Bcl-2). In addition, the levels of norepinephrine (NE), dopamine (DA) and acetylcholine esterase (AChE) activity were decreased. This was accompanied by the alterations in the major excitatory and inhibitory amino acids neurotransmitters levels. The present findings indicated that DBP could exert its neuronal damage through oxidative stress, DNA oxidation, neuroinflammation, activation of apoptotic proteins and altering the monoaminergic, cholinergic and amino acids transmission.


Asunto(s)
Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Dibutil Ftalato/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Encéfalo/metabolismo , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Malondialdehído/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Transmisión Sináptica/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo
10.
Toxicology ; 412: 48-54, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30503584

RESUMEN

The prevalence of skin allergies could be partly due to the increased exposure to chemicals from consumer products. Chemicals that can enhance hypersensitivity caused by other chemicals are the focus of this study. We have demonstrated that phthalate esters with short chain alcohols enhance fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) in a mouse model. We have also found that tributyrin, a triacylglycerol (TAG) with three butyric acids, enhances sensitization to FITC. To elucidate such an enhanced skin sensitization might be based on a general feature of TAG, we compared tributyrin and triolein, a natural TAG, as to an adjuvant effect on FITC-CHS. Triolein is the dominant TAG in olive oil and contains long chain mono-unsaturated fatty acids. Unlike tributyrin and dibutyl phthalate (DBP), triolein did not exhibit an adjuvant effect. With triolein, enhancement of FITC-presenting CD11c+ dendritic cell trafficking to draining lymph nodes was weak, and the activation status of DC, as revealed as CD86 expression, was low. We found a difference in the pattern of skin cytokine production, i.e., that thymic stromal lymphopoietin was produced with DBP and interleukin-1ß with tributyrin. Triolein did not induce either of these cytokines. This illustrates that the adjuvant effect of tributyrin on FITC-CHS is not a general phenomenon for TAGs. Although beneficial effects may be expected through oral administration of tributyrin, the effect on skin immune systems should be considered.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Alérgenos/toxicidad , Dermatitis por Contacto/inmunología , Dibutil Ftalato/farmacología , Fluoresceína-5-Isotiocianato/toxicidad , Triglicéridos/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/fisiología , Femenino , Ganglios Linfáticos/inmunología , Ratones Endogámicos BALB C , Piel/efectos de los fármacos , Piel/inmunología
11.
Biol. Res ; 52: 41, 2019. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1019505

RESUMEN

BACKGROUND: Di-N-butyl-phthalate (DBP) is an endocrine disrupting substance. We investigated the adverse effect of DBP on testis of male rat and reveal its potential mechanism of MAPK signaling pathway involved this effect in vivo and in vitro. Gonadal hormone, sperm quality, morphological change and the activation status of JNK, ERK1/2 and p38 was determined in vivo. Primary Sertoli cell was established and cultivated with JNK, ERK1/2 inhibitors, then determine the cell viability, apoptosis and the expression of p-JNK, p-ERK1/2. Data in this study were presented as mean ± SD and determined by one-way analysis of variance (ANOVA) followed by Bonferroni's test. Difference was considered statistically significant at P < 0.05. RESULTS: In vivo experiment, DBP impaired the normal structure of testicular tissue, reduced testosterone levels in blood serum, decreased sperm count and increased sperm abnormality, p-ERK1/2 and p-JNK in rat testicular tissue increased in a dose-dependent manner. In vitro studies, DBP could decrease the viability of Sertoli cells and increase p-ERK1/2 and p-JNK. Cell apoptosis in SP600125 + DBP group was significantly lower than in DBP group (P < 0.05). p-JNK was not significantly decreased in SP600125 + DBP group, while p-ERK1/2 was significantly decreased in U0126 + DBP group. CONCLUSIONS: These results suggest that DBP can lead to testicular damage and the activation of ERK1/2 and JNK pathways, the JNK signaling pathway may be primarily associated with its effect.


Asunto(s)
Animales , Masculino , Ratas , Testículo/lesiones , Testículo/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Dibutil Ftalato/farmacología , Testículo/efectos de los fármacos , Ratas Sprague-Dawley , Proteínas Quinasas Activadas por Mitógenos/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología
12.
J Pharm Biomed Anal ; 160: 195-201, 2018 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-30099291

RESUMEN

The aim of this article is to assess the effect of phthalates on the activities of CYP2C9 and CYP2C19 in vitro. In this study, recombinant CYP2C9*1 and CYP2C19*1 microsomes were used to investigate the effects of phthalates and their metabolites on corresponding enzyme activities in vitro. 2-100 µM substrate of enzyme was incubated with series concentration of phthalates for 30 min at 37 °C. The metabolic products were detected using ultra-high performance liquid chromatography (UHPLC) and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) methods. The results showed dibutyl phthalate (DBP) significantly inhibited CYP2C9*1 with an activity inhibition rate of 67.3% and half-maximal inhibitory concentration (IC50) of 29.63 µmol L-1, but its metabolite monobutyl phthalate (MBP) had no significant effect. On the other hand, di(2-ethylhexyl)phthalate (DEHP) had no effect on CYP2C9*1, but its metabolite monoethylhexyl phthalate (MEHP) significantly inhibited the enzyme activity with an activity inhibition rate of 90.6% and IC50 of 6.37 µmol L-1. With regards to CYP2C19*1, DBP completely inhibited the enzyme activity with an activity inhibition rate of 100% and IC50 of 2.63 µmol L-1, but its metabolite MBP had no effect on it. DEHP and MEHP also inhibited the activity of CYP2C19*1. Further investigation showed MEHP was a competitive inhibitor of CYP2C9*1 (Ki = 7.063 µmol L-1), and DBP was a competitive inhibitor of CYP2C19*1 (Ki = 7.013 µmol L-1) against their substrates, both phthalates were non-competitive inhibitors of the cofactor NADPH. Our results suggested that DBP, DEHP, and their metabolites exhibited significant inhibitory effects toward either CYP2C9*1 or CYP2C19*1. These findings provided valuable information for a potentially toxic mechanism of DEHP and DBP on endocrine disruption and a useful guidance for safe and effective usage of drugs in patients with long-term DEHP and DBP exposure.


Asunto(s)
Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Dibutil Ftalato/farmacología , Dietilhexil Ftalato/farmacología , Inhibidores del Citocromo P-450 CYP2C19/farmacología , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Humanos , Concentración 50 Inhibidora , Microsomas/metabolismo , Ácidos Ftálicos/farmacología
13.
Reprod Fertil Dev ; 30(12): 1604-1615, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29898815

RESUMEN

Phthalate esters are endocrine disrupters that can affect the development of the testis in a species-specific manner. However, their interference in the male gonads of the Mongolian gerbil is unknown. The aim of the present study was to evaluate whether gestational exposure to di-n-butyl phthalate (DBP) interferes with the development of the gerbil testis during the first six weeks of life. Males were evaluated at 1, 7, 14, 28, 35 and 42 days of age in an untreated (control) group or groups exposed from 8 to 23 days gestation to DBP (100mgkg-1day-1 in mineral oil) or vehicle by maternal gavage. DBP exposure impaired cell proliferation within the seminiferous cords at birth, but increased proliferation at the end of the first week, when higher testosterone concentrations were observed. The vehicle (mineral oil) reduced the total number of gonocytes and attenuated the decrease in testosterone concentrations at 7 days. The vehicle also altered gonocyte relocation at 14 days and increased oestrogen concentrations at 28 days by approximately 112%. In summary, both DBP and oil interfered in gonadal development and testosterone plasma concentrations in the first week of postnatal life. However, the changes observed at the beginning of puberty were not seen after exposure to DBP, indicating a more harmful effect of mineral oil in this period.


Asunto(s)
Dibutil Ftalato/farmacología , Disruptores Endocrinos/farmacología , Aceite Mineral/farmacología , Plastificantes/farmacología , Efectos Tardíos de la Exposición Prenatal , Testículo/efectos de los fármacos , Testosterona/sangre , Animales , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Estrógenos/sangre , Femenino , Gerbillinae , Células Intersticiales del Testículo/efectos de los fármacos , Masculino , Embarazo , Testículo/crecimiento & desarrollo
14.
Bratisl Lek Listy ; 118(8): 460-466, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29050483

RESUMEN

OBJECTIVE: The effects of dimethyl phthalate, diethyl phthalate, diisobutyl phthalate, di-n-butyl phthalate, benzylbutyl phthalate, di-2-ethylhexyl phthalate were investigated on human prostate cancer cell lines DU145 and PC3 in vitro. MATERIALS AND METHODS: Standards of dimethyl phthalate, diethyl phthalate, di-isobutyl phthalate, dibutyl phthalate, benzyl butyl phthalate, and di-ethyl hexyl phthalate were used. Alpha lipoic acid was used as antioxidant compound. DU145 and PC3 human prostate carcinoma cells were used. MTT assay were used for cytotoxicity assay. RESULTS: A low dose proliferative effect of phthalates in vitro was observed. With the hypothesis of the inhibition of aerobic glycolysis activity in cancer treatment, α-lipoic acid was applied to cells; where as a contrary to previous studies, no change in the cell proliferation was observed. In combination with ALA, at IC50 and lower doses, an increase of the cytotoxic effect was found for DIBP, DBP and BBP; while for DMP, DEP and DEHP, a decrease was observed for DU145 cells. In PC3 cells, a decrease was observed for DMP, DEP and DBPs; while no significant difference were observed for DEHP, DIBP and BBP. CONCLUSSION: The present study demonstrates preliminary information regarding the low dose proliferative effects of phthalates in prostate cancer in vitro (Tab. 2, Fig. 2, Ref. 65).


Asunto(s)
Adenocarcinoma , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos Ftálicos/farmacología , Neoplasias de la Próstata , Ácido Tióctico/farmacología , Línea Celular Tumoral , Dibutil Ftalato/análogos & derivados , Dibutil Ftalato/farmacología , Dietilhexil Ftalato/farmacología , Humanos , Masculino
15.
Biol Pharm Bull ; 40(11): 2010-2013, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28845027

RESUMEN

Dibutyl phthalate (DBP) is a plasticizer used for many consumer products including cosmetics. Potential health concerns regarding DBP include reproductive and developmental toxicity, endocrine disruption and neurotoxicity. DBP is a high priority chemical as to reduction of exposure of children to it. Through reproductive toxicity studies, monobutyl phthalate (MBP) has been proposed to be the active metabolite derived from DBP. We previously demonstrated that DBP activates transient receptor potential ankyrin 1 (TRPA1) cation channels expressed on sensory neurons. We have also shown that DBP enhanced skin sensitization in a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) mouse model. Through MBP formation by esterase in the skin, it is possible that MBP exerts a major effect on the biological activity we observed. To test this possibility, we directly compared DBP and MBP. A more than 40-fold higher concentration of MBP as compared with DBP was required for activation of TRPA1 in vitro. Unlike DBP, MBP did not enhance skin sensitization to FITC. These results demonstrated that DBP directly, i.e., not through its metabolite MBP, activates TRPA1 and enhances FITC-CHS. It is noteworthy that butyl benzoate, a related compound, activated TRPA1 and enhanced FITC-CHS.


Asunto(s)
Dermatitis por Contacto/metabolismo , Dibutil Ftalato/farmacología , Ácidos Ftálicos/farmacología , Canal Catiónico TRPA1/metabolismo , Animales , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Femenino , Fluoresceína-5-Isotiocianato , Ratones Endogámicos BALB C , Canal Catiónico TRPA1/genética
16.
Food Chem Toxicol ; 105: 34-43, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28363850

RESUMEN

Di-n-butyl phthalate (DBP) has been reported to cause disruptions in hippocampal plasticity, but its specific mechanism has not yet been ascertained. In this research, a mouse model of chronic DBP exposure was generated by intragastric administration of DBP (10, 50, or 250°mg/kg/d) for 5 weeks. Chronic exposure to high concentrations of DBP (250°mg/kg/d) induced a spatial learning deficit in the Morris water maze in male mice. By determining the activity of Rho-GTPase signaling pathways in the hippocampal tissues, we found that DBP exposure inhibited the activity of Rac1/PAK1/LIMK1 but activated RhoA/ROCK/LIMK2 signaling and eventually suppressed cofilin activity by phosphorylation. Consistent with this, the differential activation was also observed in the acute exposure model of neuronal cells generated by incubation with DBP (100°ng/ml, 1, 10, or 100°µg/ml) for 72 hours. Moreover, acute exposure to high concentrations of DBP (100°µg/ml) altered cell morphology by inhibiting neurite outgrowth. A ROCK inhibitor, but not inhibitors of Rac1 or PAK1, reversed the inhibition of DBP to the activity of cofilin and neurite outgrowth in cells. These findings provide the first evidence that DBP exposure results in impairment of neuroplasticity by differential regulation of Rho-GTPase signaling pathways.


Asunto(s)
Dibutil Ftalato/farmacología , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Proteínas de Unión al GTP rho/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos ICR , Neuronas/citología , Neuronas/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas de Unión al GTP rho/genética
17.
Toxicol Lett ; 272: 38-48, 2017 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-28315385

RESUMEN

Some reports indicate that the silver released from dermally applied products containing silver nanoparticles (AgNP) (e.g. wound dressings or cosmetics) can penetrate the skin, particularly if damaged. AgNP were also shown to have cytotoxic and genotoxic activity. In the present study percutaneous absorption of AgNP of two different nominal sizes (Ag15nm or Ag45nm by STEM) and surface modification, i.e. citrate or PEG stabilized nanoparticles, in combination with cosmetic ingredients, i.e. aluminum chloride (AlCl3), methyl paraben (MPB), or di-n-butyl phthalate (DBPH) was assessed using in vitro model based on dermatomed pig skin. The inductively coupled plasma mass spectrometry (ICP-MS) measurements after 24h in receptor fluid indicated low, but detectable silver absorption and no statistically significant differences in the penetration between the 4 types of AgNP studied at 47, 470 or 750µg/ml. Similarly, no significant differences were observed for silver penetration when the AgNP were used in combinations with AlCl3 (500µM), MPB (1250µM) or DBPH (35µM). The measured highest amount of Ag that penetrated was 0.45ng/cm2 (0.365-0.974ng/cm2) for PEG stabilized Ag15nm+MPB.


Asunto(s)
Cosméticos/farmacología , Nanopartículas del Metal/química , Plata/farmacocinética , Absorción Cutánea/efectos de los fármacos , Piel/efectos de los fármacos , Cloruro de Aluminio , Compuestos de Aluminio/administración & dosificación , Compuestos de Aluminio/química , Compuestos de Aluminio/farmacología , Animales , Cloruros/administración & dosificación , Cloruros/química , Cloruros/farmacología , Cosméticos/administración & dosificación , Cosméticos/química , Dibutil Ftalato/administración & dosificación , Dibutil Ftalato/química , Dibutil Ftalato/farmacología , Técnicas In Vitro , Espectrometría de Masas , Nanopartículas del Metal/administración & dosificación , Parabenos/administración & dosificación , Parabenos/química , Parabenos/farmacología , Tamaño de la Partícula , Plata/administración & dosificación , Plata/química , Piel/metabolismo , Propiedades de Superficie , Porcinos
18.
PLoS One ; 11(8): e0161167, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27532513

RESUMEN

A spectrum of reproductive system anomalies (cryptorchidism, hypospadias, dysgenesis of Wolffian duct-derived tissues and prostate, and reduced sperm production) in male rats exposed in utero to phthalate esters (PEs) are thought to be caused by PE inhibition of fetal testosterone production. Recently, dibutyl and dipentyl phthalate (DBuP, DPnP) were shown to disrupt the retinol signaling pathway (RSP) in mouse pluripotent P19 embryonal carcinoma cells in vitro. The RSP regulates the synthesis and cellular levels of retinoic acid (RA), the active metabolite of retinol (vitamin A). In this new study, a total of 26 di- and mono-esters were screened to identify additional phthalate structures that disrupt the RSP and explore their mechanisms of action. The most potent PEs, those causing > 50% inhibition, contained aryl and cycloalkane groups or C4-C6 alkyl ester chains and were the same PEs reported to cause malformations in utero. They shared similar lipid solubility; logP values were between 4 and 6 and, except for PEs with butyl and phenyl groups, were stable for prolonged periods in culture. Mono- and cognate di-esters varied in ability to disrupt the RSP; e.g., DEHP was inactive but its monoester was active while DBuP was active yet its monoester was inactive. DBuP and dibenzyl phthalate both disrupted the synthesis of RA from retinol but not the ability of RA to activate gene transcription. Both PEs also disrupted the RSP in C3H10T1/2 multipotent mesenchymal stem cells. Based on this in vitro study showing that some PEs disrupt retinol signaling and previous in vivo studies that vitamin A/RA deficiency and PEs both cause strikingly similar anomalies in the male rat reproductive system, we propose that PE-mediated inhibition of testosterone and RA synthesis in utero are both causes of malformations in male rat offspring.


Asunto(s)
Feto/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ácidos Ftálicos/farmacología , Testículo/crecimiento & desarrollo , Tretinoina/metabolismo , Vitamina A/metabolismo , Animales , Línea Celular , Dibutil Ftalato/farmacología , Dietilhexil Ftalato/farmacología , Exposición a Riesgos Ambientales , Masculino , Ratones , Ratones Endogámicos C3H , Ácidos Ftálicos/química , Testosterona/biosíntesis
19.
Chemosphere ; 155: 498-508, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27151426

RESUMEN

The occurrence of phthalate esters (PAEs), a class of widely used and environmentally prevalent chemicals, raises concern to environmental and human health globally. The PAEs have been demonstrated to inhibit algae growth, but the underlying mechanisms remain unclear. In this research, diethyl ortho-phthalate (DEP), diallyl phthalate (DAP), di-n-butyl ortho-phthalate (DBP), di-iso-butyl ortho-phthalate, and benzyl-n-butyl ortho-phthalate (BBP) were screened from 11 species of PAEs to study their inhibitory effects on Karenia brevis and determine their target sites on algae. With increasing the alkyl chains of these five PAEs, the values of EC50,96h decreased. The content of malondialdehyde increased with the continuous accumulation of reactive oxygen species (ROS) in the algae cells. Moreover, the superoxide dismutase and catalase contents were first activated and then inhibited. The ultrastructures of Karenia brevis cells were detected by transmission electron microscopy, and cells treated with PAEs exhibiting distorted shapes and large vacuoles. Thus, the algae were damaged by ROS accumulation, resulting in lipid oxidation and algal growth inhibition. The inhibitors of the electron transport chain showed that the sites of ROS production and accumulation in K. brevis cells under DEP and BBP were the mitochondria and chloroplast, respectively. Moreover, the target sites of DAP and DBP were both the chloroplast and mitochondria. These results are useful for controlling PAEs contamination in and revealing the fate of PAEs in aquatic ecosystem.


Asunto(s)
Cloroplastos/efectos de los fármacos , Dinoflagelados/efectos de los fármacos , Ésteres/farmacología , Mitocondrias/efectos de los fármacos , Ácidos Ftálicos/farmacología , Catalasa/metabolismo , Dibutil Ftalato/análogos & derivados , Dibutil Ftalato/química , Dibutil Ftalato/farmacología , Dinoflagelados/crecimiento & desarrollo , Humanos , Malondialdehído/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo
20.
Endocrinology ; 157(7): 2595-603, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27058814

RESUMEN

Phthalate exposure impairs testis development and function; however, whether phthalates affect nonreproductive functions is not well understood. To investigate this, C57BL/6J mice were fed 1-500 mg di-n-butyl phthalate (DBP) in corn oil, or vehicle only, daily from 4 to 14 days, after which tissues were collected (prepubertal study). Another group was fed 1-500 mg/kg·d DBP from 4 to 21 days and then maintained untreated until 8 weeks for determination of adult consequences of prepubertal exposure. Bones were assessed by microcomputed tomography and dual-energy X-ray absorptiometry and T by RIA. DBP exposure decreased prepubertal femur length, marrow volume, and mean moment of inertia. Adult animals exposed prepubertally to low DBP doses had lower bone mineral content and bone mineral density and less lean tissue mass than vehicle-treated animals. Altered dynamics of the emerging Leydig population were found in 14-day-old animals fed 100-500 mg/kg·d DBP. Adult mice had variable testicular T and serum T and LH concentrations after prepubertal exposure and a dose-dependent reduction in cytochrome p450, family 11, subfamily A, polypeptide 1. Insulin-like 3 was detected in Sertoli cells of adult mice administered the highest dose of 500 mg/kg·d DBP prepubertally, a finding supported by the induction of insulin-like 3 expression in TM4 cells exposed to 50 µM, but not 5 µM, DBP. We propose that low-dose DBP exposure is detrimental to bone but that normal bone mineral density/bone mineral content after high-dose DBP exposure reflects changes in testicular somatic cells that confer protection to bones. These findings will fuel concerns that low-dose DBP exposure impacts health beyond the reproductive axis.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Dibutil Ftalato/farmacología , Fémur/efectos de los fármacos , Células Intersticiales del Testículo/efectos de los fármacos , Células de Sertoli/efectos de los fármacos , Absorciometría de Fotón , Animales , Fémur/diagnóstico por imagen , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/sangre , Masculino , Ratones , Plastificantes/farmacología , Células de Sertoli/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Testosterona/metabolismo , Microtomografía por Rayos X
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