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1.
Sci Total Environ ; 719: 136965, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32120090

RESUMO

Phthalates are SVOCs (Semi-volatile Organic Compounds) that are widely used in industrial and daily home products. This study aimed to investigate exposure levels to phthalates in Chinese homes and to relate these to building characteristics and lifestyles. Dust in 399 homes of 410 children in urban Tianjin and rural Cangzhou was analyzed for concentrations of six target phthalates. The median concentrations were 0.31µg/g for diethyl phthalate (DEP), 16.39µg/g for di-isobutyl phthalate (DiBP), 42.60µg/g for di-n-butyl phthalate (DnBP), 0.10µg/g for benzyl butyl phthalate (BBzP), 127.11µg/g for di (2-ethylhexyl) phthalate (DEHP) and 0.28µg/g for di-isononyl phthalate (DiNP). Strong associations were found between modern flooring materials (laminated wood/wood) and concentrations of DiBP, BBzP and DiNP; modern window frame (aluminum/plastic steel) and BBzP concentration; leather polish and DEHP concentration; perfume and DEP concentration. Concentrations of phthalates were significantly higher in Tianjin urban homes than Cangzhou rural homes. Concentrations of phthalates increased significantly with increasing household income. Our study indicates that exposure to phthalates in Chinese homes increases with attributes of modern life.


Assuntos
Ácidos Ftálicos/toxicidade , Criança , Poeira , Exposição Ambiental , Poluentes Ambientais , Pisos e Cobertura de Pisos , Produtos Domésticos , Humanos
2.
Chemosphere ; 249: 126144, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32086060

RESUMO

Phthalates (phthalate esters, PAEs) are commonly used as plasticizers and are emerging concerns worldwide for their potential influence on the environment and general public health. Thus, identification of the negative effects and involved mechanisms of PAEs is necessary. Herein, we found that embryonic exposure of zebrafish to di-(2-ethylhexyl) phthalate (DEHP) and di-butyl phthalate (DBP) significantly induced spinal defects, such as inhibited spontaneous movement at 24 h post-fertilization (hpf), spine curvature and body length decrease at 96 hpf. The transcriptional level of the genes that are related to the development of the notochord (col8a1a and ngs), muscle (stac3, klhl41a and smyd2b) and skeleton (bmp2, spp1) were significantly altered by DEHP and DBP at 50 and 250 µg/L, which might be associated with the observed morphological changes. Notably, DBP and DEHP altered the locomotor activity of zebrafish larvae at 144 hpf, which might be due to the abnormal development of the spine and skeletal system. In conclusion, phthalates caused spinal birth defects in zebrafish embryos, induced transcriptional alterations of the spinal developmental genes, and led to abnormal behavior.


Assuntos
Bioensaio , Ácidos Ftálicos/toxicidade , Coluna Vertebral/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Dibutilftalato , Dietilexilftalato , Embrião não Mamífero/efeitos dos fármacos , Larva , Plastificantes , Proteínas de Peixe-Zebra
3.
Chemosphere ; 249: 126034, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32062553

RESUMO

Some thyroid-disrupting chemicals (TDCs) affect thyroid function by activating the pathways mediated by a typical thyroid hormone (TH) membrane receptor, integrin αvß3. The present study introduces improved competitive binding assays for the rapid and sensitive evaluation of the binding affinities of TDCs for integrin αvß3. Based on different probes, two assays were modified: a fluorescence competitive binding assay and a radioligand competitive binding assay. The chemicals tested included the known TH, 3,3',5,5'-tetraiodo-l-thyronine (T4); a deaminated analog of T4, tetraiodothyroacetic acid (tetrac); and phthalate esters (PAEs). The relative binding potency of T4 was studied, and the concentration required to displace 50% of the ligands from their receptors (RIC50) of T4 was 4.9 × 105 and 9.7 × 104 nM for the fluorescence and radioligand competitive binding assays, respectively, suggesting that the radioligand competitive binding assay might be more sensitive for the evaluation of the binding affinity for integrin αvß3. The three PAEs, including diethyl hexyl phthalate (DEHP), benzyl butyl phthalate (BBP) and dibutyl phthalate (DnBP), demonstrated binding affinities for integrin αvß3 in the following order of potency: DnBP > DEHP > BBP tested by the radioligand competitive binding assay. A docking simulation of each of the three PAEs with integrin αvß3 confirmed the calculated binding energies, which had a strong positive relationship with the log RIC20 values of the 3 PAEs (R = 0.99, p < 0.001). The present study shows that the established radioligand competitive binding assay could be used as a valuable tool for quantifying the affinity of TDCs for integrin αvß3.


Assuntos
Bioensaio , Integrina alfaVbeta3/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Glândula Tireoide/efeitos dos fármacos , Ligação Competitiva , Dibutilftalato , Ésteres , Ácidos Ftálicos/toxicidade , Glândula Tireoide/metabolismo , Tiroxina/análogos & derivados
4.
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
5.
Chemosphere ; 246: 125828, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31927381

RESUMO

People are inevitably exposed to phthalates (PEs) ubiquitously existing in environment. Our previous studies, simulating the actual situations of people exposure to PEs, have shown that the sub-chronic exposure to low-doses PEs mixture (MIXPs) impaired reproductive function in male rats. Zinc is an important element in maintaining male reproductive functions. However, it is still unknown whether zinc supplement could mitigate PEs-induced male reproductive toxicity or not with sub-chronic low-dose mixture exposure. This study aimed to explore the effect of zinc supplement on the reproductive toxicity caused by sub-chronic MIXPs exposure (160 mg/(kg•body weight)/d, for 90 days) in male rats, and further to reveal the underlying mechanisms. Testosterone (T), FSH and LH in serum, early toxicity indicators in urine, PIWI proteins (PIWIL1 and PIWIL2) expression in testes and pathological examination were performed for toxicity evaluation. Steroidogenic proteins (17ß-HSD, StAR, CYP17A1, P450scc and SRD5A) were measured for mechanisms of exploration. The results indicated that zinc supplement could inhibit the T, LH, FSH level decreases in serum, abolish the effect of 5 early toxicity indicators' levels in urine, restrain the alteration of PIWI proteins expression and improve the constructional injury of testes. These effects might be relevant with the suppressed alteration of the expression of steroidogenic proteins induced by MIXPs in rat testicular cells. This work may offer further insights into reducing health risks of MIXPs exposure.


Assuntos
Poluentes Ambientais/toxicidade , Ácidos Ftálicos/toxicidade , Reprodução/efeitos dos fármacos , Zinco/metabolismo , Animais , Proteínas Argonauta , Masculino , Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testosterona/sangue
6.
Chemosphere ; 238: 124584, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31470313

RESUMO

Exposure to endocrine disrupting chemicals has been suggested to contribute to the ongoing globally increasing obesity trend. The complex chemical mixtures that humans and wildlife are exposed to include a number of compounds that may have obesogenic properties. In this study we examined a mixture consisting of phthalate-monoesters, triclosan, and perfluorinated compounds. The mixture was designed within the EDC-MixRisk project based on serum levels of the compounds in pregnant women of a Swedish mother-child cohort. The compounds were negatively associated with birth weight of the children. We assessed whether developmental exposure to this mixture in combination with a calorie-rich diet affected metabolic rate, blood lipids, adipogenesis and lipid storage, and the whole-body level of neutral lipids in zebrafish (Danio rerio). Wildtype zebrafish were exposed to the mixture from 3 h post fertilization to 5, 14 or 17 days post fertilization (dpf) at water concentrations corresponding to 1, 10, 20, or 100 times the geometrical mean of the serum concentration (hsc) in the women. Exposure to the mixture at 20 times hsc lowered metabolic rate at 2-5 dpf, and increased the number of adipocytes and the amount of visceral adipose tissue at 14 and 17 dpf respectively. Also, mRNA expression of fatty acid binding protein 11a was increased at 17 dpf by 10 and 20 times hsc of the mixture. This study shows that a human-relevant mixture of environmental pollutants affects metabolic rate, adipogenesis and lipid storage in young zebrafish fed a calorie-rich diet, thus demonstrating its potential to disrupt metabolism.


Assuntos
Adipogenia/efeitos dos fármacos , Metabolismo Basal/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Peso ao Nascer/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/biossíntese , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Humanos , Hidrocarbonetos Fluorados/toxicidade , Ácidos Ftálicos/toxicidade , Gravidez , Triclosan/toxicidade , Proteínas de Peixe-Zebra/biossíntese , Proteínas de Peixe-Zebra/genética
7.
Food Chem ; 311: 125918, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869647

RESUMO

Multilayer materials used in food packaging are commonly manufactured with a polyurethane adhesive layer in its structure that may contain cyclic esters oligomers as potential migrants. However, little is known about their toxicity. In this work, two cyclic esters of polyurethane are evaluated in migration from 20 multilayer packaging samples. They were composed by adipic acid (AA), diethylene glycol (DEG) and isophthalic acid (IPA) and their structure was AA-DEG and AA-DEG-IPA-DEG. The concentration of these compounds in migration exceeded the maximum level established by Regulation EU/10/2011 (10 ng g-1). Bioaccessibility of both compounds was evaluated by studying gastric and intestinal digestion. The studies showed that the concentration of the compounds decreased during digestion and that their hydrolysed molecules increased. Furthermore, endocrine activity in vitro assays were performed. A weak androgen receptor antagonism was identified, whereas no arylhydrocarbon receptor activity or binding to the thyroid hormone transport protein was found.


Assuntos
Adesivos/química , Embalagem de Alimentos/instrumentação , Poliésteres/química , Poliuretanos/química , Adipatos/química , Adipatos/toxicidade , Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/toxicidade , Linhagem Celular , Etilenoglicóis/química , Etilenoglicóis/toxicidade , Contaminação de Alimentos/análise , Humanos , Ácidos Ftálicos/química , Ácidos Ftálicos/toxicidade , Poliuretanos/toxicidade
8.
Ecotoxicol Environ Saf ; 188: 109884, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31706241

RESUMO

BACKGROUND: Phthalate exposure was reported to induce defects in ovarian function, and further influence embryo development and pregnancy outcomes. However, the data about the associations of phthalates with intermediate and pregnancy outcomes of in vitro fertilization (IVF) cycles are scarce in the Chinese population. METHODS: A total of 663 women receiving IVF/intracytoplasmic sperm injection (ICSI) treatments in our center were enrolled in this analysis. They provided one urine sample on the day of oocyte retrieval. We measured urinary concentrations of eight phthalate metabolites. Generalized linear models were used to analyze the associations of urinary phthalate metabolites with ovarian response, fertilization, early embryo development, and pregnancy outcomes. RESULTS: Among all the phthalate metabolites, mono-n-butyl phthalate (MBP) had the highest urinary concentration with a median level of 101.51 µg/g creatinine (Cr). MBP concentration was inversely associated with normal fertilization odds (overall P-trend < 0.01). There was a significant correlation of monoethyl phthalate (MEP) with decreased odds of normal fertilization in medium-concentration group compared to low-concentration group (overall P-trend = 0.02). No significant associations of metabolite concentrations with the odds of good-quality embryos on day 3 or blastocyst formation were found. Monomethyl phthalate (MMP) and MEP in medium-concentration group reduced 22.4% (95% CI: 0.64-0.94, overall P-trend = 0.04) and 21.9% (95% CI: 0.64-0.95, overall P-trend = 0.05) of the odds to gain good-quality blastocyst compared to low-concentration group. The eight phthalate metabolites were not correlated to clinical pregnancy rate, live birth rate, or early miscarriage rate. There was no significant association of di (2-ethylhexyl) phthalate (DEHP) metabolites observed with any clinical outcomes in the total population. After excluding male infertility, mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in medium-concentration group turned to be associated with a higher number of retrieved oocytes (overall P-trend = 0.04), whereas mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) in medium-concentration group was associated with a lower odds of normal fertilization compared to low-concentration group (overall P-trend = 0.02). CONCLUSIONS: Urinary MBP concentration was much higher compared to other phthalate metabolites in this cohort of Chinese IVF/ICSI women, and also higher than it was reported by studies in other countries. MBP showed adverse impacts on fertilization. MMP and MEP could affect blastocyst quality, but not embryo quality on day 3. DEHP metabolites didn't show consistent reproductive toxicities as demonstrated in previous studies.


Assuntos
Poluentes Ambientais/urina , Fertilização In Vitro , Exposição Materna/efeitos adversos , Ácidos Ftálicos/urina , Resultado da Gravidez/epidemiologia , Adulto , China/epidemiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Feminino , Fertilização/efeitos dos fármacos , Humanos , Ácidos Ftálicos/metabolismo , Ácidos Ftálicos/toxicidade , Gravidez , Estudos Prospectivos
9.
Ecotoxicol Environ Saf ; 187: 109848, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670182

RESUMO

Dimethyl terephthalate (DMT) is a primary ingredient widely used in the manufacture of polyesters and industrial plastics; its environmental fate is of concern due to its global use. Microorganisms play key roles in the dissipation of DMT from the environment; however, the enzymes responsible for the initial transformation of DMT and the possible altered toxicity due to this biotransformation have not been extensively studied. To reduce DMT toxicity, we identified the esterase gene dmtH involved in the initial transformation of DMT from the AOPP herbicide-transforming strain Sphingobium sp. C3. DmtH shows 24-41% identity with α/ß-hydrolases and belongs to subfamily V of bacterial esterases. The purified recombinant DmtH was capable of transforming DMT to mono-methyl terephthalate (MMT) and potentially transforming other p-phthalic acid esters, including diallyl terephthalate (DAT) and diethyl terephthalate (DET). Using C. elegans as an assay model, we observed the severe toxicity of DMT in inducing reactive oxygen species (ROS) production, decreasing locomotion behavior, reducing lifespan, altering molecular basis for oxidative stress, and inducing mitochondrial stress. In contrast, exposure to MMT did not cause obvious toxicity, induce oxidative stress, and activate mitochondrial stress in nematodes. Our study highlights the usefulness of Sphingobium sp. C3 and its esterase DmtH in transforming p-phthalic acid esters and reducing the toxicity of DMT to organisms.


Assuntos
Poluentes Ambientais/toxicidade , Esterases/genética , Genes Bacterianos , Ácidos Ftálicos/toxicidade , Sphingomonadaceae/metabolismo , Animais , Biodegradação Ambiental , Biotransformação , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Poluentes Ambientais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácidos Ftálicos/metabolismo , Plásticos/química , Sphingomonadaceae/enzimologia , Sphingomonadaceae/genética
10.
Environ Sci Pollut Res Int ; 27(5): 5503-5510, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853848

RESUMO

Diethyl phthalate (DEP) is a compound which is used in many industrial fields, especially in cosmetic sector and causes contamination in air, water, and soil due to its widespread usage. In this study, the potential toxic effects of DEP were investigated by using physiological, anatomical, biochemical, and cytogenetic parameters in Allium cepa. The micronucleus (MN) test specifically aimed to elucidate the aneugenic and clastogenic effects of DEP. Physiological effects were determined by germination percentage, root length, weight gain parameters, and cytogenetic effects were investigated by mitotic index (MI) and chromosomal abnormality (CA) test. Malondialdehyde (MDA) level, catalase (CAT), and superoxide dismutase (SOD) activities were investigated as oxidative damage indicators and structural changes were investigated with anatomical cross sections. For this purpose, Allium cepa bulbs were divided into four groups as control and application groups and the application groups were germinated with 1.0, 2.2, and 4.4 µM DEP for 72 h. As a result, it was determined that germination percentage, weight gain and root length decreased, CA frequency, MDA level, SOD, and CAT activities were increased in DEP-treated groups when compared with the control group. DEP has been found to induce CA in root tip cells such as fragment, chromosome bridge, c-mitosis, sticky chromosome, and unequal chromatin distribution. When MN formations induced by DEP application were examined, both large-scale and small-scale MNs were determined. MN formation in both sizes indicates that DEP has both clastogenic and aneugenic effects. And also, it was found that DEP application caused structural changes and especially anatomic damages such as necrosis in 4.4 µM DEP application. As a result, it was found that DEP caused various toxic effects depending on the dose and that A. cepa test material was a useful indicator in determining these effects.


Assuntos
Aneugênicos/toxicidade , Ácidos Ftálicos/toxicidade , Malondialdeído , Cebolas , Raízes de Plantas , Testes de Toxicidade
11.
Artigo em Inglês | MEDLINE | ID: mdl-31878152

RESUMO

A great deal of attention has been paid lately to release of phthalate esters (PAEs) from polyethylene terephthalate (PET) bottles into PET bottled drinking water due to their potential endocrine-disrupting effects. Three kinds of PAEs, including diethyl phthalate (DEP), dimethyl phthalate (DMP) and dibutyl phthalate (DBP), were detected in 10 popular brands of PET bottles in Beijing, ranging from 101.97 µg/kg to 709.87 µg/kg. Meanwhile, six kinds of PAEs, including DEP, DMP, DBP, n-butyl benzyl phthalate (BBP), di-n-octyl phthalate (DOP) and di(2-ethylhexyl) phthalate (DEHP), were detected in PET bottled water, ranging from 0.19 µg/L to 0.98 µg/L, under an outdoor storage condition, while their concentrations ranged from 0.18 µg/L to 0.71 µg/L under an indoor storage condition. Furthermore, the concentrations of PAEs in brand D and E bottles were slightly increased when the storage time was prolonged. In addition, the concentrations of PAEs in commercial water contained in brand B and H bottles and pure water contained in brand E and G bottles were also slightly increased with the increase of storage temperature. Interestingly, DBP mainly contributed to the increased PAEs levels in simulation water. These results suggest that a part of the PAEs in PET bottled water originated from plastic bottles, which was related to the storage time and temperature. However, the PAEs in PET bottled water only pose a negligible risk to consumers if they follow the recommendations, such as storage at a common place (24 °C), away from sun and in a short period of time.


Assuntos
Água Potável/análise , Disruptores Endócrinos/toxicidade , Ésteres/análise , Ésteres/toxicidade , Ácidos Ftálicos/toxicidade , Polietilenotereftalatos/análise , Polietilenotereftalatos/toxicidade , Pequim
12.
Environ Int ; 133(Pt B): 105254, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31675562

RESUMO

BACKGROUND: Urinary phthalate metabolites and psychosocial stress in pregnancy have each been associated with preterm birth (PTB), but no study has examined the joint impact of these two environmental exposures. We hypothesized that there would be stronger associations between phthalate exposure and PTB in mothers with higher stress in pregnancy compared to mothers with lower stress. METHODS: We addressed this question using data from The Infant Development and the Environment Study (TIDES), a prospective birth cohort conducted at four US sites (N = 783). We examined urinary phthalate metabolite concentrations measured in samples collected from up to three trimesters of pregnancy. Mothers reported their exposure to stressful life events (SLE) in each trimester in a questionnaire administered in the third trimester. PTB was defined as delivery before 37 weeks completed gestation (n = 71, 9.1%). We examined associations between urinary phthalate metabolite concentrations (individual time points and on average) and PTB using logistic regression models adjusted for maternal race, age, pre-pregnancy body mass index, education, specific gravity, and gestational age at sample collection. In addition, we created models stratified by whether or not mothers were exposed to any or no SLE in pregnancy. RESULTS: Summed di-2-ethylhexyl phthalate (ΣDEHP) metabolites measured in urine samples from the third trimester, but not the first trimester, were associated with an increased odds ratio (OR) of PTB (OR = 1.44, 95% confidence interval [CI] = 1.06, 1.95). In models stratified by SLE, associations between third trimester ΣDEHP concentrations and PTB were significant only for women experiencing one or more SLE during pregnancy (OR for ΣDEHP: 2.09, 95% CI: 1.29, 3.37) but not for women with no SLE during pregnancy (OR for ΣDEHP: 1.04, 95% CI: 0.66, 1.63) (p for interaction = 0.07). CONCLUSIONS: We observed an association between urinary ΣDEHP levels and PTB that was modified by whether a mother was exposed to one or more psychosocial stressors during pregnancy. Additional research to understand the joint impacts of chemical and non-chemical exposures, with an emphasis on timing of exposure, is needed in order to advance the state of the science on how the environment influences pregnancy.


Assuntos
Exposição Materna/efeitos adversos , Ácidos Ftálicos/toxicidade , Nascimento Prematuro/epidemiologia , Estresse Psicológico , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Ácidos Ftálicos/urina , Gravidez , Trimestres da Gravidez , Nascimento Prematuro/etiologia , Estudos Prospectivos , Fatores Socioeconômicos , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto Jovem
13.
Environ Pollut ; 255(Pt 1): 113193, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31521998

RESUMO

Phthalate esters (PAEs), as widely used plasticizers, have been concerned for their possible disruption of estrogen functions via binding to and activating the transcription of estrogen receptors (ERs). Nevertheless, the computational interpretation of the mechanism of ERs activities modulated by PAEs at the molecular level is still insufficient, which hinders the reliable screening of the ERs-active PAEs with high speed and high throughput. To bridge the gap, the in silico simulations considering the effects of coactivators were accomplished to explore the molecular mechanism of action for the purpose of predicting the estrogenic potencies of PAEs. The transcriptional activation functions of human ERα (hERα) modulated by PAEs is predicted via the simulations including binding interaction of PAEs and hERα, conformational changes of PAEs-hERα complexes and recruitment of coactivators. Molecular insight into the diverse estrogen mechanism of action among PAEs with regard to hERα agonists and selective estrogen receptor modulators (SERMs) is provided. Agonist-modulated conformational change of hERα leads to the optimal exposure of its Activation Function 2 (AF-2) surface which, in turn, facilitates the recruitment of coactivators, therefore promoting the transcriptional activation functions of hERα. Conversely, binding interaction of hERα with SERMs among PAEs leads to the conformational change with blocked AF-2 surface, thus preventing the recruitment of coactivators and consequently inhibiting the AF-2 activity. The two-hybrid recombinant yeast is experimentally used for verification. The established in silico evaluation methodology exhibits great promise to speed up the prediction of chemicals which work as hERα agonist or SERMs.


Assuntos
Poluentes Ambientais/toxicidade , Antagonistas de Estrogênios/química , Receptor alfa de Estrogênio/química , Estrogênios/química , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Estrona , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Ativação Transcricional/efeitos dos fármacos
14.
Environ Pollut ; 255(Pt 1): 113154, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546122

RESUMO

Diisononyl phthalate (DINP) is a high-molecular-weight phthalate, and has been recently introduced as di-(2-ethyl hexyl) phthalate (DEHP) substitute and commonly used in a large variety of plastic items. The fat tissue is an important target for DINP exposure, however, very little is understood about its toxicity and mechanism(s) in adipocyte cells. Therefore, the present work aimed to investigate the role of DINP in adipogenesis using 3T3-L1 preadipocytes. DINP exposure for 10 days extensively induced adipogenesis in 3T3-L1 preadipocytes to adipocytes as assessed by lipid accumulation and gene expression of adipogenic markers. The RT-qPCR results showed that DINP could upregulate the expression of peroxisome proliferator-activated receptor-gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα) and C/EBPß, while the expression of sterol regulatory element binding transcription factor 1 (SREBF1) and C/EBPδ was not affected. The DINP-induced adipogenesis could be inhibited by using the selective PPARγ antagonist GW9662. The RNA-seq analysis was used to study the systemic toxicities of DINP on preadipocytes. A total of 1181 differently expressed genes (DEGs) (640 genes were up-regulated, 541 genes were down-regulated) were detected in 3T3-L1 preadipocytes under 50 µM DINP. The GO enrichment showed the GO term of "fat cell differentiation" was the most significantly affected metabolic functions, and the KEGG pathway enrichment showed the PPAR pathway was the top affected pathway. The interactive pathway (iPath) analysis showed that the changed metabolic pathways were focus on the lipid metabolism.


Assuntos
Adipócitos/citologia , Adipogenia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Células 3T3-L1 , Tecido Adiposo/metabolismo , Anilidas/farmacologia , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/biossíntese , Proteína beta Intensificadora de Ligação a CCAAT/biossíntese , Proteínas Estimuladoras de Ligação a CCAAT/biossíntese , Linhagem Celular , Regulação para Baixo , Expressão Gênica/efeitos dos fármacos , Camundongos , PPAR gama/antagonistas & inibidores , PPAR gama/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Ativação Transcricional , Regulação para Cima
15.
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
16.
Artigo em Inglês | MEDLINE | ID: mdl-31394816

RESUMO

The contamination status and the potential carcinogenic and non-carcinogenic health risks from six phthalate esters (PAEs), nominated as priority pollutants by the United States Environmental Protection Agency (USEPA), were investigated in 40 typical greenhouses in three large-scale intensive greenhouse production areas in Jingmen city, Hubei province, central China. The total concentrations of PAEs in 40 soil samples and 80 vegetable samples ranged from 919 ± 134 to 7015 ± 475 µg kg-1 (dry weight, DW), and from 387 ± 63, to 11,683 ± 1313 µg kg-1 (DW), respectively. No carcinogenic risk was detected. The heat-map of the hazard quotient (HQ) values indicates the non-carcinogenic risks to children from di-n-butyl phthalate (DBP), at two sampling sites out of the 40, and from diethylhexyl phthalate (DEHP) (20 to young children and three to older children and adults) at 23 of the sites. The contamination risk from PAEs at Pengdun is of concern because only two of the 14 sampling sites selected there showed the non-carcinogenic risk to humans was unclear. The results of this study help to close a long-term knowledge gap resulting from a shortage of experimental data on PAE contamination in intensive greenhouse vegetable production in central China. The inclusion of DEHP in the Chinese list of priority pollutants is recommended, due to its increasing contamination and risk. This study provides valuable information for protected agricultural soil management and risk avoidance. It is a timely reminder to take PAE contamination and associated health risks into consideration, during the planning and introduction of intensively-managed greenhouse production systems.


Assuntos
Carcinógenos/toxicidade , Ésteres/toxicidade , Ácidos Ftálicos/toxicidade , Poluentes do Solo/toxicidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Agricultura , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Medição de Risco , Adulto Jovem
17.
Toxicol Lett ; 314: 53-62, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319113

RESUMO

Benzyl butyl phthalate (BBP) is a widely used plasticizer and has raised public health concerns. Here, we report the effects of BBP on the testis development during rat puberty. BBP (0, 10, 100 or 1000 mg/kg) was gavaged to 35-day-old male Sprague Dawley rats for 21 days. The serum testosterone levels, Leydig cell number, the expressions of Leydig and Sertoli cell genes and proteins were measured. The in vitro effects on steroidogenesis and gene expression in immature Leydig cells were observed. BBP significantly increased serum testosterone level at 10 mg/kg but lowered its level at 1000 mg/kg without affecting serum luteinizing hormone and follicle-stimulating hormone levels. BBP increased Leydig cell number at all doses but inhibited steroidogenic capacity per Leydig cell at 1000 mg/kg. BBP significantly increased the ratio of phosphos-AKT2 (pAKT2)/AKT2, and phosphos-ERK1/2 (pERK1/2)/ERK1/2 in the testis. Mono-benzyl phthalate (the metabolite of BBP) inhibited steroidogenesis but BBP did not affect androgen production in immature Leydig cells in vitro. In conclusion, BBP non-linearly regulates Leydig cell development by increasing Leydig cell number but inhibiting steroidogenesis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Desenvolvimento Sexual/efeitos dos fármacos , Testosterona/biossíntese , Fatores Etários , Animais , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Masculino , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testosterona/sangue
18.
Environ Pollut ; 253: 239-245, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319240

RESUMO

In the study, the effects of dimethyl phthalate (DMP) on the antioxidant defense capacity and immune functions of human erythrocytes were experimentally explored. DMP affected the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) and the contents of glutathione (GSH) and malondialdehyde (MDA) in erythrocytes, thus impairing the function of antioxidant defense system of erythrocytes. When DMP concentration increased from 0 to 28 µmol L-1, the SOD and GPX activities were increased firstly and then gradually decreased. When DMP concentration was below 20 µmol L-1, the relative activity of SOD was enhanced by DMP and the effect was known as hormesis. The relative activity of GPX was also increased when the concentration of DMP was below 12 µmol L-1. The CAT activity was more significantly inhibited by DMP than the activities of SOD and GPX, whereas the relative GSH content was increased by DMP. MDA levels were significantly changed after the exposure to DMP (0-24 µmol L-1). The experimental results of the activity of SOD and CAT, and the content of MDA also suggested that DMP could inhibit the immune functions of red blood cells (RBCs), which were further proved by the decrease of two indicators (RBC-C3b and RBC-IC) due to the destruction of C3b receptor with immune adherence function on erythrocyte membrane. The study provides a deep understanding of the toxicity of DMP on erythrocytes.


Assuntos
Ácidos Ftálicos/toxicidade , Testes de Toxicidade , Antioxidantes/farmacologia , Catalase/metabolismo , Eritrócitos/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Malondialdeído , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
19.
Toxicol Lett ; 314: 82-88, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306742

RESUMO

For decades, phthalates have been widely used as plasticizers in a large number of consumer products, leading to a complex exposure to humans via ingestion, inhalation or dermal uptake. Children may have a higher unintended dust intake per day compared to adults. Therefore, dust intake of children could pose a relevant exposure and subsequently a potential health risk. The aim of this study was to determine the relative bioavailability of certain phthalates, such as di(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and the non-phthalate plasticizer diisononyl 1,2-cyclohexanedicarboxylic acid (DINCH®, Hexamoll®), after ingestion of dust. Seven 5-week-old male piglets were fed five different dust samples collected from daycare centers. Overall, 0.43 g to 0.83 g of dust sieved to 63 µm were administered orally. The piglets' urine was collected over a period of 38 h. The excreted metabolites were quantified using an LC-MS/MS method. The mean uptake rates of the applied doses for DEHP, DINP, and DINCH® were 43% ± 11%, 47% ± 26%, and 9% ± 3.5%, respectively. The metabolites of DEHP and DINP showed maximum concentrations in urine after three to five hours, whereas the metabolites of DINCH®, reached maximum concentrations 24 h post-dose. The oral bioavailability of the investigated plasticizers was higher compared to the bioaccessibility reported from in vitro digestion tests. Furthermore, the bioavailability of DEHP did not vary substantially between the dust samples, whereas a dose-dependent saturation process for DINP was observed. In addition to other intake pathways, dust could be a source of plasticizers in children using the recent intake rates for dust ingestion.


Assuntos
Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/administração & dosagem , Poeira , Ácidos Ftálicos/administração & dosagem , Plastificantes/administração & dosagem , Administração Oral , Fatores Etários , Animais , Animais Recém-Nascidos , Disponibilidade Biológica , Cromatografia Líquida , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/toxicidade , Ácidos Cicloexanocarboxílicos/urina , Ácidos Dicarboxílicos/farmacocinética , Ácidos Dicarboxílicos/toxicidade , Ácidos Dicarboxílicos/urina , Masculino , Ácidos Ftálicos/farmacocinética , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/urina , Plastificantes/farmacocinética , Plastificantes/toxicidade , Medição de Risco , Sus scrofa , Espectrometria de Massas em Tandem , Toxicocinética , Urinálise
20.
Environ Int ; 130: 104580, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31351310

RESUMO

OBJECTIVE: We performed a systematic review of the epidemiology literature to identify the female reproductive and developmental effects associated with phthalate exposure. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: Six phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of female reproductive and developmental effects in humans, and outcomes were selected for full systematic review based on data availability. STUDY EVALUATION AND SYNTHESIS METHODS: For each outcome, studies were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. RESULTS: The primary outcomes reviewed here are (number of included/excluded studies in parentheses): pubertal development (5/13), time to pregnancy (3/4), preterm birth (8/12), and spontaneous abortion (5/0). Among these outcomes, preterm birth had moderate evidence of a positive association with phthalate exposure (specifically DEHP, DBP, and DEP). Exposure levels for BBP, DIBP, and DINP were generally lower than for the phthalates with an observed effect, which may partially explain the difference due to lower sensitivity. Other phthalate/outcome combinations were considered to have slight or indeterminate evidence of an association. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Overall, these results support that some phthalates may be associated with higher odds of preterm birth in humans, though there is some remaining inconsistency. More evidence is needed on the mechanism and relevant exposure window for this association. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.


Assuntos
Exposição Ambiental/análise , Ácidos Ftálicos/toxicidade , Nascimento Prematuro/induzido quimicamente , Puberdade/efeitos dos fármacos , Aborto Espontâneo/induzido quimicamente , Feminino , Humanos , Exposição Materna , Gravidez
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