RESUMEN
Aqueous film-forming foams (AFFFs), containing per- and polyfluoroalkyl substances (PFASs), are released into the environment during response to fire-related emergencies. Repeated historical applications of AFFF at military sites were a result of fire-fighter training exercises and equipment testing. Recent data on AFFF-impacted groundwater indicates that â¼25% of the PFASs remain unidentified. In an attempt to close the mass balance, a systematic evaluation of 3M and fluorotelomer-based AFFFs, commercial products, and AFFF-impacted groundwaters from 15 U.S. military bases was conducted to identify the remaining PFASs. Liquid chromatography quadrupole time-of-flight mass spectrometry was used for compound discovery. Nontarget analysis utilized Kendrick mass defect plots and a "nontarget" R script. Suspect screening compared masses with those of previously reported PFASs. Forty classes of novel anionic, zwitterionic, and cationic PFASs were discovered, and an additional 17 previously reported classes were observed for the first time in AFFF and/or AFFF-impacted groundwater. All 57 classes received an acronym and IUPAC-like name derived from collective author knowledge. Thirty-four of the 40 newly identified PFAS classes derive from electrochemical fluorination (ECF) processes, most of which have the same base structure. Of the newly discovered PFASs found only in AFFF-impacted groundwater, 11 of the 13 classes are ECF-derived, and the remaining two classes are fluorotelomer-derived, which suggests that both ECF- and fluorotelomer-based PFASs are persistent in the environment.
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Fluorocarburos , Contaminantes Químicos del Agua , Cromatografía Liquida , Agua Subterránea/química , AguaRESUMEN
Polybrominated diphenyl ether (PBDE) flame retardants are endocrine disruptors and suspected neurodevelopmental toxicants. While the direct mechanisms of neurodevelopmental toxicity have not been fully elucidated, it is conceivable that alterations in thyroid hormone levels in the developing brain may contribute to these effects. Cells within the brain locally convert thyroxine (T4) to the biologically active triiodothyronine (T3) through the action of the selenodeiodinase type 2 iodothyronine deiodinase (DIO2). Previous studies have demonstrated that PBDEs can alter hepatic deiodinase activity both in vitro and in vivo; however, the effects of PBDEs on the deiodinase isoforms expressed in the brain are not well understood. Here, we studied the effects of several individual PBDEs and hydroxylated metabolites (OH-BDEs) on DIO2 activity in astrocytes, a specialized glial cell responsible for production of more than 50% of the T3 required by the brain. Primary human astrocytes and H4 glioma cells were exposed to individual PBDEs or OH-BDEs at concentrations up to 5 µM. BDE-99 decreased DIO2 activity by 50% in primary astrocyte cells and by up to 80% in the H4 cells at doses of ≥500 nM. 3-OH-BDE-47, 6-OH-BDE-47, and 5'-OH-BDE-99 also decreased DIO2 activity in cultured H4 glioma cells by 45-80% at doses of approximately 1-5 µM. Multiple mechanisms appear to contribute to the decreased DIO2 activity, including weakened expression of DIO2 mRNA, competitive inhibition of DIO2, and enhanced post-translational degradation of DIO2. We conclude that decreases in DIO2 activity caused by exposure to PBDEs may play a role in the neurodevelopmental deficits caused by these toxicants.
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Éteres Difenilos Halogenados/farmacología , Yoduro Peroxidasa/antagonistas & inhibidores , Yoduro Peroxidasa/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/enzimología , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Éteres Difenilos Halogenados/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas , Yodotironina Deyodinasa Tipo IIRESUMEN
Thyroid hormones are critical regulators of normal development and physiological functioning in all vertebrates. Radioimmunoassay (RIA) approaches have been the method of choice for measuring circulating levels of thyroid hormones in vertebrates. While sensitive, RIA-based approaches only allow for a single analyte measurement per assay, can lack concordance across platforms and laboratories, and can be prone to analytical interferences especially when used with fish plasma. Ongoing advances in liquid chromatography tandem mass spectrometry (LC/MS/MS) have led to substantial decreases in detection limits for thyroid hormones and other biomolecules in complex matrices, including human plasma. Despite these advances, current analytical approaches do not allow for the measurement of native thyroid hormone in teleost fish plasma by mass spectrometry and continue to rely on immunoassay. In this study, we developed a new method that allows for the rapid extraction and simultaneous measurement of total T4 (TT4) and total T3 (TT3) in low volumes (50 µL) of fish plasma by LC/MS/MS. Methods were optimized initially in plasma from rainbow trout (Oncorhynchus mykiss) and applied to plasma from other teleost fishes, including fathead minnows (Pimephales promelas), mummichogs (Fundulus heteroclitus), sockeye salmon (Oncorhynchus nerka), and coho salmon (Oncorhynchus kisutch). Validation of method performance with T4- and T3-spiked rainbow trout plasma at 2 and 4 ng/mL produced mean recoveries ranging from 82 to 95 % and 97 to 105 %, respectively. Recovery of (13)C12-T4 internal standard in plasma extractions was: 99 ± 1.8 % in rainbow trout, 85 ± 11 % in fathead minnow, 73 ± 5.0 % in mummichog, 73 ± 1.7 % in sockeye salmon, and 80 ± 8.4 % in coho salmon. While absolute levels of thyroid hormones measured in identical plasma samples by LC/MS/MS and RIA varied depending on the assay used, T4/T3 ratios were generally consistent across both techniques. Less variability was measured among samples subjected to LC/MS/MS suggesting a more precise estimate of thyroid hormone homeostasis in the species targeted. Overall, a sensitive and reproducible method was established that takes advantage of LC/MS/MS techniques to rapidly measure TT4 and TT3 with negligible interferences in low volumes of plasma across a variety of teleost fishes.
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Análisis Químico de la Sangre/métodos , Cromatografía Liquida , Peces , Espectrometría de Masa por Ionización de Electrospray , Hormonas Tiroideas/sangre , Animales , Límite de Detección , Estructura Molecular , Factores de Tiempo , TruchaRESUMEN
Gymnastics training facilities contain large volumes of polyurethane foam, a material that often contains additive flame retardants such as PentaBDE. While investigations of human exposure to flame retardants have focused on the general population, potentially higher than background exposures may occur in gymnasts and certain occupational groups. Our objectives were to compare PentaBDE body burden among gymnasts to the general United States population and characterize flame retardants levels in gym equipment, air, and dust. We recruited 11 collegiate female gymnasts (ages 18-22) from one gym in the eastern United States. The geometric mean (GM) concentration of BDE-153 in gymnast sera (32.5 ng/g lipid) was 4-6.5 times higher than in the general United States population groups. Median concentrations of PentaBDE, TBB, and TBPH in paired handwipe samples were 2-3 times higher after practice compared to before, indicating the gymnasts contacted these flame retardants during practice. GM concentrations of PentaBDE, TBB, and TBPH were 1-3 orders of magnitude higher in gym air and dust than in residences. Our findings suggest that these collegiate gymnasts experienced higher exposures to PentaBDE flame retardants compared to the general United States population and that gymnasts may also have increased exposure to other additive flame retardants used in polyurethane foam such as TBB and TBPH.
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Exposición a Riesgos Ambientales/análisis , Monitoreo del Ambiente , Retardadores de Llama/análisis , Gimnasia , Universidades , Adolescente , Aire/análisis , Polvo/análisis , Contaminantes Ambientales/sangre , Femenino , Éteres Difenilos Halogenados/sangre , Humanos , Poliuretanos/química , Espectrometría por Rayos X , Estados Unidos , Adulto JovenRESUMEN
Firemaster® 550 (FM 550), a fire-retardant mixture used in foam-based products, was recently identified as a common contaminant in household dust. The chemical structures of its principle components suggest they have endocrine disrupting activity, but nothing is known about their physiological effects at environmentally relevant exposure levels. The goal of this exploratory study was to evaluate accumulation, metabolism and endocrine disrupting effects of FM 550 in rats exposed to 100 or 1000 µg/day across gestation and lactation. FM 550 components accumulated in tissues of exposed dams and offspring and induced phenotypic hallmarks associated with metabolic syndrome in the offspring. Effects included increased serum thyroxine levels and reduced hepatic carboxylesterease activity in dams, and advanced female puberty, weight gain, male cardiac hypertrophy, and altered exploratory behaviors in offspring. Results of this study are the first to implicate FM 550 as an endocrine disruptor and an obesogen at environmentally relevant levels.
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Sistema Endocrino/metabolismo , Retardadores de Llama/efectos adversos , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/sangre , Tiroxina/sangre , Animales , Cardiomegalia/sangre , Cardiomegalia/inducido químicamente , Cardiomegalia/patología , Sistema Endocrino/patología , Sistema Endocrino/fisiología , Femenino , Masculino , Obesidad/sangre , Obesidad/inducido químicamente , Obesidad/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas WistarRESUMEN
Due to the phaseout of polybrominated diphenyl ether (PBDE) flame retardants, new chemicals, such as 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) and bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate (TBPH), have been used as replacements in some commercial flame retardant mixtures. Both chemicals have been detected in indoor dust at concentrations approaching the concentrations of PBDEs; however, little is known about their fate, metabolism, or toxicity. The goal of this study was to investigate the potential metabolism of these two brominated flame retardants in human and rat tissues by conducting in vitro experiments with liver and intestinal subcellular fractions. In all the experiments, TBB was consistently metabolized to 2,3,4,5-tetrabromobenzoic acid (TBBA) via cleavage of the 2-ethylhexyl chain without requiring any added cofactors. TBBA was also formed in purified porcine carboxylesterase but at a much faster rate of 6.29 ± 0.58 nmol min(-1) mg protein(-1). The estimated K(m) and V(max) values for TBB metabolism in human microsomes were 11.1 ± 3.9 µM and 0.644 ± 0.144 nmol min(-1) mg protein(-1), respectively. A similar K(m) of 9.3 ± 2.2 µM was calculated for porcine carboxylesterase, indicating similar enzyme specificity. While the rapid formation of TBBA may reduce the bioaccumulation potential of TBB in mammals and may be useful as a biomarker of TBB exposure, the toxicity of this brominated benzoic acid is unknown and may be a concern based on its structural similarity to other toxic pollutants. In contrast to TBB, no metabolites of TBPH were detected in human or rat subcellular fractions. However, a metabolic product of TBPH, mono(2-ethylhexyl) tetrabromophthalate (TBMEHP), was formed in purified porcine carboxylesterase at an approximate rate of 1.08 pmol min(-1) mg protein(-1). No phase II metabolites of TBBA or TBMEHP were observed. More research is needed to understand the in vivo toxicokinetics and health effects of these compounds given their current ubiquitous presence in most US households and the resulting probability of chronic exposure, particularly to young children.
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Benzoatos/metabolismo , Retardadores de Llama/metabolismo , Éteres Difenilos Halogenados/metabolismo , Ácidos Ftálicos/metabolismo , Contaminación del Aire/análisis , Animales , Benzoatos/química , Carboxilesterasa/metabolismo , Cromatografía Líquida de Alta Presión , Monitoreo del Ambiente , Retardadores de Llama/toxicidad , Cromatografía de Gases y Espectrometría de Masas , Éteres Difenilos Halogenados/toxicidad , Humanos , Cinética , Hígado/efectos de los fármacos , Hígado/metabolismo , Microsomas Hepáticos/metabolismo , Ácidos Ftálicos/química , Ratas , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP), and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.
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Retardadores de Llama/toxicidad , Compuestos Organofosforados/toxicidad , Células PC12/efectos de los fármacos , Animales , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismo , ADN/análisis , Proteínas del Tejido Nervioso/análisis , Organofosfatos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Células PC12/química , Fosfinas/toxicidad , Porfirinas/toxicidad , Ratas , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Previous studies have suggested that there may be species-specific differences in the metabolism of polybrominated diphenyl ethers (PBDEs) among different fish species. In this study, we investigated the in vitro hepatic metabolism of eleven individual PBDE congeners (tri- through decaBDEs) in three different fish species: rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), and Chinook salmon (O. tschwatcha). In addition, we evaluated the influence of PBDE structural characteristics (i.e., bromine substitution patterns) on metabolism. Six of the eleven congeners we evaluated, BDEs 99, 153, 183, 203, 208, and 209, were metabolically debrominated to lower brominated congeners. All of the congeners that were metabolized contained at least one meta-substituted bromine. Metabolites were not detected for congeners without one meta-substituted bromine (e.g., BDEs 28, 47, and 100). Metabolite formation rates were generally 10 to 100 times faster in carp than in trout and salmon. BDEs 47, 49, 101, 154, and 183 were the major metabolites observed in all three species with the exception of BDE 47, which was only detected in carp. Carp demonstrated a preference toward meta-debromination, while trout and salmon debrominated meta- and para-bromine atoms to an equal extent. We compared glutathione-S-transferase (GST) and deiodinase (DI) activity among all three species as these enzyme systems have been hypothesized to play a role in PBDE debromination in teleosts. Carp exhibited a preference for meta-deiodination of the thyroid hormone thyroxine, which was consistent with the preference for meta-debromination of PBDEs observed in carp.
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Carpas/metabolismo , Retardadores de Llama/metabolismo , Éteres Difenilos Halogenados/metabolismo , Salmón/metabolismo , Contaminantes Químicos del Agua/metabolismo , Animales , Biotransformación , Glutatión Transferasa/metabolismo , Halogenación , Yoduro Peroxidasa/metabolismo , Hígado/metabolismo , Oncorhynchus mykiss/metabolismo , Relación Estructura-ActividadRESUMEN
In nationwide mammography screening, thousands of mammography examinations must be processed. Each consists of two standard views of each breast, and each mammogram must be visually examined by an experienced radiologist to assess it for any anomalies. The ability to detect an anomaly in mammographic texture is important to successful outcomes in mammography screening and, in this study, a large number of mammograms were digitized with a highly accurate scanner; and textural features were derived from the mammograms as input data to a SONNET selforganizing neural network. The paper discusses how SONNET was used to produce a taxonomic organization of the mammography archive in an unsupervised manner. This process is subject to certain choices of SONNET parameters, in these numerical experiments using the craniocaudal view, and typically produced O(10), for example, 39 mammogram classes, by analysis of features from O(10(3)) mammogram images. The mammogram taxonomy captured typical subtleties to discriminate mammograms, and it is submitted that this may be exploited to aid the detection of mammographic anomalies, for example, by acting as a preprocessing stage to simplify the task for a computational detection scheme, or by ordering mammography examinations by mammogram taxonomic class prior to screening in order to encourage more successful visual examination during screening. The resulting taxonomy may help train screening radiologists and conceivably help to settle legal cases concerning a mammography screening examination because the taxonomy can reveal the frequency of mammographic patterns in a population.
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Algoritmos , Neoplasias de la Mama/diagnóstico por imagen , Mamografía/métodos , Redes Neurales de la Computación , Reconocimiento de Normas Patrones Automatizadas/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Femenino , Humanos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
This review summarizes the endocrine and neurodevelopmental effects of two current-use additive flame retardants (FRs), tris (1,3-dichloro-isopropyl) phosphate (TDCPP) and Firemaster(®) 550 (FM 550), and the recently phased-out polybrominated diphenyl ethers (PBDEs), all of which were historically or are currently used in polyurethane foam applications. Use of these chemicals in consumer products has led to widespread exposure in indoor environments. PBDEs and their hydroxylated metabolites appear to primarily target the thyroid system, likely due to their structural similarity to endogenous thyroid hormones. In contrast, much less is known about the toxicity of TDCPP and FM 550. However, recent in vitro and in vivo studies suggest that both should be considered endocrine disruptors as studies have linked TDCPP exposure with changes in circulating hormone levels, and FM 550 exposure with changes in adipogenic and osteogenic pathways.
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Disruptores Endocrinos , Exposición a Riesgos Ambientales , Retardadores de Llama , Animales , Disruptores Endocrinos/toxicidad , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/toxicidad , Humanos , Organofosfatos/toxicidad , Compuestos Organofosforados/toxicidadRESUMEN
Firemaster(®) BZ-54 is a flame retardant additive and consists of a brominated benzoate (2-ethylhexyl 2,3,4,5-tetrabromobenzoate; TBB) and a brominated phthalate (bis (2-ethylhexyl) 2,3,4,5-tetrabromophthalate; TBPH). Previous research has shown that fathead minnows exposed in vivo to Firemaster(®) BZ-54 accumulate TBB and TBPH. This study examined the in vitro biotransformation potential of TBB and TBPH in hepatic subcellular fractions (i.e., S9, microsomes and cytosol) in the fathead minnow, common carp, mouse and snapping turtle. Metabolism was evaluated by measuring the loss of the parent TBB or TBPH and identifying potential metabolites in the sample extracts. Metabolic loss of TBPH was measured for all species, while TBB loss was observed for all species except for the snapping turtle. Several metabolites were observed in all of the incubations except for snapping turtle. Metabolites observed appeared to be derived from TBB, given their structures and lack of appearance in the snapping turtle incubations. One of these metabolites, 2,3,4,5-tetrabromomethylbenzoate has been identified for the first time in a biological system. When metabolized, TBB and TBPH loss was found in each subcellular fraction suggesting that the enzyme(s) involved are present in both soluble and membrane-bound forms. It can be concluded that a broad range of species are capable of metabolizing TBB and TBPH to various metabolites and further research should be carried out to ascertain the specific products formed from metabolism of TBB and TBPH.
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Benzoatos/metabolismo , Retardadores de Llama/metabolismo , Hígado/metabolismo , Ácidos Ftálicos/metabolismo , Animales , Carpas/metabolismo , Cyprinidae/metabolismo , Ratones , Especificidad de la Especie , Tortugas/metabolismoRESUMEN
BACKGROUND: Bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a replacement for polybrominated diphenyl ethers (PBDEs) in commercial flame retardant mixtures such as Firemaster 550. It is also used in a commercial mixture called DP 45. Mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) is a potentially toxic metabolite. OBJECTIVES: We used in vitro and rodent in vivo models to evaluate human exposure and the potential metabolism and toxicity of TBPH. METHODS: Dust collected from homes, offices, and cars was measured for TBPH by gas chromatography followed by mass spectrometry. Pregnant rats were gavaged with TBMEHP (200 or 500 mg/kg) or corn oil on gestational days 18 and 19, and dams and fetuses were evaluated histologically for toxicity. We also assessed TBMEHP for deiodinase inhibition using rat liver microsomes and for peroxisome proliferator-activated receptor (PPAR) α and γ activation using murine FAO cells and NIH 3T3 L1 cells. RESULTS: TBPH concentrations in dust from office buildings (median, 410 ng/g) were higher than in main living areas in homes (median, 150 ng/g). TBPH was metabolized by purified porcine esterases to TBMEHP. Two days of TBMEHP exposure in the rat produced maternal hypothyroidism with markedly decreased serum T3 (3,3´,5-triiodo-l-thyronine), maternal hepatotoxicity, and increased multinucleated germ cells (MNGs) in fetal testes without antiandrogenic effects. In vitro, TBMEHP inhibited deiodinase activity, induced adipocyte differentiation in NIH 3T3 L1 cells, and activated PPARα- and PPARγ-mediated gene transcription in NIH 3T3 L1 cells and FAO cells, respectively. CONCLUSIONS: TBPH a) is present in dust from indoor environments (implying human exposure) and b) can be metabolized by porcine esterases to TBMEHP, which c) elicited maternal thyrotoxic and hepatotoxic effects and d) induced MNGs in the fetal testes in a rat model. In mouse NIH 3T3 L1 preadipocyte cells, TBMEHP inhibited rat hepatic microsome deiodinase activity and was an agonist for PPARs in murine FAO and NIH 3T3 L1 cells.