RESUMEN
As alternatives to traditional per- and polyfluoroalkyl substances, perfluoroalkyl phosphonic acids (PFPiAs) are frequently detected in aquatic environments, but the neurotoxic effects and underlying mechanisms remain unclear. In this study, male zebrafish were exposed to 6:6 PFPiA (1 and 10 nM) for 28 days, which exhibited anxiety-like symptoms. Gut microbiome results indicated that 6:6 PFPiA significantly increased the abundance of Gram-negative bacteria, leading to enhanced levels of lipopolysaccharide (LPS) and inflammation in the gut. The LPS was delivered to the brain through the gut-brain axis (GBA), damaged the blood-brain barrier (BBB), stimulated neuroinflammation, and caused apoptosis as well as neural injury in the brain. This mechanism was verified by the fact that antibiotics reduced the LPS levels in the gut and brain, accompanied by reduced inflammatory responses and anxiety-like behavior. The BBB damage also resulted in the enhanced accumulation of 6:6 PFPiA in the brain, where it might bind strongly with and activate aryl hydrocarbon receptor (AhR) to induce brain inflammation directly. Additionally, as the fish received treatment with an inhibitor of AhR, the inflammation response and anxiety-like behavior decreased distinctly. This study sheds light on the new mechanisms of neurotoxicity-induced 6:6 PFPiA due to the interruption on GBA.
Asunto(s)
Eje Cerebro-Intestino , Microbioma Gastrointestinal , Ácidos Fosforosos , Animales , Masculino , Inflamación , Lipopolisacáridos , Pez Cebra , Ácidos Fosforosos/toxicidadRESUMEN
Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Adenina/análogos & derivados , Fármacos Anti-VIH/toxicidad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Ácidos Fosforosos/toxicidad , Polimorfismo de Nucleótido Simple/genética , Lesión Renal Aguda/genética , Adenina/sangre , Adenina/toxicidad , Adulto , Fármacos Anti-VIH/sangre , Femenino , Marcadores Genéticos/genética , Técnicas de Genotipaje , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/genética , Ácidos Fosforosos/sangre , Estudios RetrospectivosRESUMEN
Upon surface functionalization and stabilization of ß-NaYF4:Yb/Er upconversion nanoparticles (UCNPs) with phosphoryl pillar[5]arenes (PP5) via a facile ligand exchange method, we constructed a new hybrid material (PP5-UCNPs) with good water dispersibility especially in a physiological environment and superior capability of controlled cargo release and cell imaging.
Asunto(s)
Portadores de Fármacos/química , Fluoruros/química , Nanopartículas/química , Ácidos Fosforosos/química , Compuestos de Amonio Cuaternario/química , Itrio/química , Antiinflamatorios no Esteroideos/química , Calixarenos , Línea Celular , Portadores de Fármacos/efectos de la radiación , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Erbio/química , Fluoruros/efectos de la radiación , Fluoruros/toxicidad , Humanos , Concentración de Iones de Hidrógeno , Rayos Infrarrojos , Macrófagos/efectos de los fármacos , Mesalamina/química , Microscopía Fluorescente/métodos , Nanopartículas/efectos de la radiación , Nanopartículas/toxicidad , Tamaño de la Partícula , Ácidos Fosforosos/efectos de la radiación , Ácidos Fosforosos/toxicidad , Compuestos de Amonio Cuaternario/efectos de la radiación , Compuestos de Amonio Cuaternario/toxicidad , Solubilidad , Iterbio/química , Itrio/efectos de la radiación , Itrio/toxicidadRESUMEN
Aluminum methylcyclohexylphosphinate (AMHP), calcium methylcyclohexylphosphinate (CMHP), aluminum diethylphosphinate (ADEP), and aluminum methylethylphosphinate (AMEP) are organic dialkyl phosphinates (DPs) and emerging phosphorus-based flame retardants. The broad-spectrum DPs flame retardants occupy high-end industrial markets, but their ecologic risk has been reported rarely. By exposing male BALB/c mice to DPs and dialkyl phosphinic acids, we studied the toxic effects of these chemicals, and measured AMHP and methylcyclohexylphosphinic acid (MHPA) in blood and feces. We found that DPs and their main hydrolysates had mild toxicity in BALB/c mice. Exposure to 10 and 50 mg/kg/d of AMEP and ADEP caused mild hepatotoxicity in mice. Toxicity of CMHP was in the liver and kidneys. Toxicity of AMHP and its hydrolysate MHPA was low and affected the liver. These data suggest that AMHP has lower toxicity than the other DPs that we tested. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1578-1586, 2017.
Asunto(s)
Aluminio/toxicidad , Retardadores de Llama/toxicidad , Ácidos Fosforosos/toxicidad , Aluminio/química , Animales , Exposición a Riesgos Ambientales , Hidrólisis , Masculino , Ratones , Ratones Endogámicos BALB C , Ácidos Fosforosos/química , Riesgo , Pruebas de ToxicidadRESUMEN
Perfluoroalkyl phosphonic and phosphinic acids (PFPAs and PFPiAs) are sub-groups of per- and polyfluoroalkyl substances (PFASs) that have been commercialized since the 1970s, particularly as defoamers in pesticide formulations and wetting agents in consumer products. Recently, C4/C4 PFPiA and its derivatives have been presented as alternatives to long-chain PFASs in certain applications. In this study, we systematically assess the publicly available information on the hazardous properties, occurrence, and exposure routes of PFPAs and PFPiAs, and make comparisons to the corresponding properties of their better-known carboxylic and sulfonic acid analogs (i.e. PFCAs and PFSAs). This comparative assessment indicates that [i] PFPAs likely have high persistence and long-range transport potential; [ii] PFPiAs may transform to PFPAs (and possibly PFCAs) in the environment and biota; [iii] certain PFPAs and PFPiAs can only be slowly eliminated from rainbow trout and rats, similarly to long-chain PFCAs and PFSAs; [iv] PFPAs and PFPiAs have modes-of-action that are both similar to, and different from, those of PFCAs and PFSAs; and [v] the measured levels of PFPAs/PFPiAs in the global environment and biota appear to be low in comparison to PFCAs and PFSAs, suggesting, for the time being, low risks from PFPAs and PFPiAs alone. Although risks from individual PFPAs/PFPiAs are currently low, their ongoing production and use and high persistence will lead to increasing exposure and risks over time. Furthermore, simultaneous exposure to PFPAs, PFPiAs and other PFASs may result in additive effects necessitating cumulative risk assessments. To facilitate effective future research, we highlight possible strategies to overcome sampling and analytical challenges.
Asunto(s)
Monitoreo del Ambiente/métodos , Contaminantes Ambientales/análisis , Fluorocarburos/análisis , Sustancias Peligrosas/análisis , Ácidos Fosfínicos/análisis , Ácidos Fosforosos/análisis , Animales , Ecotoxicología , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Fluorocarburos/farmacocinética , Fluorocarburos/toxicidad , Sustancias Peligrosas/farmacocinética , Sustancias Peligrosas/toxicidad , Humanos , Ácidos Fosfínicos/farmacocinética , Ácidos Fosfínicos/toxicidad , Ácidos Fosforosos/farmacocinética , Ácidos Fosforosos/toxicidad , Proyectos de Investigación , Medición de RiesgoRESUMEN
A series of novel α-amino phosphonate derivatives containing a uracil moiety 3a-3l were designed and synthesized by a Lewis acid (magnesium perchlorate) catalyzed the Kabachnik-Fields reaction. The bioassays {in vitro, in vivo [Glass House 1 (GH1) and Glass House 2 (GH2)]} showed that most of compounds 3 exhibited excellent and selective herbicidal activities; for example, in GH1 test, compounds 3b, 3d, 3f, 3h and 3j showed excellent and wide spectrum herbicidal activities at the dose of 1000 g/ha, and compounds 3b and 3j exhibited 100% inhibition activities against the four plants in both post- and pre-emergence treatments. Moreover, most of compounds 3 showed higher inhibition against Amaranthus retroflexus and Digitaria sanguinalis than Glyphosate did in pre-emergence treatment. In GH2 test, the four compounds (3b, 3d, 3h and 3j) exhibited 100% inhibition against Solanum nigrum, Amaranthus retroflexus and Ipomoea hederacea in post-emergence treatment and displayed 100% inhibition against Solanum nigrum, Amaranthus retroflexus in pre-emergence treatment at the rate of 250 g/ha, and compound 3b showed the best and broad spectrum herbicidal activities against the six test plants. However, the four compounds displayed weaker herbicidal activities against Lolium perenne and Echinochloa crus-galli than the other four plants at the rate of 250 g/ha in both pre- and post-emergence treatments. So, compounds 3 can be used as a lead compound for further structure optimization for developing potential selective herbicidal agent. Their preliminary structure-activity relationships were also investigated.
Asunto(s)
Herbicidas/síntesis química , Ácidos Fosforosos/química , Uracilo/química , Amaranthus/efectos de los fármacos , Digitaria/efectos de los fármacos , Glicina/análogos & derivados , Glicina/toxicidad , Herbicidas/química , Herbicidas/toxicidad , Ipomoea/efectos de los fármacos , Ácidos Fosforosos/síntesis química , Ácidos Fosforosos/toxicidad , Solanum nigrum/efectos de los fármacos , Relación Estructura-Actividad , GlifosatoRESUMEN
Perfluoroalkyl phosphonic acids (PFPAs), a new class of perfluoroalkyl substances used primarily in the industrial sector as surfactants, were recently detected in surface water and wastewater treatment plant effluents. Toxicological effects of PFPAs have as yet not been investigated in aquatic organisms. The objective of the present study was to evaluate the effects of perfluorooctylphosphonic acid (C8-PFPA) and perfluorodecylphosphonic acid (C10-PFPA) exposure (31-250µg/L) on Chlamydomonas reinhardtii using genomic (qRT-PCR), biochemical (reactive oxygen species production (ROS) and lipid peroxidation), and physiological (cellular viability) indicators. After 72h of exposure, no differences were observed in cellular viability for any of the two perfluorochemicals. However, increase in ROS concentrations (36% and 25.6% at 125 and 250µg/L, respectively) and lipid peroxidation (35.5% and 35.7% at 125 and 250µg/L, respectively) was observed following exposure to C10-PFPA. C8-PFPA exposure did not impact ROS production and lipid peroxidation in algae. To get insights into the molecular response and modes of action of PFPA toxicity, qRT-PCR-based assays were performed to analyze the transcription of genes related to antioxidant responses including superoxide dismutase (SOD-1), glutathione peroxidase (GPX), catalase (CAT), glutathione S-transferase (GST), and ascorbate peroxidase (APX I). Genomic analyses revealed that the transcription of CAT and APX I was up-regulated for all the C10-PFPA concentrations. In addition, PFPAs were quantified in St. Lawrence River surface water samples and detected at concentrations ranging from 250 to 850pg/L for C8-PFPA and 380 to 650pg/L for C10-PFPA. This study supports the prevalence of PFPAs in the aquatic environment and suggests potential impacts of PFPA exposure on the antioxidant defensive system in C. reinhardtii.
Asunto(s)
Chlamydomonas reinhardtii/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Ácidos Fosforosos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Chlamydomonas reinhardtii/genética , Activación Enzimática/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Oxidorreductasas/metabolismo , Quebec , Especies Reactivas de Oxígeno/metabolismo , RíosRESUMEN
The aim of this work was to synthesize selected furaldimines and their aminophosphonic derivatives and evaluation the phytotoxicity of new obtained products according to OECD 208 Guideline. Four Schiff bases, N-furfurylidene-p-anisidine (1a), N-furfurylidene-p-toluidine (1b), N-furfurylidene-benzhydrylamine (1c), and N-(2-nitrofurfurylidene)-p-toluidine (1d) were synthesized and three new furan-derived N-substituted aminomethylphosphonic acids, namely: 2-furyl N-(p-methoxyphenyl)-aminomethylphosphonic acid (2a), 2-furyl N-(p-methylphenyl)-aminomethylphosphonic acid (2b) and 2-furyl N-(diphenylmethyl)-aminomethylphosphonic acid (2c) were synthesized by the addition of in situ generated bis-(trimethylsilyl) phosphite to azomethine bond of corresponding Schiff bases 1a-c. Three Schiff bases 1a-b and 1d as well as all three aminophosphonic acids 2a-c were analyzed in regard with their phytotoxicity toward two plants, radish (Raphanus sativus) and oat (Avena sativa). It has been found that tested N-furfurylidene-p-anisidine (1a), N-(2-nitrofurfurylidene)-p-toluidine (1d) and aminophosphonic acids 2a-c are toxic for selected plants. N-furfurylidene-p-toluidine (1b) did not show any ecotoxicological impact in used plant growth test.
Asunto(s)
Avena/efectos de los fármacos , Furanos/química , Furanos/toxicidad , Ácidos Fosforosos/toxicidad , Raphanus/efectos de los fármacos , Avena/crecimiento & desarrollo , Estructura Molecular , Ácidos Fosforosos/química , Raphanus/crecimiento & desarrolloRESUMEN
The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC(50) values of 0.4±0.2 µM (3f) and 0.2±0.005 µM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.
Asunto(s)
Fármacos Anti-VIH/química , VIH-1/efectos de los fármacos , Nucleósidos/química , Ácidos Fosforosos/química , Quinolonas/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/toxicidad , Humanos , Ácidos Fosforosos/síntesis química , Ácidos Fosforosos/toxicidad , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
These inorganic polyphosphate salts all function as chelating agents in cosmetic formulations. In addition, Sodium Metaphosphate functions as an oral care agent, Sodium Trimetaphosphate as a buffering agent, and Sodium Hexametaphosphate as a corrosion inhibitor. Only Sodium Hexametaphosphate is currently reported to be used. Although the typical concentrations historically have been less than 1%, higher concentrations have been used in products such as bath oils, which are diluted during normal use. Sodium Metaphosphate is the general term for any polyphosphate salt with four or more phosphate units. The four-phosphate unit version is cyclic, others are straight chains. The hexametaphosphate is the specific six-chain length form. The trimetaphosphate structure is cyclic. Rats fed 10% Sodium Trimetaphosphate for a month exhibited transient tubular necrosis; rats given 10% Sodium Metaphosphate had retarded growth and those fed 10% Sodium Hexametaphosphate had pale and swollen kidneys. In chronic studies using animals, growth inhibition, increased kidney weights (with calcium deposition and desquamation), bone decalcification, parathyroid hypertrophy and hyperplasia, inorganic phosphaturia, hepatic focal necrosis, and muscle fiber size alterations. Sodium Hexametaphosphate was a severe skin irritant in rabbits, whereas a 0.2% solution was only mildly irritating. A similar pattern was seen with ocular toxicity. These ingredients were not genotoxic in bacterial systems nor were they carcinogenic in rats. No reproductive or developmental toxicity was seen in studies using rats exposed to Sodium Hexametaphosphate or Sodium Trimetaphosphate. In clinical testing, irritation is seen as a function of concentration; concentrations as high as 1% produced no irritation in contact allergy patients. Because of the corrosive nature of Sodium Hexametaphosphate, it was concluded that these ingredients could be used safely if each formulation was prepared to avoid skin irritation; for example, low concentration in a leave-on product or dilution of a higher concentration as part of product usage.
Asunto(s)
Cosméticos/efectos adversos , Fosfatos/efectos adversos , Ácidos Fosforosos/efectos adversos , Polifosfatos/efectos adversos , Animales , Pruebas de Carcinogenicidad , Cosméticos/química , Cosméticos/toxicidad , Oftalmopatías/inducido químicamente , Humanos , Pruebas de Mutagenicidad , Fosfatos/química , Fosfatos/toxicidad , Ácidos Fosforosos/química , Ácidos Fosforosos/toxicidad , Polifosfatos/química , Polifosfatos/toxicidad , Enfermedades de la Piel/inducido químicamente , Teratógenos/química , Teratógenos/toxicidad , Pruebas de Toxicidad AgudaRESUMEN
As part of a comprehensive effort to evaluate the toxicological potential of calcium sodium metaphosphate fiber (Phosphate Fiber), the in vitro cytotoxicity of the fiber in cultured cells was studied. Two pulmonary-derived cell systems (rat alveolar macrophages, RAM; rat lung epithelial cells, LEC) and an established cell line (Chinese hamster ovary, CHO) were used. Release of lactate dehydrogenase (LDH) was used as an endpoint for cytotoxicity for all three cell types. In addition, inhibition of colony formation was used for CHO cells. The cytotoxicity of Phosphate Fiber was compared to a variety of mineral dusts and fibers including chrysotile asbestos, crocidolite asbestos, two glass fibers, calcium sulfate fiber, titanium dioxide, as well as the nonfibrous raw material, calcium sodium metaphosphate glass. Results with all three cell culture systems demonstrated that the Phosphate Fiber was less cytotoxic than the two asbestos fibers, similar in cytotoxicity to the glass fibers, and more cytotoxic than the calcium sulfate fiber and titanium dioxide. To further investigate the cytotoxicity of the Phosphate Fiber, it was fractionated by sedimentation into small and large fibers. The small Phosphate Fiber was found to be more cytotoxic and the large Phosphate Fiber to be less cytotoxic than the unfractionated Phosphate Fiber. The in vitro data suggest that Phosphate Fiber is less cytotoxic than asbestos, but further determination of safety can only be made after the in vivo data have been obtained.