RESUMEN

Organophosphate flame retardants (OPFRs) pose the significant risks to the environment and human health and have become a serious public health issue. Tricresyl phosphates (TCPs), a group of aryl OPFRs, exhibit neurotoxicity and endocrine disrupting toxicity. However, the binding mechanisms between TCPs and human serum albumin (HSA) remain unknown. In this study, through fluorescence and ultraviolet-visible (UV-vis) absorption spectroscopy, molecular docking and molecular dynamics (MD), tri-para-cresyl phosphate (TpCP) was selected to explore potential interactions between HSA and TCPs. The results of the fluorescence spectroscopy demonstrated that a decrease in the fluorescence intensity of HSA and a blue shift were observed with the increasing concentrations of TpCP. The binding constant (Ka) was 2.575 × 104 L/mol, 4.701 × 104 L/mol, 5.684 × 104 L/mol and 9.482 × 104 L/mol at 293 K, 298 K, 303 K, and 310 K, respectively. The fluorescence process between HSA and TpCP involved a mix of static and dynamic quenching mechanism. The gibbs free energy (ΔG0) of HSA-TpCP system was -24.452 kJ/mol, -25.907 kJ/mol, -27.363 kJ/mol, and - 29.401 kJ/mol at 293 K, 298 K, 303 K, and 310 K, respectively, suggesting that the HSA-TpCP reaction was spontaneous. The enthalpy change (ΔH0) and thermodynamic entropy change (ΔS0) of the HSA-TpCP system were 60.83 kJ/mol and 291.08 J/(mol·>k), respectively, indicating that hydrophobic force was the major driving force in the HSA-TpCP complex. Furthermore, multispectral analysis also revealed that TpCP could alter the microenvironment of tryptophan residue and the secondary structure of HSA and bind with the active site I of HSA. Molecular docking and MD simulations confirmed that TpCP could spontaneously form a stable complex with HSA, which was consistent with the fluorescence experimental results. This study provides novel insights into the mechanisms of underlying the transportation and distribution of OPFRs in humans.

Asunto(s)

Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Espectrometría de Fluorescencia , Termodinámica , Humanos , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Retardadores de Llama/metabolismo , Espectrofotometría Ultravioleta , Sitios de Unión , Tritolilfosfatos/química , Tritolilfosfatos/metabolismo , Albúmina Sérica/química , Albúmina Sérica/metabolismo , Enlace de Hidrógeno

RESUMEN

Tricresyl phosphate (TCP) has received extensive attentions due to its potential adverse effects, while the toxicological information of TCP isomers is limited. In this study, 2 h post-fertilization zebrafish embryos were exposed to tri-o-cresyl phosphate (ToCP), tri-m-cresyl phosphate (TmCP) or tri-p-cresyl phosphate (TpCP) at concentrations of 0, 100, 300 and 600 µg/L until 120 hpf, and the cardiotoxicity and mechanism of TCP isomers in zebrafish embryos/larvae were evaluated. The results showed that ToCP or TmCP exposure induced cardiac morphological defects and dysfunction in zebrafish, characterized by increased distance between sinus venosus and bulbus arteriosis, increased atrium and pericardial sac area, trabecular defects, and decreased heart rate and blood flow velocity, while no adverse effects of TpCP on zebrafish heart were found. Transcriptomic results revealed that extracellular matrix (ECM) and motor proteins, as well as PPAR signaling pathways, were included in the cardiac morphological defects and dysfunction induced by ToCP and TmCP. Co-exposure test with D-mannitol indicated that the inhibition of energy metabolism by ToCP and TmCP affected cardiac morphology and function by decreasing osmoregulation. This study is the first to report the cardiotoxicity induced by TCP in zebrafish from an isomer perspective, providing a new insight into the toxicity of TCP isomers and highlighting the importance of evaluating the toxicity of different isomers.

Asunto(s)

Cardiotoxicidad , Embrión no Mamífero , Pez Cebra , Animales , Pez Cebra/embriología , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/anomalías , Cardiotoxicidad/etiología , Larva/efectos de los fármacos , Corazón/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Tritolilfosfatos/toxicidad

RESUMEN

Triocresyl phosphate (TOCP) was commonly used as flame retardant, plasticizer, lubricant, and jet fuel additive. Studies have shown adverse effects of TOCP on the reproductive system. However, the potential harm brought by TOCP, especially to mammalian female reproductive cells, remains a mystery. In this study, we employed an in vitro model for the first time to investigate the effects of TOCP on the maturation process of mouse oocytes. TOCP exposure hampered the meiotic division process, as evidenced by a reduction in the extrusion of the first polar body from oocytes. Subsequent research revealed the disruption of the oocyte cell cytoskeleton induced by TOCP, resulting in abnormalities in spindle organization, chromosome alignment, and actin filament distribution. This disturbance further extended to the rearrangement of organelles within oocytes, particularly affecting the mitochondria. Importantly, after TOCP treatment, mitochondrial function in oocytes was impaired, leading to oxidative stress, DNA damage, cell apoptosis, and subsequent changes of epigenetic modifications. Supplementation with nicotinamide mononucleotide (NMN) alleviated the harmful effects of TOCP. NMN exerted its mitigating effects through two fundamental mechanisms. On one hand, NMN conferred stability to the cell cytoskeleton, thereby supporting nuclear maturation. On the other hand, NMN enhanced mitochondrial function within oocytes, reducing the excess reactive oxygen species (ROS), restoring meiotic division abnormalities caused by TOCP, preventing oocyte DNA damage, and suppressing epigenetic changes. These findings not only enhance our understanding of the molecular basis of TOCP induced oocyte damage but also offer a promising avenue for the potential application of NMN in optimizing reproductive treatment strategies.

Asunto(s)

Mononucleótido de Nicotinamida , Fosfatos , Tritolilfosfatos , Femenino , Ratones , Animales , Mononucleótido de Nicotinamida/metabolismo , Mononucleótido de Nicotinamida/farmacología , Fosfatos/metabolismo , Oocitos , Citoesqueleto , Mitocondrias , Especies Reactivas de Oxígeno/metabolismo , Mamíferos

RESUMEN

Neurotoxic organophosphorus compounds can induce a type of delayed neuropathy in humans and sensitive animals, known as organophosphorus-induced delayed neuropathy (OPIDN). OPIDN is characterized by axonal degeneration akin to Wallerian-like degeneration, which is thought to be caused by increased intra-axonal Ca2+ concentrations. This study was designed to investigate that deregulated cytosolic Ca2+ may function downstream of mitodysfunction in activating Wallerian-like degeneration and necroptosis in OPIDN. Adult hens were administrated a single dosage of 750 mg/kg tri-ortho-cresyl phosphate (TOCP), and then sacrificed at 1 day, 5 day, 10 day and 21 day post-exposure, respectively. Sciatic nerves and spinal cords were examined for pathological changes and proteins expression related to Wallerian-like degeneration and necroptosis. In vitro experiments using differentiated neuro-2a (N2a) cells were conducted to investigate the relationship among mitochondrial dysfunction, Ca2+ influx, axonal degeneration, and necroptosis. The cells were co-administered with the Ca2+-chelator BAPTA-AM, the TRPA1 channel inhibitor HC030031, the RIPK1 inhibitor Necrostatin-1, and the mitochondrial-targeted antioxidant MitoQ along with TOCP. Results demonstrated an increase in cytosolic calcium concentration and key proteins associated with Wallerian degeneration and necroptosis in both in vivo and in vitro models after TOCP exposure. Moreover, co-administration with BATPA-AM or HC030031 significantly attenuated the loss of NMNAT2 and STMN2 in N2a cells, as well as the upregulation of SARM1, RIPK1 and p-MLKL. In contrast, Necrostatin-1 treatment only inhibited the TOCP-induced elevation of p-MLKL. Notably, pharmacological protection of mitochondrial function with MitoQ effectively alleviated the increase in intracellular Ca2+ following TOCP and mitigated axonal degeneration and necroptosis in N2a cells, supporting mitochondrial dysfunction as an upstream event of the intracellular Ca2+ imbalance and neuronal damage in OPIDN. These findings suggest that mitochondrial dysfunction post-TOCP intoxication leads to an elevated intracellular Ca2+ concentration, which plays a pivotal role in the initiation and development of OPIDN through inducing SARM1-mediated axonal degeneration and activating the necroptotic signaling pathway.

Asunto(s)

Calcio , Pollos , Mitocondrias , Necroptosis , Degeneración Walleriana , Animales , Necroptosis/efectos de los fármacos , Calcio/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Degeneración Walleriana/inducido químicamente , Degeneración Walleriana/patología , Degeneración Walleriana/metabolismo , Femenino , Ratones , Tritolilfosfatos/toxicidad , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Compuestos Organofosforados/toxicidad , Compuestos Organofosforados/farmacología , Línea Celular Tumoral

RESUMEN

Dermal exposure to phosphorus flame retardants (PFRs) has received much attention as a major alternative exposure route in recent years. However, the information regarding dermal exposure via direct contact with a product is limited. In addition, in the commonly used dermal permeability test, the target substance is dissolved in a solvent, which is unrealistic. In this study, a dermal permeability test of PFRs in three car seats was performed using artificial skin. The PFR concentrations in the car seats are 0.12 wt% tris(2-chloroethyl) phosphate (TCEP), 0.030-0.25 wt% tris(2-chloroisopropyl) phosphate (TCPP), 0.15 wt% triphenyl phosphate (TPhP), 0.89 wt% cresyl diphenyl phosphate (CsDPhP), 0.074 wt% tricresyl phosphate (TCsP), and 0.46-4.7 wt% diethylene glycol bis [di (2-chloroisopropyl) phosphate (DEG-BDCIPP). The mean skin permeation rates for a contact time of 24 h are 14 (TCEP), 5.4-160 (TCPP), 0.67 (CsDPhP), 0.38 (TPhP), and 3.3-58 ng cm-2 h-1 (DEG-BDCIPP). The concentrations of TCsP in receptor liquid were lower than the limit of quantification at the contact time of 24 h. The skin permeation rates were significantly affected by the type of car seat (e.g., fabric or non-fabric). The potential dermal TCPP exposure rate for an adult via direct contact with the car seat during the average daily contact time (1.3 h), which was the highest value assessed in this study, was estimated to be 16,000 ng kg-1 day-1, which is higher than that related to inhalation and dust ingestion reported as significant exposure route of PFRs in previous studies. These facts reveal that dermal exposure associated with direct contact with the product might be an important exposure pathway for PFRs.

Asunto(s)

Sistemas de Retención Infantil , Retardadores de Llama , Fosfinas , Piel Artificial , Tritolilfosfatos , Humanos , Adulto , Fósforo , Retardadores de Llama/análisis , Organofosfatos/análisis , Fosfatos , Polvo , Exposición a Riesgos Ambientales

RESUMEN

Tri-ortho-cresyl phosphate (TOCP), an organophosphorus compound (OP), which is widely used as plasticizer, flame retardant and other industrial products, has been reported to cause multiple toxicities including neurotoxicity and reproductive toxicity. However, it remains to be elusive whether TOCP induces hepatotoxicity. The purpose of this study was to investigate the effect of TOCP on hepatocytes and the lipid metabolism in particular. The adult mice were given a single dose of TOCP (800 mg/kg, p.o.) and the histological changes in liver tissue and lipid content in serum were determined. The results showed that more vacuoles and lipid droplets were observed in the liver of the mice exposed to TOCP. And triglyceride concentrations in serum and liver tissue significantly increased. However, the histopathological changes of the liver and the elevated triglyceride levels in the exposed mice can be reversed by endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid and mTOR signal inhibitor rapamycin. It was also found that the changes of expression levels of the biomarkers of ER stress and mTOR signaling pathway, such as GRP78, CHOP, and p-mTOR, in the exposed mice were consistent with those observed in the cultured primary hepatocytes treated with the same chemicals. These results showed that TOCP activated mTOR signal and ER stress to induce de novo lipid synthesis, which led to the hepatic steatosis in mouse.

Asunto(s)

Fosfatos , Serina-Treonina Quinasas TOR , Tritolilfosfatos , Ratones , Animales , Triglicéridos , Lípidos

RESUMEN

Background: Polyvinyl chloride (PVC) gloves are recommended as a safe alternative for patients with rubber accelerator allergy. However, allergic contact dermatitis to other chemicals in PVC gloves has been reported. Objective: To analyze single-use PVC medical examination gloves in the United States for the presence of potential contact allergens. Methods: Using liquid chromatography-mass spectrometry, 20 unique PVC gloves were analyzed in triplicate for 6 chemicals: benzisothiazolinone, bisphenol A, mono(2-ethylhexyl) maleate, tricresyl phosphate, triphenyl phosphate, and triphenyl phosphite. Results: All 20 PVC gloves contained detectable quantities of benzisothiazolinone (range, 0.001-1.48 parts per million [ppm]), bisphenol A (0.01-0.11 ppm), triphenyl phosphate (0.01-2.11 ppm), and triphenyl phosphite (0.001-0.22 ppm). Eighteen (90%) gloves contained mono(2-ethylhexyl) maleate (0.001-0.14 ppm) and 3 (15%) contained tricresyl phosphate (0.001-0.002 ppm). Conclusions: Known allergens were present in all 20 PVC gloves. However, the detected levels were mostly low and their relationship with sensitization and elicitation thresholds requires further study.

Asunto(s)

Compuestos de Bencidrilo , Dermatitis Alérgica por Contacto , Organofosfatos , Fenoles , Fosfitos , Tiazoles , Tritolilfosfatos , Humanos , Estados Unidos , Alérgenos/efectos adversos , Cloruro de Polivinilo/efectos adversos , Cloruro de Polivinilo/química , Guantes Protectores , Pruebas del Parche , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/etiología , Maleatos , Goma

RESUMEN

One of the major environmental issues that have an impact on humans, animals, and their surroundings is plastic garbage. The use of biodegradable polymers in place of traditional plastics is one of the best solutions to this significant issue. The bio-circular-green (BCG) economic model is supported by the use of microcrystalline cellulose (MCC) as a bio-filler for polylactide (PLA) composites, which may also help to address the issue of improper plastic waste management. This study explores the chemical modification of MCC derived from oil palm empty fruit bunch waste (OPMC). Maleic anhydride-modified OPMC (MAMC) is successfully synthesized by a solvent-free and low temperature heating procedure. MAMC and tricresyl phosphate (TCP) were used as additives in PLA composites which were processed by melt extrusion and compression molding. Characterization studies confirmed the successful modification of MAMC and indicated that TCP played a crucial role as an effective plasticizer and flame retardant for PLA. All PLA/TCP composites showed significantly improved toughness and delayed ignition. The appropriate TCP level was 10 phr. The incorporation of TCP and MAMC resulted in a synergistic enhancement of impact strength and maintained excellent flame inhibition. Moreover, the thermal stability of the PLA composites increased with increments of MAMC.

Asunto(s)

Tritolilfosfatos , Animales , Humanos , Tritolilfosfatos/análisis , Frutas/química , Poliésteres/química

RESUMEN

Organophosphate flame retardants (OPFRs) are environmental pollutants of increasing interest, widely distributed in the environment and exerting possible deleterious effects towards the human health. The present study investigates in vitro their possible interactions with human drug transporters, which are targets for environmental chemicals and actors of their toxicokinetics. Some OPFRs, i.e., tris(2-butoxyethyl) phosphate (TBOEP), tris(1,3-dichloroisopropyl) phosphate (TDCPP), tri-o-cresyl phosphate (TOCP) and triphenyl phosphate (TPHP), were found to inhibit activities of some transporters, such as organic anion transporter 3 (OAT3), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter 2 (OCT2) or breast cancer resistance protein (BCRP). These effects were concentration-dependent, with IC50 values ranging from 6.1 µM (for TDCPP-mediated inhibition of OCT2) to 51.4 µM (for TOCP-mediated inhibition of BCRP). OPFRs also blocked the transporter-dependent membrane passage of endogenous substrates, notably that of hormones. OAT3 however failed to transport TBOEP and TPHP. OPFRs additionally repressed mRNA expressions of some transporters in cultured human hepatic HepaRG cells, especially those of OAT2 and OCT1 in response to TOCP, with IC50 values of 2.3 µM and 2.5 µM, respectively. These data therefore add OPFRs to the expanding list of pollutants interacting with drug transporters, even if OPFR concentrations required to impact transporters, in the 2-50 µM range, are rather higher than those observed in humans environmentally or dietarily exposed to these chemicals.

Asunto(s)

Contaminantes Ambientales , Retardadores de Llama , Tritolilfosfatos , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Retardadores de Llama/toxicidad , Proteínas de Neoplasias , Proteínas de Transporte de Membrana/genética , Contaminantes Ambientales/toxicidad

RESUMEN

Tricresyl phosphate (TCP) is extensively used organophosphorus flame retardants and plasticizers that posed risks to organisms and human beings. In this study, the translocation and biotransformation behavior of isomers tri-p-cresyl phosphate (TpCP), tri-m-cresyl phosphate (TmCP), and tri-o-cresyl phosphate (ToCP) in rice and rhizosphere microbiome was explored by hydroponic exposure. TpCP and TmCP were found more liable to be translocated acropetally, compared with ToCP, although they have same molecular weight and similar Kow. Rhizosphere microbiome named microbial consortium GY could reduce the uptake of TpCP, TmCP, and ToCP in rice tissues, and promote rice growth. New metabolites were successfully identified in rice and microbiome, including hydrolysis, hydroxylated, methylated, demethylated, methoxylated, and glucuronide- products. The methylation, demethylation, methoxylation, and glycosylation pathways of TCP isomers were observed for the first time in organisms. What is more important is that the demethylation of TCPs could be an important and overlooked source of triphenyl phosphate (TPHP), which broke the traditional understanding of the only manmade source of toxic TPHP in the environment. Active members of the microbial consortium GY during degradation were revealed and metagenomic analysis indicated that most of active populations contained TCP-degrading genes. It is noteworthy that the strains and function genes in microbial consortium GY that responsible for TCP isomers' transformation were different. These results can improve our understanding of the translocation and transformation of organic pollutant isomers in plants and rhizosphere microbiome.

Asunto(s)

Retardadores de Llama , Microbiota , Oryza , Tritolilfosfatos , Humanos , Organofosfatos , Retardadores de Llama/análisis , Fosfatos

RESUMEN

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in industrial and commercial products. It is generally believed that OPEs in street dust mainly originate from road traffic and anthropogenic activities. The influence of atmospheric deposition is still unknown. In this study, leaves were employed as a novel passive air sampler to collect particle matters (PM) in 12 cities in the central province of Henan, China. Similar compositional profiles of OPEs were found in street dust and PM samples. The concentrations of individual OPEs in PM were 1-4 times higher than in street dust. Chlorinated OPEs concentration in PM shows a moderate correlation (r2 = 0.538, p < 0.01) with that in street dust. The concentration of alkyl OPEs in PM has a high correlation (r2 = 0.843, p < 0.01) with that in street dust. No significant correlation (r2 = 0.133, p = 0.132) was found on the aryl OPEs concentrations between street dust and PM. Spearman correlation reveals that the emission sources of tricresyl phosphate (TCrP) and triethyl phosphate (TEP) may be different from other OPEs in dust and PM samples. Principle component analysis (PCA) provides an appropriate explanation that tris (2-chloroethyl) phosphate (TCEP), triphenyl phosphate (TPhP), tris (chloropropyl) phosphate (TCPP), tributyl phosphate (TnBP), and TEP in street dust and PM may be emitted from the same sources, suggesting that PM has a significant influence on the occurrence of OPEs in street dust. The estimated dry deposition fluxes of particle-bound OPEs show a significant correlation (R2 = 0.969, p < 0.01) with OPEs concentrations in street dust, revealing that the input of atmospheric deposition could be a major source of OPEs in street dust.

Asunto(s)

Polvo , Tritolilfosfatos , Fosfatos

RESUMEN

Monitoring glucose levels is important not only for diabetics, but also for tracking embryonic development in human embryo culture media. In this study, an optochemical sensor (glucose-selective polymer membrane) was fabricated for the determination of glucose in serum from diabetic patients and the culture media of human embryos. The optode membranes were formulated using polyvinyl chloride (PVC) as the polymer matrix and 4',5'-dibromofluorescein octadecyl ester (ETH 7075) as the chromoionophore. The sensitivity of the optode membranes was optimized using two different plasticizers (tricresyl phosphate-TCP and nitrophenyloctyl ether-NOPE) and three ionophores (nitrophenylboronic acid-NPBA, trifluorophenyboronic acid-TFPBA, 4'-nitrobenzo-15-crown-5) and tested for glucose detection. The best optode membrane was formulated from 49.5% PVC, 49.5% TCP, 1% NPBA, and 1% ETH 7075. It showed a linear dynamic range of 10-3 M to 10-1 M, with a detection limit of 9 × 10-4 M and a response time of 2 min. The detection mechanism involves H-bonding between NPBA and glucose, which was confirmed by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR). The reaction also involves the formation of boronate esters in basic media with deprotonation of the chromoionophore (ETH 7075), leading to a decrease in UV-Vis absorbance at λmax = 530 nm. The membrane optode was used for glucose determination in synthetic culture medium, commercial embryo culture medium (GLOBAL® TOTAL® W/HEPES), and serum from normal and diabetic patients, showing good accuracy and precision of the optode.

Asunto(s)

Diabetes Mellitus , Tritolilfosfatos , Glucemia , Automonitorización de la Glucosa Sanguínea , Ácidos Borónicos , Medios de Cultivo , Ésteres , Éteres , HEPES , Humanos , Ionóforos/química , Membranas Artificiales , Plastificantes/química , Cloruro de Polivinilo/química

RESUMEN

The effects of aryl-organophosphate esters (aryl-OPEs) on female reproduction health are still unclear owing to the lack of specific exposure biomarkers. Here, we analyzed the hydroxylated metabolites of three aryl-OPEs (phenyl diphenyl phosphate [TPhP], 2-ethylhexyl diphenyl phosphate [EHDPP], and tricresyl phosphate [TCrP]) and diphenyl phosphate (DPhP) in urine samples from 913 women of childbearing age, and explored the association between exposure to the aryl-OPEs and reproductive hormone levels. The detection frequencies of 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), phenyl di-p-tolyl phosphate (4-OH-MDTP), and 4-hydroxyphenyl diphenyl phosphate (4-OH-TPhP) were 94.6 %, 93.3 %, and 84.2 %, respectively. Multivariate linear regression analyses revealed that the quartiles of 4-OH-TPhP were positively associated with the progesterone (P4) level (p-trend = 0.008), and the P level in the highest quartile of 5-OH-EHDPP was 7.2 % (95 % CI, 5.7 % to 8.7 %) higher than that in the lowest quartile. The 17ß-estradiol levels in the highest quartiles of 4-OH-TPhP and 5-OH-EHDPP were 15.0 % (95 % CI, 13.7 % to16.1 %) and 5.9 % (95 % CI, 15.7 % to 16.1 %) lower than those in the lowest quartiles, respectively. The anti-Müllerian hormone level linearly increased across the quartiles of 4-OH-MDTP (p-trend = 0.036), and the follicle-stimulating hormone exhibited the opposite trend (p-trend = 0.0047). These results indicate that aryl-OPEs may disrupt hormone homeostasis using their specific biomarkers and may negatively affect female reproduction.

Asunto(s)

Retardadores de Llama , Tritolilfosfatos , Hormona Antimülleriana , Biomarcadores , Compuestos de Bifenilo , China , Ésteres/análisis , Estradiol , Femenino , Retardadores de Llama/análisis , Hormona Folículo Estimulante , Homeostasis , Humanos , Metacrilatos , Organofosfatos/orina , Compuestos Organofosforados , Fosfatos/análisis , Progesterona

RESUMEN

A related group of phosphotriesters known as organophosphate flame retardants (OPFRs) has become emerging contaminants due to its worldwide use. The lack of an easily hydrolysable bond renders OPFRs inert to the well-known phosphotriesterases capable of hydrolyzing the neurotoxic organophosphates. An OPFRs phosphotriesterase gene stpte was cloned from plasmid pStJH of strain Sphingopyxis terrae subsp. terrae YC-JH3 and was heterologously expressed in Escherichia coli. The recombinant protein St-PTE was purified and analyzed. St-PTE showed the highest catalytic activity at pH 8.5 and 35 °C. The optimal substrate for St-PTE is triphenyl phosphate, with kcat/Km of 5.03 × 106 M-1 s-1, two orders of magnitude higher than those of tricresyl phosphate (4.17 × 104 M-1 s-1), 2-ethylhexyl diphenyl phosphate (2.03 × 104 M-1 s-1) and resorcinol bis(diphenyl phosphate) (6.30 × 104 M-1 s-1). St-PTE could break the P-O bond of tri-esters and convert aryl-OPFRs into their corresponding di-ester metabolites, including polymers of resorcinol bis(diphenyl phosphate). Mediated by transposase, the gene of OPFRs phosphotriesterase could be transferred horizontally among closely related strains of Sphingomonas, Sphingobium and Sphingopyxis. KEY POINTS: • St-PTE from Sphingopyxis terrae subsp. terrae YC-JH3 could hydrolyze aryl-OPFRs. • Metabolites of RBDPP hydrolyzed by phosphotriesterase were identified. • St-PTE could hydrolyze the P-O cleavage of dimer and trimer of RBDPP. • Phosphotriesterase genes transfer among Sphingomonadaceae mediated by transposase.

Asunto(s)

Retardadores de Llama , Hidrolasas de Triéster Fosfórico , Tritolilfosfatos , Compuestos de Bifenilo , Ésteres , Retardadores de Llama/metabolismo , Organofosfatos/metabolismo , Fosfatos , Hidrolasas de Triéster Fosfórico/química , Hidrolasas de Triéster Fosfórico/genética , Hidrolasas de Triéster Fosfórico/metabolismo , Polímeros , Proteínas Recombinantes , Resorcinoles , Sphingomonadaceae , Transposasas

RESUMEN

Microcrystalline cellulose (MCC) was extracted from oil palm empty fruit bunch (OPEFB) waste by integrated chemical treatments of delignification, bleaching, and acidic hydrolysis. The obtained MCC (OPMC) and tricresyl phosphate (TCP) were used as additives for polylactide (PLA) composites. The influences of OPMC and TCP contents, separately and in combination, were evaluated on the properties of the composites. Characterization studies confirmed the successful extraction of OPMC from OPEFB waste. With regard to the properties of the PLA composite, the appropriate content of OPMC should be 5 phr. The good distribution of OPMC in the polymer matrix changed the failure behavior of the composite from brittle to ductile. All the PLA composites with TCP and OPMC showed flame inhibition and retarded ignition. The synergistic effect of TCP and OPMC resulted in outstanding improvement of impact strength and flame retardancy of composites. The impact toughness of PT10M5 increased to about 218.4 % and 72.3 % that of neat PLA and PT0M5, respectively. Moreover, PT10M5 achieved V-0 rating with high LOI (38.5 %). All these characteristics promise extended applications for PLA composite in bio, circular, and green (BCG) economies and electronics industries.

Asunto(s)

Frutas , Tritolilfosfatos , Celulosa , Frutas/química , Aceite de Palma , Poliésteres/análisis , Polímeros/química , Tritolilfosfatos/análisis

RESUMEN

Wallerian degeneration (WD) is a well-known process by which degenerating axons and myelin are cleared after nerve injury. Although organophosphate-induced delayed neuropathy (OPIDN) is characterized by Wallerian-like degeneration of long axons in human and sensitive animals, the precise pathological mechanism remains unclear. In this study, we cultured embryonic chicken dorsal root ganglia (DRG) neurons, the model of OPIDN in vitro, to investigate the underlying mechanism of axon degeneration induced by tri-ortho-cresyl phosphate (TOCP), an OPIDN inducer. The results showed that TOCP exposure time- and concentration-dependently induced a serious degeneration and fragmentation of the axons from the DRG neurons. A collapse of mitochondrial membrane potential and a dramatic depletion of ATP levels were found in the DRG neurons after TOCP treatment. In addition, nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) expression and nicotinamide adenine dinucleotide (NAD+) level was also found to be decreased in the DRG neurons exposed to TOCP. However, the TOCP-induced Wallerian degeneration in the DRG neurons could be inhibited by ATP supplementation. And exogenous NAD+ or NAD+ processor nicotinamide riboside can rescue TOCP-induced ATP deficiency and prevent TOCP-induced axon degeneration of the DRG neurons. These findings may shed light on the pathophysiological mechanism of TOCP-induced axonal damages, and implicate the potential application of NAD+ to treat OPIDN.

Asunto(s)

Enfermedades del Sistema Nervioso Periférico , Tritolilfosfatos , Adenosina Trifosfato/metabolismo , Animales , Axones , Pollos , Ganglios Espinales , NAD/metabolismo , Neuronas , Organofosfatos/metabolismo , Fosfatos , Tritolilfosfatos/metabolismo , Tritolilfosfatos/toxicidad , Degeneración Walleriana/inducido químicamente , Degeneración Walleriana/metabolismo , Degeneración Walleriana/patología

RESUMEN

A novel microbial consortium ZY1 capable of degrading tricresyl phosphates (TCPs) was isolated, it could quickly degrade 100% of 1 mg/L tri-o-cresyl phosphate (ToCP), tri-p-cresyl phosphate (TpCP) and tri-m-cresyl phosphate (TmCP) within 36, 24 and 12 h separately and intracellular enzymes occupied the dominated role in TCPs biodegradation. Additionally, triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPP), bisphenol-A bis (diphenyl phosphate) (BDP), tris (2-chloroethyl) phosphate (TCEP) and tris (1-chloro-2-propyl) phosphate (TCPP) could also be degraded by ZY1 and the aryl-phosphates was easier to be degraded. The TCPs reduction observed in freshwater and seawater indicated that high salinity might weak the degradability of ZY1. The detected degradation products suggested that TCPs was mainly metabolized though the hydrolysis and hydroxylation. Sequencing analysis presented that the degradation of TCPs relied on the cooperation between sphingobacterium, variovorax and flavobacterium. The cytochrome P450/NADPH-cytochrome P450 reductase and phosphatase were speculated might involve in TCPs degradation. Finally, toxicity evaluation study found that the toxicity of the diesters products was lower than their parent compound based on the generation of the intracellular reactive oxygen (ROS) and the apoptosis rate of A549 cell. Taken together, this research provided a new insight for the bioremediation of TCPs in actual environment.

Asunto(s)

Retardadores de Llama , Tritolilfosfatos , Biodegradación Ambiental , Retardadores de Llama/análisis , Isomerismo , Consorcios Microbianos , Organofosfatos/toxicidad , Fosfatos/análisis , Tritolilfosfatos/análisis

RESUMEN

As tricresyl phosphate (TCrP) is commonly found in global water sources, its potential reproductive toxicity to fish is of increasing concern. Japanese medaka larvae were exposed to TCrP at 657.9, 1,511, and 4042 ng/L for 100 days. We identified significant fertilization inhibition (6.9%-12.8%) in all exposure groups. Intersex was significantly induced at 4042 ng/L, with an incidence of 22.0%. TCrP exposure also caused dilation of the efferent duct in the testes with maximum duct widths of 83.3, 93.2, and 149.7 µm in the 657.9, 1,511, and 4042 ng/L exposure groups, respectively. These widths were all significantly larger than that observed in the control group (37.7 µm) and likely contributed substantially to fertilization inhibition. The TCrP metabolites 4-OH-MDTP and 3-OH-MDTP, were detected at high concentrations in the liver and elicited 5.8-fold and 5.3-fold greater androgen receptor antagonistic activity than that elicited by TCrP (39.8 µM), which may explain the intersex observed in low exposure groups. 4-OH-MDTP and 3-OH-MDTP elicited anti-estrogenic activities by blocking the estrogen receptor, and the concentrations at which its responses were equal to the IC20 of tamoxifen were 16.1 µM and 18.9 µM, respectively, as detected using the yeast two-hybrid assay. Such anti-estrogenic activities were likely the main driver of dilation of the efferent duct. Observed adverse outcomes after exposure to TCrP all occurred under environmentally relevant concentrations, suggesting considerable ecological risk to wild fish.

Asunto(s)

Trastornos del Desarrollo Sexual , Oryzias , Tritolilfosfatos , Contaminantes Químicos del Agua , Animales , Fertilización , Contaminantes Químicos del Agua/toxicidad

RESUMEN

Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2',4,4'-tetrabromodiphenylether (BDE-47), 2,2',4,4',5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell-based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 µM (5 FRs), 1<10 µM (7 FRs) to the >10 µM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell-based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment.

Asunto(s)

Retardadores de Llama , Tritolilfosfatos , Femenino , Humanos , Compuestos de Bifenilo , Exposición a Riesgos Ambientales/análisis , Retardadores de Llama/análisis , Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/análisis , Técnicas In Vitro , Organofosfatos , Fosfatos/análisis

RESUMEN

An emerging experimental framework suggests that endocrine-disrupting compounds are candidate obesogens. However, this potential effect has not yet been determined for Tricresyl phosphate (TCP), a mass-produced organophosphate flame retardant (OPFR) that has been exposed to human beings in many ways. Many OPFRs, including TCP, have been shown to activate pregnane X receptor (PXR), a nuclear receptor that regulates lipid metabolism. Accordingly, we found that TCP exposure caused lipid accumulation in HepG2 cells in this study. Therefore, to elucidate the role of PXR played in TCP metabolism and promotion of lipid accumulation, HepG2 cells were exposed to different concentrations (5 × 10-8 to 5 × 10-5 M) of TCP for 24 h. The enlarged hepatic lipid droplets and increased hepatic triglyceride contents were observed in HepG2 cells after TCP exposure for 24 h. This is the result of a confluence of lipogenesis increase and ß-oxidation suppression imposed by PXR activation which was verified by the up regulation of genes in fatty acid (FA) synthesis and the down regulation of genes in ß-oxidation. Surface plasmon resonance (SPR) analysis and molecular docking revealed favorable binding mode of TCP to PXR and the knockout of PXR gene with CRISPR/cpf1 system in HepG2 cells abolished TCP-induced triglyceride accumulation, thus underlying the crucial role of PXR in hepatic lipid metabolism resulting from OPFRs exposure. This study enhances our understanding of molecular mechanisms and associations of PXR in lipid metabolism disturbance induced by TCP and provides novel evidence regarding the lipotoxicity effect and potential metabolism pathway of OPFRs.

Asunto(s)

Retardadores de Llama , Receptores de Esteroides , Tritolilfosfatos , Retardadores de Llama/toxicidad , Homeostasis , Humanos , Simulación del Acoplamiento Molecular , Receptor X de Pregnano/genética , Receptores de Esteroides/genética