A common flame-retardant and plasticizer, triphenyl phosphate (TPhP) is an aryl phosphate ester found in many aquatic environments at nM concentrations. Yet, most studies interrogating its toxicity have used µM concentrations. In this study, we used the model organism zebrafish (Danio rerio) to uncover the developmental impact of nM exposures to TPhP at the phenotypic and molecular levels. At concentrations of 1.5-15 nM (0.5 µg/L-5 µg/L), chronically dosed 5dpf larvae were shorter in length and had pericardial edema phenotypes that had been previously reported for exposures in the µM range. Cardiotoxicity was observed but did not present as cardiac looping defects as previously reported for µM concentrations. The RXR pathway does not seem to be involved at nM concentrations, but the tbx5a transcription factor cascade including natriuretic peptides (nppa and nppb) and bone morphogenetic protein 4 (bmp4) were dysregulated and could be contributing to the cardiac phenotypes. We also demonstrate that TPhP is a weak pro-oxidant, as it increases the oxidative stress response within hours of exposure. Overall, our data indicate that TPhP can affect animal development at environmentally relevant concentrations and its mode of action involves multiple pathways.

UNASSIGNED: Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant, which can be transformed in vivo into diphenyl phosphate (DPHP) and 4-hydroxyphenyl phosphate (diphenyl) ester (OH-TPHP) through biotransformation process. Accumulation of TPHP and its derivatives in biological tissues makes it necessary to investigate their toxicity and molecular mechanism.
UNASSIGNED: The present study evaluated the cellular effects of TPHP, DPHP, and OH-TPHP on cell survival, cell membrane damage, oxidative damage, and cell apoptosis using HeLa cells as in vitro model. RNA sequencing and bioinformatics analysis were conducted to monitor the differently expressed genes, and then RT-qPCR and Western bolt were used to identify potential molecular mechanisms and key hub genes.
UNASSIGNED: Results showed that OH-TPHP had the most significant cytotoxic effect in HeLa cells, followed by TPHP; and no significant cytotoxic effects were observed for DPHP exposure within the experimental concentrations. Biological function enrichment analysis suggested that TPHP and OH-TPHP exposure may induce endoplasmic reticulum stress (ERS) and cell apoptosis. The nodes filtering revealed that ERS and apoptosis related genes were involved in biological effects induced by TPHP and OH-TPHP, which may be mediated through the eukaryotic translation initiation factor 2α/activating transcription factor 4 (ATF4)/ATF3- CCAAT/ enhancer-binding protein homologous protein (CHOP) cascade pathway and death receptor 5 (DR5) /P53 signaling axis.
UNASSIGNED: Above all, these findings indicated that ERS-mediated apoptosis might be one of potential mechanisms for cytotoxicity of TPHP and OH-TPHP.

In recent years, organophosphate ester flame retardants (OPFRs) have emerged as preferred alternatives to brominated flame retardants (BFRs) in materials such as building supplies, textiles, and furnishings. Simultaneously, a notable surge in bladder cancer incidences has been observed globally, particularly in developed nations, placing it as the 10th most prevalent cancer type. Among the extensive OPFRs, the linkage between triphenyl phosphate (TPP) and bladder cancer remains inadequately investigated. Hence, our study endeavors to elucidate this potential association. We sourced transcriptome profiles and TPP-related data from The Cancer Genome Atlas and Comparative Toxicogenomics databases. Using the ssGSEA algorithm, we established TPP-correlated scores within the bladder cancer cohort. Differentially expressed analysis enabled us to identify key genes in bladder cancer patients. We utilized the LASSO regression analysis, along with univariate and multivariate COX regression analyses to construct a prognostic prediction model. To uncover critical pathways involving key genes, we employed GSEA and GSVA enrichment analyses. Molecular docking analysis was performed to determine the binding capability between TPP and proteins. Our findings reveal that the TPP-centric risk model offers valuable prediction for bladder cancer cohorts. Furthermore, the reliability of this TPP-influenced risk model was verified through ROC curve analysis and survival studies. Intriguingly, TPP exposure appears to bolster the proliferation and invasiveness of bladder cancer cells. This study furnishes new insights into the possible benefits of minimizing TPP exposure for hindering bladder cancer progression.

Triphenyl phosphate (TPHP) - a widely used organophosphate-based flame retardant - blocks cardiac looping during zebrafish development in a concentration-dependent manner, a phenotype that is dependent on disruption of embryonic osmoregulation and pericardial edema formation. However, it\'s currently unclear whether (1) TPHP-induced effects on osmoregulation are driven by direct TPHP-induced injury to the embryonic epidermis and (2) whether TPHP-induced pericardial edema is reversible or irreversible following cessation of exposure. Therefore, the objectives of this study were to determine whether TPHP-induced pericardial edema is reversible and whether TPHP causes injury to the embryonic epidermis by quantifying the number of DAPI-positive epidermal cells and analyzing the morphology of the yolk sac epithelium using scanning electron microscopy. First, we found that exposure to 5 μM TPHP from 24-72 h post-fertilization (hpf) did not increase prolactin - a hormone that regulates ions and water levels - in embryonic zebrafish, whereas high ionic strength exposure media was associated with elevated levels of prolactin. Second, we found that exposure to 5 μM TPHP from 24-72 hpf did not decrease DAPI-positive epidermal cells within the embryonic epithelium, and that co-exposure with 2.14 μM fenretinide - a synthetic retinoid that promotes epithelial wound repair - from 24-72 hpf did not mitigate the prevalence of TPHP-induced epidermal folds within the yolk sac epithelium when embryos were exposed within high ionic strength exposure media. Finally, we found that the pericardial area and body length of embryos exposed to 5 μM TPHP from 24-72 hpf were similar to vehicle-treated embryos at 120 hpf following transfer to clean water and depuration of TPHP from 72-120 hpf. Overall, our findings suggest that (1) the ionic strength of exposure media may influence the baseline physiology of zebrafish embryos; (2) TPHP does not cause direct injury to the embryonic epidermis; and (3) TPHP-induced effects on pericardial area and body length are reversible 48 h after transferring embryos to clean water.

Microbiological contamination of cinematographic films can cause damage and loss of image information. A large part of the films is made with the base of cellulose triacetate, which has been used from the 1940s until today. Cellulose triacetate is relatively resistant to common organic solvents, but some types of microorganisms can contribute to its faster degradation. In this work, we tested four types of disinfectants suitable for mass disinfection and sufficiently effective against various types of microorganisms. Butanol vapours, a commercial mixture of alcohols (Bacillol® AF), Septonex® (an aqueous solution of [1-(ethoxycarbonyl)pentadecyl] trimethylammonium bromide) and ethylene oxide applied as a gas mixed with carbon dioxide were tested. Samples of a commercial film made of cellulose triacetate were disinfected. The samples were aged for 56 days at 70 °C and 55% RH. Changes in optical, mechanical and chemical properties were studied. None of the disinfectants affected the change in the degree of substitution. For samples disinfected with Bacillol® AF (alcohol mixture), part of the plasticiser (triphenyl phosphate) was extracted and the intrinsic viscosity of the cellulose triacetate solution was reduced after ageing. A slight decrease in intrinsic viscosity also occurred after disinfection with ethylene oxide. Compared to the non-disinfected samples, butanol vapours and Septonex® appear to be the most gentle disinfectants for the cellulose triacetate film base, within the studied parameters.

Human exposures to organophosphate flame retardants result from their use as additives in numerous consumer products. These agents are replacements for brominated flame retardants but have not yet faced similar scrutiny for developmental neurotoxicity. We examined a representative organophosphate flame retardant, triphenyl phosphate (TPP) and its potential effects on behavioral development and dopaminergic function.
Female Sprague-Dawley rats were given low doses of TPP (16 or 32 mg kg-1  day-1 ) via subcutaneous osmotic minipumps, begun preconception and continued into the early postnatal period. Offspring were administered a battery of behavioral tests from adolescence into adulthood, and littermates were used to evaluate dopaminergic synaptic function.
Offspring with TPP exposures showed increased latency to begin eating in the novelty-suppressed feeding test, impaired object recognition memory, impaired choice accuracy in the visual signal detection test, and sex-selective effects on locomotor activity in adolescence (males) but not adulthood. Male, but not female, offspring showed marked increases in dopamine utilization in the striatum, evidenced by an increase in the ratio of the primary dopamine metabolite (3,4-dihydroxyphenylacetic acid) relative to dopamine levels.
These results indicate that TPP has adverse effects that are similar in some respects to those of organophosphate pesticides, which were restricted because of their developmental neurotoxicity.

Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)-P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood-brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP\'s neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.

This study explored the combined effects of titanium dioxide nanoparticles (nano-TiO2) and triphenyl phosphate (TPhP) on the neurodevelopment of zebrafish larvae as well as the underlying mechanisms. With this regard, zebrafish embryos were exposed to nano-TiO2 of 100 μg·L-1, TPhP of 0, 8, 24, 72, and 144 μg·L-1, or their combinations until 120 h post-fertilization (hpf). Results indicated 100 μg·L-1 nano-TiO2 alone to be nontoxic to zebrafish larvae. However, obvious developmental toxicity manifested as inhibition of surviving rate, heart rate and body length as well as increased malformation was observed in the higher concentrations of TPhP (72 and 144 μg·L-1) alone and the co-exposure groups. Additionally, results suggested that nano-TiO2 significantly enhanced the bioaccumulation of TPhP in zebtafish larvae, and thus aggravated the abnormities of spontaneous movement and swimming behavior in zebrafish larvae induced by TPhP. Nano-TiO2 also exacerbated the TPhP-induced inhibition of the axonal growth on the secondary motor neuron, and aggravated the TPhP-induced decrease on expressions of neuron-specific green fluorescent protein (GFP) and neuronal marker genes (ngn1 and elavl3). Further, the content of neurotransmitter serotonin was not altered by TPhP alone exposure, but was decreased significantly in the co-exposure group of 144 μg·L-1 TPhP and nano-TiO2. Our data indicated that nano-TiO2 might aggravate the neuron abnormities and serotonin system dysfunction by enhancing the TPhP accumulation, leading to exacerbated abnormal locomotors in zebrafish larvae.

The global phase-out has decreased the use of polybrominated diphenyl ethers (PBDEs), thereby, rapidly increasing the production and use of their important surrogates, organophosphorus flame retardants (OPFRs). Currently, OPFRs are often found at higher levels in the environments compared to PBDEs. Although the two typical OPFRs, tris (1,3-dichloroisopropyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP), have been frequently detected in marine environments with significant concentrations, their toxicity to marine organisms remains unknown. We used Oryzias melastigma to investigate and compare their developmental toxicity in marine organisms through two-generational chronic exposure. The results showed that TDCIPP and TPhP exposure shortened the body length and length of the pectoral fin of O. melastigma. Both TDCIPP and TPhP deformed the pectoral fins in the 1st fry and caused spinal curvature in adult fish. Therefore, these two chemicals may pose potential risks to marine fish and marine ecosystems. Further studies suggested that although these two chemicals caused similar developmental bone toxicity, they had different modes of modulating the expression of bone developmental genes such as, bmp4, bmp2 and runx2.

The toxicity of microplastics to marine organisms has attracted much attention; however, studies of their effects on marine microalgae remain limited. Here, the effects of the single and combined toxicity of polystyrene (PS) and triphenyl phosphate (TPhP) on the cell growth, photosynthesis, and oxidative stress of Chaetoceros meülleri were investigated. PS inhibited growth of the algae cells and caused a dose-dependent effect on oxidative stress. The significantly high production of reactive oxygen species (ROS) induced severe cell membrane damage, as confirmed by high fluorescence polarization. However, there was no obvious decrease in chlorophyll a content, and 80 mg/L of PS significantly promoted chlorophyll a synthesis. The TPhP also inhibited cell growth, except at low concentrations (0.2-0.8 mg/L), which stimulated algae growth over 48 h. Moreover, no obvious decrease in chlorophyll a and maximal photochemical efficiency of PSII was found in the TPhP experimental groups except for 3.2 mg/L TPhP, where the rapid light curves showed a significantly reduced photosynthetic capacity of algae. In addition, TPhP caused high ROS levels at 96 h, resulting in cell membrane damage. Using the additive index and independent action methods, the combined toxic effects of PS and TPhP on the algae were evaluated as antagonistic; however, cell membrane damage caused by high ROS levels was still noticeable. This study has shown the potential toxicity of PS and TPhP to marine microalgae, and provided insights into the combined risk assessment of TPhP and microplastics in the marine environment.