2-ethylhexyl Diphenyl Phosphate Research Articles

Long-Term Neurotoxic Effects and Alzheimer's Disease Risk of Early EHDPP Exposure in Zebrafish: Insights from Molecular Mechanisms to Adult Pathology.

2-Ethylhexyl diphenyl phosphate (EHDPP), ubiquitously monitored in environmental media, is highly bioaccumulative and may pose long-term risks, even after short-term exposure. In this investigation, larval zebrafish were exposed to 0.05, 0.5, and 5.0 μg/L EHDPP from 4 to 120 h postfertilization (hpf) to examine the long-term neurotoxicity effects of early exposure. Exposure to 5.0 μg/L EHDPP yielded hyperactive locomotor behavior, which was characterized by increased swimming speed, larger turning angles, and heightened sensitivity to light-dark stimulation. The predicted targets of EHDPP (top 100 potential macromolecules) were primarily associated with brain diseases like Alzheimer's disease (AD). Comparisons of differentially expressed genes (DEGs) from AD patients (GSE48350) and RNA-seq data from EHDPP-exposed zebrafish confirmed consistently abnormal regulatory pathways. EHDPP's interaction with M1 and M5 muscarinic acetylcholine receptors likely disrupted calcium homeostasis, leading to mitochondrial dysfunction and neurotransmitter imbalance as well as abnormal locomotor behavior. Especially, 5.0 μg/L EHDPP exposure during early development (4-120 hpf) triggered early- and midstage AD-like symptoms in adulthood (180 dpf), characterized by cognitive confusion, aggression, blood-brain barrier disruption, and mitochondrial damage in brains. These findings provide deep insights into the long-term neurotoxicity effects and Alzheimer's disease risks of early EHDPP exposure at extremely low dosages.

The Role of Human Adiponectin Receptor 1 in 2-Ethylhexyl Diphenyl Phosphate Induced Lipid Metabolic Disruption.

Epidemiological evidence links exposure to 2-ethylhexyl diphenyl phosphate (EHDPP) with lipid metabolic disruption, typically attributed to nuclear receptors, while the role of membrane receptors remains underexplored. This study explored the role of adiponectin receptor 1 (AdipoR1) in EHDPP-induced lipid metabolic disturbances. We examined EHDPP's binding affinity and transcriptional impact on AdipoR1. AdipoR1 knockdown (AdipoR1kd) human liver cells and coculture experiments with AdipoR1 activator (AdipoRon) were used to investigate the effect and the mechanism. EHDPP disrupted triglyceride and phospholipid synthesis and altered corresponding gene expression, mirroring effects in AdipoR1kd cells but diminishing in EHDPP-treated AdipoR1kd cells. RNA sequencing revealed that EHDPP primarily disrupted oxidative phosphorylation and insulin signaling dependent on AdipoR1. Mechanistically, EHDPP interacted with AdipoR1 and reduced AdipoR1 protein levels at 10-7 mol/L or higher, weakening the activation of the calmodulin dependent protein kinase β (CaMKKβ)/AMPK/acetyl CoA carboxylase pathway. Furthermore, EHDPP pretreatment blocked the increase in Ca2+ flux and the corresponding kinase CaMKKβ, as well as liver kinase B1 (LKB1) activation induced by AdipoRon, which is necessary for AMPK activation. Collectively, these findings demonstrate that EHDPP-induced lipid imbalance is partially dependent on AdipoR1, expanding the understanding of environmental metabolic disruptors beyond nuclear receptors.

Occurrence of legacy and emerging organophosphate flame retardants (OPFRs) on silicone wristbands: Comparison within couples

Novel organophosphate flame retardants (OPFRs) are recently identified and highly detected in indoor dusts, but their personal exposure was not clear. Here, wristband was used to estimate non-dietary exposure to emerging OPFRs in comparison with legacy OPFRs in 93 adults in Beijing, China. Comparison of studies in wristband monitoring data showed a clear difference in profiles of legacy OPFRs between China and United States, where tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) was usually the dominant OPFR in the United States, but triphenyl phosphate has the highest contribution to total OPFRs in China. Five emerging OPFRs, including diethylene glycol bis(bis(2-chloroisopropyl) phosphate) (DEGBBCPP) and bis(2-ethylhexyl) phenyl phosphate (BEHPP), were detected in above 45 % of wristbands. The median concentration of DEGBBCPP (2.2 ng/g) was about three times higher than TDCIPP (0.76 ng/g), a legacy chloro-OPFR. Both emerging and legacy OPFRs were significantly correlated within 40 pairs of couples, suggesting major exposure in their homes. Wristbands from husbands had significantly higher tris(2-butoxyethyl) phosphate (TBOEP) and DEGBBCPP, while 2-ethylhexyl diphenyl phosphate (EHDPP) was significantly higher in wives' bands, suggesting gender-related exposure sources for these OPFRs.

Aryl phosphate ester-induced pericardial edema in zebrafish embryos is influenced by the ionic composition of exposure media

Pericardial edema – fluid accumulation within the pericardium – is a frequently observed malformation in zebrafish embryo-based chemical toxicity screens. We recently discovered that the severity of triphenyl phosphate (TPHP)-induced pericardial edema was dependent on the ionic strength of exposure media. TPHP is an aryl phosphate ester (APE) widely used as a plasticizer and flame retardant. APEs are characterized by having one or more aryl groups bound to a phosphate center, with TPHP containing only unsubstituted aryl groups. Therefore, the objective of this study was to begin investigating whether, similar to TPHP, pericardial edema induced by other structurally related APEs is dependent on the ionic composition of exposure media. We first mined the peer-reviewed literature to identify other APEs that 1) induced pericardial edema in zebrafish embryos within a minimum of three peer-reviewed publications, and 2) demonstrated a statistically significant induction of pericardial edema in at least 70 % of the studies evaluated. Based on this meta-analysis, we identified four other APEs that caused pericardial edema in zebrafish embryos: isopropylated triphenyl phosphate (IPTPP), cresyl diphenyl phosphate (CDP), tricresyl phosphate (TMPP), and 2-ethylhexyl diphenyl phosphate (EDHPHP). Using TPHP as a positive control and pericardial edema as a readout, we developed concentration-response curves for all four APEs based on static exposure from 24 to 72 h post-fertilization (hpf). We then conducted co-exposures with D-Mannitol (an osmotic diuretic) and exposures within reverse osmosis (RO) water determine whether the ionic composition of exposure media mitigated APE-induced pericardial edema at 72 hpf. Using pericardial edema as an endpoint, the approximate EC50s for TPHP (positive control), IPTPP, CDP, TMPP, and EDHPHP were 6.25, 3.125, 3.125, 25, and 100 µM, respectively, based on exposure from 24 to 72 hpf. Interestingly, similar to our findings with TPHP, co-exposure with D-Mannitol and exposure within ion-deficient water significantly mitigated IPTPP- CDP-, TMPP-, and EDHPHP-induced pericardial edema in zebrafish embryos, suggesting that chemically-induced pericardial edema may be 1) dependent on the ionic composition of exposure media and 2) driven by a disruption in osmoregulation across the embryonic epidermis. Therefore, similar to other assay parameters, our findings underscore the need to standardize the osmolarity of exposure media in order to minimize the potential for false positive/negative hits in zebrafish embryo-based chemical toxicity screens conducted around the world.

Nationwide Profiling and Source Identification of Organophosphate Esters in Korean Surface Waters Using Target, Suspect, and Non-Target HRMS Analysis

Organophosphate esters (OPEs) are emerging contaminants that serve as alternatives to regulated substances in aquatic environments. A nationwide large-scale assessment for OPEs, including point sources, remains insufficient. To address this issue, we aimed to investigate OPEs occurrence and novel OPEs via comprehensive target, suspect and non-target analysis. Among the 11 target OPEs, 10 were detected at sampling sites distributed evenly nationwide. The highest mean concentrations were measured for tris-(2-butoxyethyl) phosphate (TBOEP) and tris(2-chloroisopropyl) phosphate (TCIPP). The multivariate statistical analysis revealed that TBOEP and TCIPP are essential components for assessing total OPEs pollution. The systematic risk assessment results evaluated the overall risk contribution of TBOEP and the significant risk impact of 2-ethylhexyl diphenyl phosphate. Promising suspect and non-target analysis enabled frequent detection and identification of 6 antioxidant transformation products (TPs), as well as the tentative identification of 14 OPEs and TPs, including 3 di-OPEs. Based on sampling site classification, we confirmed that major OPEs are significantly discharged near point sources. We believe that this is the first attempt to assess the nationwide risk and potential sources of OPEs in Korean surface waters, providing insights that could support further prioritization and regulation efforts.

Identification of Primary Organophosphate Esters Contributing to Enhanced Risk of Gestational Diabetes Mellitus Based on a Case-Control Study.

Epidemiological studies on associations of organophosphate ester (OPE) exposure and gestational diabetes mellitus (GDM) risk, which remain rare and inconclusive, were carried out with a case-control population comprising 287 GDM and 313 non-GDM pregnant women recruited from Tianjin. The GDM group suffered distinctly higher serum concentrations of tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP), tri-iso-propyl phosphate (TIPP), and tri(1-chloro-2-propyl) phosphate (TCIPP) than the healthy control group (p < 0.001). Traditional analysis methods employed for either individual or mixture effects found positive correlations (p < 0.05) between the concentrations of five OPEs (i.e., TNBP, TBOEP, TPHP, TIPP, and TCIPP) and the incidence of GDM, while 2-ethylhexyl diphenyl phosphate, tri(1-chloro-2-propyl) phosphate, and bis(2-ethylhexyl) phosphate exhibited opposite effects. Three machine learning methods considering the concurrence of OPE mixture exposure and population characteristics were applied to clarify their relative importance to GDM risk, among which random forest performed the best. Several OPEs, particularly TNBP and TBOEP ranking at the top, made greater contributions than some demographical characteristics, such as prepregnancy body mass index and family history of diabetes, to the occurrence of GDM. This was further validated by another independent case-control population obtained from Hangzhou.

Dermal exposure assessment of formal e-waste dismantlers to flame retardants and plasticizers using passive sampling methodologies

The recycling of e-waste can lead to the release of organic chemicals when materials containing additives are subjected to dismantling and grinding. In this context, the exposure of workers from a Catalonian e-waste facility to flame retardants and plasticizers (including organophosphate esters (OPEs), polybrominated diphenyl ethers (PBDEs), novel brominated flame retardants (NBFRs) and dechloranes) was assessed using T-shirts and wristbands as passive samplers. The study area includes an area exclusively dedicated to cathodic ray-tube (CRT) TVs dismantling, and a grinding area where the rest of e-waste is ground. All the families of compounds were detected in both T-shirts and wristbands, with the highest concentration levels corresponding to OPEs, followed by PBDEs, NBFRs, and dechloranes. The CRT area presented higher concentration levels than the grinding area. The compounds with higher concentrations in T-shirts were 2-ethylhexyl diphenyl phosphate (EHDPP), diphenyl cresyl phosphate (DCP) and triphenyl phosphate (TPHP), and the total concentration of all groups ranged between 293 and 8324 ng/dm2-h (hour). In the case of the wristbands, the most abundant compounds were DCP, TPHP, and BDE-209, with total concentrations between 188 and 2248 ng/dm2-h. The two sampling methods appear to be complementary, as T-shirts collect coarser particles, while wristbands also capture volatile compounds. Based on normalized surface and time concentrations, the estimated daily intake (EDI) through dermal contact was calculated and carcinogenic and non-carcinogenic risks (CR and non-CR) associated with this activity assessed. The results show median CR 29 and 16 times below the threshold in CRT and grinding areas respectively. The non-CR medians were 2 and 3 times below the threshold, although in the CRT area one exceptional value surpassed the threshold, suggesting that risk can exist for some workers in the facility.

Occupational Exposure of On-Shift Ottawa Firefighters to Flame Retardants and Polycyclic Aromatic Hydrocarbons.

Firefighters can be exposed to complex mixtures of airborne substances, including hazardous substances released during structural fires. This study employed silicone wristbands (SWBs) as passive samplers to investigate potential exposure to polycyclic aromatic hydrocarbons (PAHs) and flame retardants (FRs). SWBs were deployed at different areas of four fire stations, in four truck cabins, and at an office control location; they were also donned outside the jackets of 18 firefighters who responded to fire calls. Overall, office areas had significantly lower PAHs than fire station areas. Vehicle bays and truck cabins had significantly higher concentrations of low molecular weight (LMW) PAHs than sleeping and living room areas. For organophosphate ester flame retardants (OPFRs), tri-n-butyl phosphate (TnBP) and tris(1-chloro-2-propyl) phosphate (TCPP) were detected in all the samples; 2-ethylhexyl diphenyl phosphate (EHDPP) was more frequently detected in the fire station areas. Triphenyl phosphate (TPP) concentrations were highest in the truck cabin and office areas, and tris(1,3-dichloro-2-propyl)phosphate (TDCPP) was highest in truck cabins. Thirteen of 16 PAHs and nine of 36 OPFRs were detected in all the SWBs worn by firefighters, and tris (2-butoxyethyl) phosphate (TBEP) was the predominant OPFR. Levels of LMW PAHs were significantly lower when firefighters did not enter the fire. LMW PAHs, HMW (high molecular weight) PAHs, and EHDPP were significantly elevated when heavy smoke was reported. This work highlights the potential for occupational exposure to PAHs and flame retardants in some fire station areas; moreover, factors that may influence exposure during fire suppression. Whilst firefighters' occupational exposure to PAHs is likely related to fire suppression and exposure to contaminated gear and trucks, exposure to OPFRs may be more related to their presence in truck interiors and electronics.

Triphenyl Phosphate Alters Methyltransferase Expression and Induces Genome-Wide Aberrant DNA Methylation in Zebrafish Larvae.

Emerging environmental contaminants, organophosphate flame retardants (OPFRs), pose significant threats to ecosystems and human health. Despite numerous studies reporting the toxic effects of OPFRs, research on their epigenetic alterations remains limited. In this study, we investigated the effects of exposure to 2-ethylhexyl diphenyl phosphate (EHDPP), tricresyl phosphate (TMPP), and triphenyl phosphate (TPHP) on DNA methylation patterns during zebrafish embryonic development. We assessed general toxicity and morphological changes, measured global DNA methylation and hydroxymethylation levels, and evaluated DNA methyltransferase (DNMT) enzyme activity, as well as mRNA expression of DNMTs and ten-eleven translocation (TET) methylcytosine dioxygenase genes. Additionally, we analyzed genome-wide methylation patterns in zebrafish larvae using reduced-representation bisulfite sequencing. Our morphological assessment revealed no general toxicity, but a statistically significant yet subtle decrease in body length following exposure to TMPP and EHDPP, along with a reduction in head height after TPHP exposure, was observed. Eye diameter and head width were unaffected by any of the OPFRs. There were no significant changes in global DNA methylation levels in any exposure group, and TMPP showed no clear effect on DNMT expression. However, EHDPP significantly decreased only DNMT1 expression, while TPHP exposure reduced the expression of several DNMT orthologues and TETs in zebrafish larvae, leading to genome-wide aberrant DNA methylation. Differential methylation occurred primarily in introns (43%) and intergenic regions (37%), with 9% and 10% occurring in exons and promoter regions, respectively. Pathway enrichment analysis of differentially methylated region-associated genes indicated that TPHP exposure enhanced several biological and molecular functions corresponding to metabolism and neurological development. KEGG enrichment analysis further revealed TPHP-mediated potential effects on several signaling pathways including TGFβ, cytokine, and insulin signaling. This study identifies specific changes in DNA methylation in zebrafish larvae after TPHP exposure and brings novel insights into the epigenetic mode of action of TPHP.

Comprehensive dietary exposure assessment of the Chinese population to organophosphate esters (OPEs): Results of the sixth China total diet study

Organophosphate esters (OPEs) are emerging pollutants, while data on their occurrence in foods and human dietary intake are limited. Based on the 6th China total diet study conducted in 2016–2019, this study implemented a comprehensive survey of OPEs in plant-derived foods of cereals, potatoes, legumes, fruits, vegetables, and further assessed dietary exposure from both plant- and animal-derived food. The sum concentrations of 15 OPEs in the plant-derived samples ranged from 0.567 to 106 ng/g ww. 2-Ethylhexyl diphenyl phosphate (EHDPP) (median: 1.14 ng/g ww) had the highest level in plant-derived foods, with a proportion of 35.6% in the total median OPEs. Regional distribution analysis showed a higher contamination of OPEs in plant-derived food from northern area of China. Estimated dietary intakes (EDIs) of ∑OPEs for Chinese population were from 109 ng/kg bw/day in Beijing to 1164 ng/kg bw/day in Gansu province, with mean and median of 296 and 222 ng/kg bw/day, respectively. Although animal-derived foods had higher levels of OPEs, plant-derived foods, specifically cereals, was the major source of dietary OPE intake. The EDIs were much lower than reference doses, which suggested the intakes of OPEs via food consumption could not cause significant health risks to the Chinese population at present.

Developmental toxicity of an emerging organophosphate ester Bis-(2-ethylhexyl)-phenyl phosphate on embryonic zebrafish: Comparison to 2-ethylhexyl diphenyl phosphate

Bis-(2-ethylhexyl)-phenyl phosphate (BEHPP) and its structural analog, 2-ethylhexyl diphenyl phosphate (EHDPP), are widely present in the environment. However, their toxic effects, particularly developmental toxicity, remain poorly understood. In this study, we evaluated the impacts of BEHPP and EHDPP on multiple developmental endpoints in zebrafish. BEHPP did not lead to mortality and malformations of embryos within the test concentration range (0.5–4.0 μM). In contrast, EHDPP had significant lethal effects, with an LC50 of 2.44 μM, and induced malformations, notably pericardial edema (PE), with an EC50 of 1.77 μM. In addition, BEHPP induced cardiac dysfunctions in embryos to a similar degree as EHDPP. Both stroke volume and cardiac output were significantly increased at BEHPP concentrations of 1.8 nM and above and at EHDPP concentrations of 4.3 nM and above. Transcriptomic analysis further corroborated the similar disturbance at the molecular level for both substances and revealed the Key Events (KEs) in the cardiac toxic regulation, including the focal adhesions, ECM-receptor interaction, cardiac muscle contraction, and the adrenergic signaling in cardiomyocytes. Taken together, the present study provided novel insights into the adverse effects of these emerging organophosphate esters and highlighted their potential risks to embryonic development in both ecosystems and humans.

2-ethylhexyl diphenyl phosphate exposure induces duodenal inflammatory injury through oxidative stress in chickens

2-ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer, which is commonly found in the environment. EHDPHP not only potentially harms the environment but also causes different degrees of damage to the organism. In this study, the duodenum of chicks was selected as the potential toxic target organ to explore the mechanism of duodenal injury induced by EHDPHP exposure. Ninety one-day-old healthy male chicks were selected and randomly divided into C1(control group), C2(solvent control group), L(800 mg/kg), M(1600 mg/kg), H(3200 mg/kg) according to different doses of EHDPHP after one week of environmental adaptation. The chicks were given continuous gavage for 14 d, 28 d, and 42 d. It was found that constant exposure to EHDPHP caused an increase in duodenal MDA content, a decrease in P-gp, SOD, GSH-Px activities, and a decrease in duodenal mucosal immune factor (sIgA, GSH-Px). The expression of sIgM and mucosal link proteins (CLDN, OCLN, ZO-1, JAM) decreased, and the expression of the inflammatory protein (NF-κB, COX2) in duodenal tissues was up-regulated. The results showed that continuous exposure to EHDPHP could cause duodenal oxidative stress, inflammation, and mucosal barrier damage in chicks, which provided a basis for studying the mechanism of toxic damage caused by EHDPHP in poultry.

Distribution Characteristics and Risk Assessment of Organophosphates in Water and Sediment in Dongting Lake

Organophosphates （OPEs） are widely used as flame retardants and additives and thus are commonly detected in the environment. In order to explore their environmental behavior, the concentrations of 13 OPEs in the surface water and sediment of Dongting Lake were analyzed using UPLC-MS/MS. The results showed that 11 OPEs were detected, with detection frequencies of 5.26%-100% and 58.3%-100%, and the concentrations of OPEs were 2.06-2 028 ng·L-1 and 19.6-2 232 ng·g-1 in water and sediment, respectively. Overall, contamination concentrations were ranked in descending order as follows： inflowing rivers, lake area, and outlet, whereas the spatial distribution of concentrations in sediment was inversely proportional to hydrodynamics. The concentration of OPEs in Dongting Lake was at a high level compared with that of domestic and foreign lakes. Among the detected 11 OPEs, tri-iso-butyl phosphate （TnBP） and （TiBP） were dominant in water, accounting for 52.3% and 22.4% of ∑OPEs, respectively. TPhP was the dominant OPEs in sediment, accounting for 31.2% of ∑OPEs. The correlation and principal component analysis indicated that OPEs pollution in Dongting Lake was mainly affected by industrial production emissions, fishery aquaculture, and atmospheric deposition. The assessment results of the risk entropy showed that most of the detected OPEs in water had relatively low ecological risks, whereas the ecological risk of 2-ethylhexyl diphenyl phosphate （EHDPP） at some sampling points requires further attention.

Fugacity- and biotransformation-based mechanistic insights into the trophic transfer of organophosphate flame retardants in a subtropical coastal food web from the Northern Beibu Gulf of China

The bioaccumulation and trophic transfer of organophosphate flame retardants (OPFRs) in marine ecosystems have attracted great attention in recent research, but our understanding of the trophic transfer mechanisms involved is limited. In this study, we investigated the trophodynamics of OPFRs and their metabolites in a subtropical coastal food web collected from the northern Beibu Gulf, China, and characterized their trophodynamics using fugacity- and biotransformation-based approaches. Eleven OPFRs and all seven metabolites were simultaneously quantified in the shellfish, crustacean, pelagic fish, and benthic fish samples, with total concentrations ranging from 164 to 4.11 × 104 and 4.56–4.28 × 103 ng/g lipid weight, respectively. Significant biomagnification was observed only for tris (phenyl) phosphate (TPHP) and tris (2-ethylhexyl) phosphate (TEHP), while other compounds except for tris(2-chloroethyl) phosphate (TCEP) displayed biomagnification trends based on Monte Carlo simulations. Using a fugacity-based approach to normalize the accumulation of OPFRs in biota to their relative biological phase composition, storage lipid is the predominant biological phase for the mass distribution of 2-ethylhexyl diphenyl phosphate (EHDPHP) and TPHP. The water content and structure protein are equally important for TCEP, whereas lipid and structure protein are the two most important phases for other OPFRs. The mass distribution of these OPFRs along with TLs can explain their trophodynamics in the food web. The organophosphate diesters (as OPFR metabolites) also displayed biomagnification trends based on bootstrapped estimation. The correlation analysis and Korganism-water results jointly suggested the metabolites accumulation in high-TL organisms was related to biotransformation processes. The metabolite-backtracked trophic magnification factors for tri-n‑butyl phosphate (TNBP) and TPHP were both greater than the values that accounted for only the parent compounds. This study highlights the incorporation of fugacity and biotransformation analysis to characterize the trophodynamic processes of OPFRs and other emerging pollutants in food webs.

Effects of 2-Ethylhexyl Diphenyl Phosphate on the Development and Growth Hormone Endocrine System in Zebrafish Larvae

Effects of 2-Ethylhexyl Diphenyl Phosphate on the Development and Growth Hormone Endocrine System in Zebrafish Larvae

Integrated Approach for Testing and Assessment for Developmental Neurotoxicity (DNT) to Prioritize Aromatic Organophosphorus Flame Retardants.

Organophosphorus flame retardants (OPFRs) are abundant and persistent in the environment but have limited toxicity information. Their similarity in structure to organophosphate pesticides presents great concern for developmental neurotoxicity (DNT). However, current in vivo testing is not suitable to provide DNT information on the amount of OPFRs that lack data. Over the past decade, an in vitro battery was developed to enhance DNT assessment, consisting of assays that evaluate cellular processes in neurodevelopment and function. In this study, behavioral data of small model organisms were also included. To assess if these assays provide sufficient mechanistic coverage to prioritize chemicals for further testing and/or identify hazards, an integrated approach to testing and assessment (IATA) was developed with additional information from the Integrated Chemical Environment (ICE) and the literature. Human biomonitoring and exposure data were identified and physiologically-based toxicokinetic models were applied to relate in vitro toxicity data to human exposure based on maximum plasma concentration. Eight OPFRs were evaluated, including aromatic OPFRs (triphenyl phosphate (TPHP), isopropylated phenyl phosphate (IPP), 2-ethylhexyl diphenyl phosphate (EHDP), tricresyl phosphate (TMPP), isodecyl diphenyl phosphate (IDDP), tert-butylphenyl diphenyl phosphate (BPDP)) and halogenated FRs ((Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(2-chloroethyl) phosphate (TCEP)). Two representative brominated flame retardants (BFRs) (2,2'4,4'-tetrabromodiphenyl ether (BDE-47) and 3,3',5,5'-tetrabromobisphenol A (TBBPA)) with known DNT potential were selected for toxicity benchmarking. Data from the DNT battery indicate that the aromatic OPFRs have activity at similar concentrations as the BFRs and should therefore be evaluated further. However, these assays provide limited information on the mechanism of the compounds. By integrating information from ICE and the literature, endocrine disruption was identified as a potential mechanism. This IATA case study indicates that human exposure to some OPFRs could lead to a plasma concentration similar to those exerting in vitro activities, indicating potential concern for human health.

Melatonin improves mouse oocyte quality from 2-ethylhexyl diphenyl phosphate-induced toxicity by enhancing mitochondrial function

2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.

EGFR and Hippo signaling pathways are involved in organophosphate esters-induced proliferation and migration of triple-negative breast cancer cells.

The widespread application of organophosphate flame retardants has led to pervasive exposure to organophosphate esters (OPEs), prompting considerable concerns regarding their potential health risk to humans. Despite hints from previous research about OPEs' association with breast cancer, their specific effects and underlying mechanisms of triple-negative breast cancer (TNBC) remain unclear. In this study, we investigated the effects of four representative OPEs on cell proliferation, cell cycle regulation, migration, and the expression of genes and proteins associated with the epidermal growth factor receptor (EGFR) and Hippo signaling pathways in TNBC (MDA-MB-231) cells. Our findings revealed that treatment with 1-25μM triphenyl phosphate (TPHP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) induced TNBC cell proliferation and accelerated cell cycle progression, with upregulation in MYC, CCND1, and BRCA1 mRNA. Moreover, exposure to 1-25μM TPHP, 10-25μM TDCIPP, and 1-10μM tris (2-chloroethyl) phosphate (TCEP) induced MMP2/9 mRNA expression and enhanced migratory capacity, except for 2-ethylhexyl diphenyl phosphate (EHDPP). Mechanistically, four OPEs treatments activated the EGFR-ERK1/2 and EGFR-PI3K/AKT signaling pathways by increasing the transcript of EGFR, ERK1/2, PI3K, and AKT mRNA. OPEs treatment also suppressed the Hippo signaling pathway by inhibiting the expression of MST1 mRNA and phosphorylation of LATS1, leading to the overactivation of YAP1 protein, thereby promoting TNBC cell proliferation and migration. In summary, our study elucidated that activation of the EGFR signaling pathway and suppression of the Hippo signaling pathway contributed to the proliferation, cell cycle dysregulation, and migration of TNBC cells following exposure to OPEs.

Children's exposure to halogenated flame retardants and organophosphate esters through dermal absorption and hand-to-mouth ingestion in Swedish preschools

Children are exposed to endocrine disrupting chemicals (EDCs) through inhalation and ingestion, as well as through dermal contact in their everyday indoor environments. The dermal loadings of EDCs may contribute significantly to children's total EDC exposure due to dermal absorption as well as hand-to-mouth behaviors. The aim of this study was to measure potential EDCs, specifically halogenated flame retardants (HFRs) and organophosphate esters (OPEs), on children's hands during preschool attendance and to assess possible determinants of exposure in preschool indoor environments in Sweden. For this, 115 handwipe samples were collected in winter and spring from 60 participating children (arithmetic mean age 4.5 years, standard deviation 1.0) and analyzed for 50 compounds. Out of these, 31 compounds were identified in the majority of samples. Levels were generally several orders of magnitude higher for OPEs than HFRs, and 2-ethylhexyl diphenyl phosphate (EHDPP) and tris(2-butoxyethyl) phosphate (TBOEP) were detected in the highest median masses, 61 and 56 ng/wipe, respectively. Of the HFRs, bis(2-ethyl-1-hexyl)-2,3,4,5-tetrabromobenzoate (BEH-TEBP) and 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) were detected in the highest median masses, 2.8 and 1.8 ng/wipe, respectively.HFR and/or OPE levels were found to be affected by the number of plastic toys, and electrical and electronic devices, season, municipality, as well as building and/or renovation before/after 2004. Yet, the calculated health risks for single compounds were below available reference dose values for exposure through dermal uptake as well as for ingestion using mean hand-to-mouth contact rate. However, assuming a high hand-to-mouth contact rate, at the 95th percentile, the calculated hazard quotient was above 1 for the maximum handwipe mass of TBOEP found in this study, suggesting a risk of negative health effects. Furthermore, considering additive effects from similar compounds, the results of this study indicate potential concern if additional exposure from other routes is as high.

Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort

BackgroundConcerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. ObjectivesWe examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. MethodsTotally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. ResultsTributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 μg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (β) ranging from −1.89 to −0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with β ranging from −5.93 to −1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DiscussionOur findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.