Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae.

Chlorinated polyfluorooctane ether sulfonate (6:2 Cl-PFESA), hydrogenated polyfluorooctane ether sulfonate (6:2 H-PFESA), and chlorinated polyfluorooctanesulfonate (Cl-PFOS) share structural similarities with the regulated perfluorooctanesulfonate (PFOS), but their toxic potential is rarely known. Here, the thyroid disrupting potential of these four compounds in zebrafish larvae has been comparably investigated. PFOS, Cl-PFOS, and 6:2 Cl-PFESA were accumulated in the larvae at similar levels, approximately 1.3-1.6 times higher than 6:2 H-PFESA. Additionally, PFOS, Cl-PFOS, and 6:2 Cl-PFESA exhibited stronger disruption than 6:2 H-PFESA on genetic regulation, particularly concerning thyroid hormone (TH) activation and action and on TH homeostasis in both free and total forms of thyroxine (T4) and 3,5,3'-triiodothyronine (T3). These results indicate that chlorination or oxygen insertion does not substantially alter the thyrotoxicity of PFOS, but hydrogenation mitigates it. Molecular docking analysis and the luciferase reporter gene assay provided mechanistic perspectives that the PFOS-like substances could competitively replace THs to bind with TH plasma and membrane transporters, thereby disrupting TH transport and action, respectively. Moreover, they are also potent to disrupt TH synthesis and activation through Na+/K+-dependent transport of I- or competitive binding to the sites of deiodinases.

Exploring Route-Specific Pharmacokinetics of PFAS in Mice by Coupling in Vivo Tests and Physiologically Based Toxicokinetic Models.

BACKGROUND: Oral ingestion, inhalation, and skin contact are important exposure routes for humans to uptake per- and polyfluoroalkyl substances (PFAS). However, nasal and dermal exposure to PFAS remains unclear, and accurately predicting internal body burden of PFAS in humans via multiple exposure pathways is urgently required. OBJECTIVES: We aimed to develop multiple physiologically based toxicokinetic (PBTK) models to unveil the route-specific pharmacokinetics and bioavailability of PFAS via respective oral, nasal, and dermal exposure pathways using a mouse model and sought to predict the internal concentrations in various tissues through multiple exposure routes and extrapolate it to humans. METHODS: Mice were administered the mixed solution of perfluorohexane sulfonate, perfluorooctane sulfonate, and perfluorooctanoic acid through oral, nasal, and dermal exposure separately or jointly. The time-dependent concentrations of PFAS in plasma and tissues were determined to calibrate and validate the individual and combined PBTK models, which were applied in single- and repeated-dose scenarios. RESULTS: The developed route-specific PBTK models successfully simulated the tissue concentrations of PFAS in mice following single or joint exposure routes as well as long-term repeated dose scenarios. The time to peak concentration of PFAS in plasma via dermal exposure was much longer (34.1-83.0 h) than that via nasal exposure (0.960 h). The bioavailability of PFAS via oral exposure was the highest (73.2%-98.0%), followed by nasal (33.9%-66.8%) and dermal exposure (4.59%-7.80%). This model was extrapolated to predict internal levels in human under real environment. DISCUSSION: Based on these data, we predict the following: PFAS were absorbed quickly via nasal exposure, whereas a distinct hysteresis effect was observed for dermal exposure. Almost all the PFAS to which mice were exposed via gastrointestinal route were absorbed into plasma, which exhibited the highest bioavailability. Exhalation clearance greatly depressed the bioavailability of PFAS via nasal exposure, whereas the lowest bioavailability in dermal exposure was because of the interception of PFAS within the skin layers. https://doi.org/10.1289/EHP11969.

2-Ethylhexyl Diphenyl Phosphate Causes Obesity in Zebrafish by Stimulating Overeating via Inhibition of Dopamine Receptor D2.

Obesity is a popular public health problem worldwide and is mainly caused by overeating, but little is known about the impacts of synthetic chemicals on obesity. Herein, we evaluated the obesogenic effect caused by 2-ethylhexyl diphenyl phosphate (EHDPHP) on zebrafish. Adult zebrafish were exposed to 5, 35, and 245 µg/L of EHDPHP for 21 days. Results showed that EHDPHP exposure significantly promoted the feeding behavior of zebrafish, as evidenced by shorter reaction time, increased average food intake, feeding rate, and intake frequency (p < 0.05). Transcriptomic, real-time quantitative PCR, and neurotransmitter analyses revealed that the dopamine (DA) receptor D2 (DRD2) was inhibited, which interfered with the DA neural reward regulation system, thus stimulating food addiction to zebrafish. This was further verified by the restored DRD2 after 7 days of Halo (a DRD2 agonist) treatment. A strong interaction between EHDPHP and DRD2 was identified via molecular docking. As a consequence of the abnormal feeding behavior, the exposed fish exhibited significant obesity evidenced by increased body weight, body mass index, plasma total cholesterol, triglyceride, and body fat content. Additionally, the pathways linked to Parkinson's disease, alcoholism, and cocaine addiction were also disrupted, implying that EHDPHP might cause other neurological disorders via the disrupted DA system.

Novel Insights on 6:6 Perfluoroalkyl Phosphonic Acid-Induced Melanin Synthesis Disorders Leading to Pigmentation in Tadpoles.

As alternatives to traditional per- and polyfluoroalkyl substances, perfluoroalkyl phosphonic acids (PFPiAs) are widely present in aquatic environments and can potentially harm aquatic organisms. Pigmentation affects the probability of aquatic organisms being preyed on and serves as an important toxic endpoint of development, but little is known about the impacts of PFPiAs on the development of aquatic organisms. In this study, Xenopus laevis embryos were exposed to 6:6 PFPiA (1, 10, and 100 nM) for 14 days. The developed tadpoles exhibited evident pigmentation with increased melanin particle size and density on the skin. Pathological and behavioral experiments revealed that the retinal layers became thinner, reducing the photosensitivity and disturbing the circadian rhythm of the tadpoles. Compared to the control group, the exposed tadpoles showed higher levels but less changes of melanin throughout the light/dark cycle, as well as distinct oxidative damage. Consequently, the expression level of microphthalmia-associated transcription factor (MITF), a key factor inducing melanin synthesis, increased significantly. Molecular docking analysis suggested that 6:6 PFPiA forms strong interactions in the binding pocket of MITF, implying that it could activate MITF directly. The activation of MITF ultimately promotes melanin synthesis, resulting in pigmentation on tadpoles.

Mechanisms for the structural dependent transformation of 6:2 and 8:2 polyfluoroalkyl phosphate diesters in wheat (Triticum aestivum L.).

Polyfluoroalkyl phosphate esters (PAPs) are widely used and detected in various environmental media and organisms, but little is known about their behaviors in plants. In this study, the uptake, translocation and transformation of 6:2 and 8:2 diPAP in wheat using hydroponic experiments were investigated. 6:2 diPAP was more easily taken up by roots and translocated to shoots than 8:2 diPAP. Their phase I metabolites were fluorotelomer saturated carboxylates (FTCAs), fluorotelomer unsaturated carboxylates (FTUCAs) and perfluoroalkyl carboxylic acids (PFCAs). PFCAs with even-numbered chain length were the primary phase I terminal metabolites suggesting that they were mainly generated through ß-oxidation. Cysteine and sulfate conjugates were the primary phase II transformation metabolites. The higher levels and ratios of phase II metabolites in the 6:2 diPAP exposure group indicated that the phase I metabolites of 6:2 diPAP were more susceptible to phase II transformation than that of 8:2 diPAP, which was confirmed by density functional theory calculation. Enzyme activity analyses and in vitro experiments demonstrated that cytochrome P450 and alcohol dehydrogenase actively participated in the phase Ⅰ transformation of diPAPs. Gene expression analyses showed that glutathione S-transferase (GST) was involved in the phase Ⅱ transformation, and the subfamily GSTU2 played a dominant role.

First insight into the sex-dependent accumulation, tissue distribution and potential toxicities of 2-ethylhexyl diphenyl phosphate and its metabolites in adult zebrafish.

The 2-ethylhexyl diphenyl phosphate (EHDPHP), a primary organophosphorus flame retardant used in various industrial products, is prone to biotransformation. However, there is a knowledge gap on the sex- and tissue-specific accumulation and potential toxicities of EHDPHP (M1) and its metabolites (M2-M16). In this study, adult zebrafish (Danio rerio) were exposed to EHDPHP (0, 5, 35 and 245 µg/L) for 21-day, which was followed by 7-day depuration. The bioconcentration factor (BCF) of EHDPHP in female zebrafish was 26.2 ± 7.7% lower than in males due to the lower uptake rate (ku) while higher depuration rate (kd) in the females. The regular ovulation and higher metabolic efficiency promoted elimination from female zebrafish, thus leading to much less (28-44%) accumulation of ∑(M1-M16) in female zebrafish. They exhibited the highest accumulation in the liver and intestine in both sexes, which might be regulated by tissue-specific transporters and histones evidenced by molecular docking results. Intestine microbiota analysis further revealed that female zebrafish were more susceptible to EHDPHP exposure, with more significant changes in phenotype number and KEGG pathways in female than male fish. Disease prediction results suggested that EHDPHP exposure might cause cancers, cardiovascular diseases as well as endocrine disorders in both sexes. These results provide a comprehensive understanding of the sex-dependent accumulation and toxicity of EHDPHP and its metabolites.

Bioaccessibility of per- and polyfluoroalkyl substances in food and dust: Implication for more accurate risk assessment.

Humans are exposed to per- and polyfluoroalkyl substances (PFASs) mainly through oral exposure route, while little is known about their bioaccessibility (BC) in oral matrices. Here, the BC of 13 PFASs in simulated vegetable (VFs) and animal foods (AFs) as well as indoor dust was investigated using a physiology-based extraction test. The BC of PFASs in the AFs (78.5 ± 13.6 %) was distinctly higher than that in the VFs (60.6 ± 13.4 %), because high-saturated and long-chain fatty acids in the animal fat favored formation of more stable micelles. The BC of most long-chain PFASs was positively correlated with the protein content while negatively correlated with the carbohydrate content in the foods. The BC of polyfluoroalkyl phosphate diesters was negatively correlated with the lipid content. The BC of the very long-chain PFASs in the foods was 2.42-6.02 times higher than that in the dust, which might be attributed to their strong sequestration in dust. With the increase in bile salt concentration, the BC of PFASs in food increased and then remained constant, which was related to the changes in fatty acids and stability of the formed micelles. Comparing with the previous results obtained from animal study, the BC obtained in this study has the potential to predict PFAS bioavailability in food.

Direct evidence of the important role of proteins in bioconcentration and biomagnification of PFASs in benthic organisms based on comparison with OPEs.

Despite the wide acceptance that bioconcentration and biomagnification of per/polyfluoroalkyl substances (PFASs) is related to proteins in organisms, few direct evidences are available. Here, bioconcentration and biomagnification of 9 organophosphate esters (OPEs) and 16 PFASs, which have similar range of log Kow (octanol-water partitioning coefficient) values, were compared in the benthic food chain of biofilm-snail in Taihu Lake, China. The ∑OPEs level in water (150-23,036 ng/L) was significantly higher than ∑PFASs (57.3-351 ng/L). Although the logarithm of bioconcentration factors of both OPEs and PFASs in biofilm positively correlated with their log Kow, the slope of PFASs was 4 times of that of OPEs, which might be due to the strong interactions of PFASs with biofilm extracellular proteins. Additionally, PFASs exhibited distinctly greater biomagnification factors from biofilm to snails (3.09-17.8) than OPEs (0.39-3.48). Significant correlations between the concentrations and protein contents in snails were observed for most long-chain PFASs, but not for any OPEs. Multiple receptor models identified polyurethane foam (77.9 %) and food packaging/metal plating (56.9 %) were the primary sources of OPEs and PFASs in Taihu Lake, respectively. We provided strong and direct evidences that proteins facilitated bioconcentration and biomagnification of PFASs.

Occurrence, bioaccumulation and trophic transfer of organophosphate esters in marine food webs: Evidence from three bays in Bohai Sea, China.

Due to the widespread use of organophosphate esters (OPEs), the occurrence and trophic transfer of OPEs have attracted attentions in ecosystems. However, as the final sink for these chemicals, the bioaccumulations and trophodynamics of OPEs in marine ecosystems are still not clear. In this study, seawater, sediment and marine organisms collected from Bohai Bay (BHB), Laizhou Bay (LZB), and Liaodong Bay (LDB) in Bohai Sea (BS), China were analyzed to investigate the occurrence, bioaccumulation and trophic transfer of typical OPEs. Total concentration of OPEs (∑9 OPEs) in surface water in LZB (255.8 ± 36.44 ng/L) and BHB (209.6 ± 35.61 ng/L) was higher than that in LDB (170.0 ± 63.73 ng/L). Marine organisms in LZB accumulated the highest concentrations of OPEs among the 3 bays (∑10OPEs, 70.56 ± 61.36 ng/g ww). Average bioaccumulation factor (BAF) of OPEs in marine organism in BHB, LZB, and LDB was ranged from -2.48 to 0.16, from -2.96 to 1.78, and from -2.59 to 0.59. We also found that trophic magnification factors (TMF) are generally <1, which suggested trophic dilutions of OPEs in BS, China. Nevertheless, the relatively high OPEs levels in BS still may bring potential risks to ecosystem and human health.

First Insight into the Formation of In Vivo Transformation Products of 2-Ethylhexyl diphenyl phosphate in Zebrafish and Prediction of Their Potential Toxicities.

As a frequently detected organophosphorus flame retardant in the environment, 2-ethylhexyl diphenyl phosphate (EHDPHP) is vulnerable to biotransformation, while the transformation mechanisms and potential toxicities of its transformation products remain unclear. In the present study, in vivo transformation products of EHDPHP in exposed zebrafish for 21d were analyzed by suspect screening and identified by mass spectrometry. Fifteen metabolites were identified, including 10 phase I and 5 phase II products with monohydroxylated products being primary, among which 5-OH-EHDPHP was the most predominant. Two sulfation products and one terminal desaturation metabolite of EHDPHP were reported for the first time. A density functional calculation coupled with molecular docking disclosed that the specific conformation of EHDPHP docked in the protein pockets favored the primary formation of 5-OH-EHDPHP, which was fortified to be a more suitable biomarker of EHDPHP exposure. The in vitro tests suggested that EHDPHP transformation took place not only in liver but also in intestine, where gut microbes played an important role. Due to lack of standards, in silico toxicity prediction combined with molecular docking indicated that several metabolites potentially cause higher toxicities than EHDPHP. The results provide deep insight into the potential health risks due to specific in vivo transformation of EHDPHP.

Cognition of the warning symptoms and risk factors for cancer among Chinese college students: a cross-sectional study based on a summer social practice activity.

BACKGROUND: To investigate the cognition of cancer warning symptoms and cancer risk factors among Chinese college students, analyze the influencing factors, and explain the correlations between cancer cognition and cancer symptom discrimination, cancer fear and psychological distress. METHODS: Chinese college students were recruited in this cross-sectional study funded by a summer social practice activity in Yunnan Province, China. Cognition rates of cancer warning symptoms and cancer risk factors were evaluated using Cancer Warning symptoms Cognition Questionnaire (CWSCQ) and Cancer Risk Factors Cognition Questionnaire (CRFCQ), respectively. Factors associated with cognition of cancer warning symptoms, and factors associated with cognition of cancer risk factors were evaluated using multiple linear regression analysis. Interactions between cancer cognition, cancer symptom discrimination, psychological distress, and cancer fear were evaluated by structural equation modeling. RESULTS: There were 846 effective samples, with an effective rate of 80.9%. The cognition rates of cancer warning symptoms were from 47.9% to 84.4%, which were affected by cancer symptom discrimination, education, attitudes towards cancer screening, living expenses, drinking history, and ways to obtain cancer knowledge (p < 0.05). The cognition rates of cancer risk factors were from 46.3% to 91.3% in participants, which were affected by education, cancer symptom discrimination, psychological distress, attitudes towards cancer screening, life satisfaction, cancer history in relatives and friends, ways to obtain cancer knowledge, smoking history, and nursing history for cancer patients (p < 0.05). Cancer cognition and cancer symptom discrimination showed intermediary effects on psychological distress and cancer fear (p < 0.001). CONCLUSIONS: The overall cancer cognition situation among Chinese college students is not optimistic, which highlights the necessity of improving the cancer health literacy among Chinese college students. With the increasing morbidity and mortality rates of cancer, it is necessary to raise awareness of early detection, and early treatment of cancer among the general public. Health education interventions are helpful to improve cancer health literacy.

Insights into the Dermal Absorption, Deposition, and Elimination of Poly- and Perfluoroalkyl Substances in Rats: The Importance of Skin Exposure.

Humans are frequently exposed to poly- and perfluoroalkyl substances (PFASs) via direct skin contact with personal care and consumer products containing them. Here, we used a rat model to estimate the dermal penetration efficiency of 15 representative PFASs. After 144 h post-dosing, 4.1-18.0 and 5.3-15.1% of the applied PFASs in the low (L) and high (H) groups, respectively, were absorbed into the rats. PFAS absorption and permeation were parabolically associated with the perfluorinated carbon chain length (CF), peaking for perfluoroheptanoic acid (PFHpA). The lipid-rich stratum corneum of the skin barrier substantially suppressed the penetration of less hydrophobic short-chain PFASs, whereas the water-rich viable epidermis and dermis served as obstacles to hydrophobic long-chain PFAS permeation. However, the renal clearance (CLrenal) of the target PFAS decreased with increasing CF, suggesting that urinary excretion is crucial to eliminate less hydrophobic short-chain PFASs. Notably, the peak times of PFASs in the systemic circulation of rats (8-72 h) were remarkably longer than those after oral administration (1-24 h). These results suggest that dermal penetration can be long-lasting and contribute considerably to the body burden of PFASs, especially for those with moderate hydrophobicity due to their favorable skin permeation and unfavorable urinary excretion.

Development and reliability and validity test of the Fear of Cancer Scale (FOCS).

OBJECTIVE: To develop a Fear of Cancer Scale (FOCS) for non-cancer populations. METHODS: FOCS was developed by classical measurement theory. A total of 15 college students were invited to conduct semi-structured interviews. Seven experts were invited for expert consultation. A total of 2012 Chinese college students who had completed the electronic questionnaire on WJX.cn platform was included. The reliability and validity of FOCS were verified. Multiple linear regression analysis was adopted to explore the influencing factors of cancer fear among college students and further verify the validity of FOCS. RESULTS: There were 17 items in the FOCS, including two subscales - direct fear (8 items), and indirect fear (9 items). FOCS had good validity and reliability. Multiple linear regression showed that GAD-7 score, CSDS score, negative coping score, positive coping score, guardian's highest education, gender, life satisfaction, nationality and major were the influencing factors of cancer fear (p < .05). CONCLUSIONS: The 17-item FOCS was a reliable and valid measure to examine the level of cancer fear in non-cancer populations.

Mechanisms Underlying the Impacts of Lipids on the Diverse Bioavailability of Per- and Polyfluoroalkyl Substances in Foods.

Food is a major source of human exposure to per- and polyfluoroalkyl substances (PFASs), yet little is known about their bioavailability in food matrices. Here, the relative bioavailability (RBA) of PFASs in foods was determined using an in vivo mouse model. Pork, which had the highest lipid content, exhibited the greatest effect on bioavailability by increasing the RBAs of perfluoroalkyl acids (PFAAs) while reducing those of fluorotelomer phosphate diesters (diPAPs). During intestinal digestion of lipids, the bioaccessibility of PFAAs increased due to their greater partition into the stable mixed micelles. However, diPAPs were more likely to partition into the undigested oil phase due to their strong hydrophobicity. Both in vitro incubation and molecular docking results indicated that the PFAAs exhibited stronger binding affinities with mouse blood chylomicrons (CMs) than with diPAPs. Collectively, both lipid digestion in the intestine and the carrier effect of CMs played important roles in modulating the bioavailability of PFASs in food. More attention should be given to further evaluating the health risks of PFASs associated with the intake of high-lipid foods.

Insights into the sex-dependent reproductive toxicity of 2-ethylhexyl diphenyl phosphate on zebrafish (Danio rerio).

As a frequently detected organophosphate ester in various environmental media, the toxic effects of 2-ethylhexyl diphenyl phosphate (EHDPHP) on aquatic organisms of different sexes remain unclear. In this study, adult zebrafish were exposed to 2.5, 50, 250 µg/L of EHDPHP for 21 days to investigate its sex-dependent reproductive toxicity and related mechanisms. EHDPHP exposure significantly inhibited the reproduction of zebrafish, evidenced by the reduced spawning of females, depressed growth and development of their offspring. EHDPHP induced greater impacts on the changes of sex hormones and vitellogenin (VTG) in the males than females. For females, the synthesis of testosterone (T) was inhibited because of the down-regulated gnrhr2, gnrhr3, gnrhr4, gnrh3, gnrh2 and er2ß in the brain, while 17ß-estradiol (E2) increased in 250 µg/L due to up-regulated cyp19a. For males, the promotion of T was directly related to the up-regulation of fshr, 3ßhsd, star, cyp11 and cyp17 in the gonad, and eventually led to the increase of E2. The decrease of plasma 11-KT in both sexes could be mainly attributed to the down-regulation of cyp11b and hsd11b. The plasma VTG decreased in females but increased in males, which was in accordance with the down and up regulation of erα and er2ß in the females and males, respectively. All these indicated EHDPHP displayed reproductive toxicity on zebrafish in a sex dependent manner. Molecular docking analysis indicated stronger interaction of EHDPHP with the antagonisms of estrogen receptor (ER) and androgen receptor (AR), as well as the agonism of CYP19A1, which further revealed the sex-dependent reproductive toxicity mechanism of EHDPHP. This study highlights the importance of distinguishing males and females in toxicity evaluation of endocrine disruption chemicals.

Underlying mechanisms for the impacts of molecular structures and water chemistry on the enrichment of poly/perfluoroalkyl substances in aqueous aerosol.

Enrichment of ionic poly/perfluoroalkyl substances (PFASs) in aqueous aerosol (AA) is an important pathway for them to enter atmosphere. In this study, the enrichment behaviors of 12 legacy and emerging PFASs in AA in both single solute and mixed solutions were investigated. The enrichment factors (EF) displayed a general increasing trend with the fluorinated carbon chain length. For the first time, a robust Quantitative Structure-Property Relationship (QSPR) model coupled with partial least-square method was established with fifteen quantum chemical descriptors. Four molecular descriptors, including dipole moment (µ), molecular weight (MW), the maximal value of the molecular surface potential (Vs, max) and molecular volume (V) were identified as the key structural variables affecting the PFASs enrichment. Inorganic salts and humic acid (HA) which are common in seawater, facilitated the PFASs enrichment as a result of enhanced hydrophobicity and the bridging effect caused by divalent cations. The typical cationic and anionic surfactants, cetyltrimethylammonium bromide and sodium dodecyl sulfate, both inhibited the enrichment due to the competition between PFASs and surfactants. It is interesting that 6:2 chlorinated polyfluorinated ether sulfonate (F53B) had the highest EF among the 12 PFASs, implying its strong potential of atmosphere transport.

Distribution and sources of ordinary monomeric and emerging oligomeric organophosphorus flame retardants in Haihe Basin, China.

With the banning of poly-brominated diphenyl ethers, organophosphorus flame retardants (OPFRs) have gained great development space as their alternatives. In this study, the concentration and partition of nine ordinary monomeric OPFRs and two emerging oligomeric OPFRs (Resorcinol bis(diphenyl phosphate) (RDP) and bisphenol A bis(diphenyl phosphate) (BDP) in the Haihe Basin of China were studied, and their possible sources were analyzed. The Æ©OPFRs in the surface water, sediments and suspended particulate matters (SPMs) in Haihe Basin were 80.1-777 ng/L, 18.9-86.5 ng/g dw and 6.40-234 ng/g dw, respectively. The detection frequencies of both oligomeric OPFRs exceeded 85%, suggesting their environmental contamination was widespread. The mean concentrations of RDP and BDP were 2.09 and 6.03 ng/L in the surface water, 0.91 and 5.09 ng/g dw in the sediments, 1.08 and 2.61 ng/g dw in SPMs, respectively. With Cl-OPFRs being predominant in all the three media, the proportions of alkyl-OPFRs, aryl-OPFRs, and oligomeric OPFRs in the sediments and SPMs were remarkably higher than those in surface water, suggesting that non-halogenated OPFRs preferred to distribute in solid phases. The water-sediment/SPM partition coefficients, logKoc, of the OPFRs were calculated based on the paired samples. The logKoc values of RDP and BDP were reported for the first time, and their logKoc water-sediment were 4.36 ± 0.47 and 4.76 ± 0.25 and their logKoc water-SPM were 3.77 ± 0.45 and 4.00 ± 0.47, respectively. The obtained logKoc values were correlated with their octanol-water partition coefficient (logKow) significantly. It suggested that their partition to sediment or SPM was dominated by hydrophobic interaction. Principal component analysis indicated that the emissions from manufacturing plants and airport operation might be two important sources of OPFRs in the Haihe Basin of China.

Estimating renal and hepatic clearance rates of organophosphate esters in humans: Impacts of intrinsic metabolism and binding affinity with plasma proteins.

The renal and hepatic clearance rates of organophosphate esters (OPEs) in humans were estimated. Six OPEs and their corresponding diester metabolites (mOPEs) were quantified respectively in 30 paired human plasma and urine samples collected in Hengshui, Hebei province, China. The renal clearance rate (CLrenal) of triphenyl phosphate (TPHP), tris(chloroethyl) phosphate (TCEP) and tris(1,3-dichloro-isopropyl) phosphate (TDCIPP) was estimated to be 68.9, 50.9 and 33.3 mL/kg/day, respectively, while it was not calculated for other three OPEs due to the low detection frequencies in human samples. To estimate the clearance rates of the target OPEs, hepatic clearance rates (CLh) of OPEs were extrapolated from their in vitro intrinsic clearance data in human liver microsomes (CLHLM). The calculated CLh values of TCEP and TDCIPP were comparable to their CLrenal, indicating that the in vitro extrapolation method was suitable for estimating the clearance rates of OPEs. The higher binding affinity of TDCIPP with plasma proteins could reduce its renal clearance. The estimated half-lives of Cl-OPEs in human were longer than those of the aryl- and alkyl-OPEs. This study provided a feasible in vitro method to predict the clearance and half-lives of OPEs in human, which is significant for their accurate health risk assessment.

Stronger estrogenic and antiandrogenic effects on zebrafish larvae displayed by 6:2 polyfluoroalkyl phosphate diester than the 8:2 congener at environmentally relevant concentrations.

Polyfluoroalkyl phosphate esters (PAPs) are one kind of emerging polyfluoroalkyl substances in the environment. However, their in vivo toxicities are largely unknown, especially at environmental relevant concentrations. To fill this gap, zebrafish embryos were exposed to 6:2 or 8:2 diPAP at environmentally relevant concentrations (0.5, 5, 50 ng/L) for 7 d. 6:2 and 8:2 diPAPs upregulated the mRNA and protein levels of aromatase in the exposed larvae, and elevated estradiol (E2) and vitellogenin (VTG) levels, but reduced testosterone (T) and 11-ketotestosterone (11-KT) levels, demonstrating estrogenic and antiandrogenic effects. Among the three ER subtypes, ERß2 displayed the highest in vivo mRNA expression and the lowest in silico binding energies, suggesting that it was the main target ER subtype responsible for the estrogenic effect. Molecular simulation results indicated that diPAPs and E2 could bind to one common residue, arginine (Arg) 87, in the binding pocket of ERß2, inducing similar estrogenic disruption mechanisms as E2. Both compounds could form hydrophobic interaction with glutamic acid (Glu) 12 and tryptophan (Trp) 80 and two hydrogen bonds with Arg81 of androgen receptor (AR) ligand-binding domains (LBDs) in antagonistic mode, resulting in a reduced level of AR upon exposure. The in silico binding energies of 6:2 diPAP with both ER and AR were lower than 8:2 diPAP, explaining the observed greater in vivo estrogenic and antiandrogenic activities of 6:2 diPAP. This study provided the first line of evidences that diPAPs could display adverse effects on the endocrine functions of fish species.

Thyroid endocrine disruption effects of perfluoroalkyl phosphinic acids on zebrafish at early development.

Perfluoroalkyl phosphinic acids (PFPiAs, including 6:6, 6:8 and 8:8 PFPiAs) are one kind of emerging perfluoroalkyl substances and usually used as leveling and wetting agents in household cleaning products and pesticide formulations. In this study, zebrafish embryos (6 h post-fertilization [hpf]) were exposed to 6:6, 6:8 and 8:8 PFPiAs individually (0.5, 5 and 50 nM) for 168 hpf. 8:8 PFPiA at 5 and 50 nM reduced the body length, while all treatments of 6:8 and 8:8 PFPiA depressed the heartbeat of the zebrafish larvae. 8:8 PFPiA at 50 nM distinctly enhanced the thyroxine (T4) and triiodothyronine (T3) contents. In a negative feedback mechanism, the three PFPiAs remarkably suppressed the genes responsible for THs regulation (corticotropin-releasing hormone, crh; thyroid stimulating hormone, tshß), and 8:8 PFPiA displayed the strongest effect. In addition, 8:8 PFPiA significantly promoted the gene expressions corresponding to THs transport, metabolism and action (transthyretin, ttr; uridine diphosphate glucuronosyltransferase, ugt1ab; deiodinases, dio1 and dio2; thyroid hormone receptors, trα and trß). As a result, 8:8 PFPiA displayed the strongest thyroid endocrine disrupting effect and significantly affected the growth of zebrafish larvae among the three PFPiAs in the present study.