Combining Network Pharmacology with Molecular Docking for Mechanistic Research on Thyroid Dysfunction Caused by Polybrominated Diphenyl Ethers and Their Metabolites.

Network pharmacology was used to illuminate the targets and pathways of polybrominated diphenyl ethers (PBDEs) causing thyroid dysfunction. A protein-protein interaction (PPI) network was constructed. Molecular docking was applied to analyze PBDEs and key targets according to the network pharmacology results. A total of 247 targets were found to be related to 16 PBDEs. Ten key targets with direct action were identified, including the top five PIK3R1, MAPK1, SRC, RXRA, and TP53. Gene Ontology (GO) functional enrichment analysis identified 75 biological items. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified 62 pathways mainly related to the regulation of the thyroid hormone signaling pathway, MAPK signaling pathway, PI3K-Akt signaling, pathways in cancer, proteoglycans in cancer, progesterone-mediated oocyte maturation, and others. The molecular docking results showed that BDE-99, BDE-153, 5-OH-BDE47, 5'-OH-BDE99, 5-BDE47 sulfate, and 5'-BDE99 sulfate have a good binding effect with the kernel targets. PBDEs could interfere with the thyroid hormone endocrine through multiple targets and biological pathways, and metabolites demonstrated stronger effects than the prototypes. This research provides a basis for further research on the toxicological effects and molecular mechanisms of PBDEs and their metabolites. Furthermore, the application of network pharmacology to the study of the toxicity mechanisms of environmental pollutants provides a new methodology for environmental toxicology.

Multicenter biomonitoring of polybrominated diphenyl ethers (PBDEs) in colostrum from China: Body burden profile and risk assessment.

Polybrominated diphenyl ethers (PBDEs) were listed in the Stockholm Convention due to their persistent and toxic nature. In utero exposure to PBDEs might affect fetal development as it is sensitive when exposed to even low dose of xenobiotic substances during the pregnancy. In this study, a multi-centre human biomonitoring study of tri-to hexa-BDEs was conducted in three Chinese cities using 60 colostrum samples from local residents. The patterns and influencing factors, correlation with the birth outcome, and potential health risks during the breastfeeding of tri-to hexa-BDEs in the colostrum samples were assessed. The median concentration of tri-to hexa-BDEs was 9.1 (Interquartile range: 3.1-19.5) ng g-1 lipid weight, and BDE-153 contributed 68% of the detected PBDEs. The PBDE levels were mostly associated with maternal age and drinking water sources, while correlations with other factors including weight gain, BMI, parity and the number of aborted pregnancies was not significant. The level of BDE-28 was positively correlated with the birth weight, while the BDE-99 was positively correlated with the head circumference, using multilinear regression. For the total hazard quotients, 60% of the infants have an estimated value higher than 1, showed potential chronic hazard for future development and possible adverse health effects to the babies from the exposure to PBDE congeners. Alternative food source seems to have a lower risk for neonates than the colostrum, but the advantages of breastfeeding undoubtedly outweigh the risks and potential adverse health effects caused by environmental PBDEs and other xenobiotic chemical exposure.

Increased coiling frequency linked to apoptosis in the brain and altered thyroid signaling in zebrafish embryos (Danio rerio) exposed to the PBDE metabolite 6-OH-BDE-47.

Polybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants that are ubiquitously detected in the environment and associated with adverse health outcomes. 6-OH-BDE-47 is a metabolite of the flame retardant, 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), and there is increasing concern regarding its developmental neurotoxicity and endocrine disrupting properties. In this study, we report that early life exposure in zebrafish (Danio rerio) embryos to 6-OH-BDE-47 (50 and 100 nM) resulted in higher coiling frequency and significantly increased apoptotic cells in the brain. These effects were partially rescued by overexpression of thyroid hormone receptor ß (THRß) mRNA. Moreover, exposure to 100 nM 6-OH-BDE-47 significantly reduced the number of hypothalamic 5-hydroxytryptamine (5-HT, serotonin)-immunoreactive (5-HT-ir) neurons and the mRNA expression of tryptophan hydroxylase 2 (TPH2). These results indicate that 6-OH-BDE-47 affected thyroid hormone regulation through THRß and negatively impacted the nervous system, in turn, affecting coiling behavior. Correlations of these endpoints suggest that coiling frequency could be used as an indicator of neurotoxicity in embryos.

Enhanced soil washing process for the remediation of PBDEs/Pb/Cd-contaminated electronic waste site with carboxymethyl chitosan in a sunflower oil-water solvent system and microbial augmentation.

An innovative ex situ soil washing technology was developed to remediate polybrominated diphenyl ethers (PBDEs) and heavy metals in an electronic waste site. Elevated temperature (50 °C) in combination with ultrasonication (40 kHz, 20 min) at 5.0 mL L(-1) sunflower oil and 2.5 g L(-1) carboxymethyl chitosan were found to be effective in extracting mixed pollutants from soil. After two successive washing cycles, the removal efficiency rates for total PBDEs, BDE28, BDE47, BDE209, Pb, and Cd were approximately 94.1, 93.4, 94.3, 99.1, 89.3, and 92.7 %, respectively. Treating the second washed soil with PBDE-degrading bacteria (Rhodococcus sp. strain RHA1) inoculation and nutrient addition for 3 months led to maximum biodegradation rates of 37.3, 52.6, 23.9, and 1.3 % of the remaining total PBDEs, BDE28, BDE47, BDE209, respectively. After the combined treatment, the microbiological functions of washed soil was partially restored, as indicated by a significant increase in the counts, biomass C, N, and functioning diversity of soil microorganisms (p < 0.05), and the residual PBDEs and heavy metals mainly existed as very slow desorbing fractions and residual fractions, as evaluated by Tenax extraction combined with a first-three-compartment model and sequential extraction with metal stability indices (I R and U ts). Additionally, the secondary environmental risk of mixed contaminants in the remediated soil was limited. Therefore, the proposed combined cleanup strategy is an environment-friendly technology that is important for risk assessment and management in mixed-contaminated sites.

Exposure of general population to PBDEs: a Progressive Total Diet Study in South Korea.

This study assessed the level of 24 polybrominated diphenyl ethers (PBDEs) in Korean foods following a Progressive Total Diet Study (TDS). The experiments comprised 96 types of dietetically representative foods, all were either cooked or edible raw. PBDEs were widely encountered in foodstuffs with the highest concentration in plant oils, fishes and shellfishes. Of all congeners tested for, BDE-47 was the most predominant and encountered in almost all food items except meats. The presence of nona-BDEs at significant levels indicated that Korean environments are still contaminated by deca-BDE. The daily dietary intake of PBDEs was estimated to be 63 ng d(-1). The highest PBDEs intake was observed in the 19-39 year old group and gradually decreased as age increased. Our study suggests that the TDS approach using foods in the table-ready form should be used for a better estimation of dietary exposure to PBDEs.

Tea saponin enhanced biodegradation of decabromodiphenyl ether by Brevibacillus brevis.

Decabromodiphenyl ether (BDE209) is a ubiquitous persistent pollutant and has contaminated the environment worldwide. To accelerate BDE209 elimination and reveal the mechanism concerned, the biosurfactant tea saponin enhanced degradation of BDE209 by Brevibacillus brevis was conducted. The results revealed that tea saponin could efficiently increase the solubility of BDE209 in mineral salts medium and improve its biodegradation. The degradation efficiency of 0.5 mg L(-1) BDE209 by 1 g L(-1) biomass with surfactant was up to 55% within 5d. Contact time was a significant factor for BDE209 biodegradation. BDE209 biodegradation was coupled with bioaccumulation, ion release and utilization, and debromination to lower brominated PBDE metabolites. During the biodegradation process, B. brevis metabolically released Na(+), NH4(+), NO2(-) and Cl(-), and utilized the nutrient ions Mg(2+), PO4(3-) and SO4(2-). GC-MS analysis revealed that the structure of BDE209 changed under the action of strain and nonabromodiphenyl ethers (BDE-208, -207 and -206), octabromodiphenyl ethers (BDE-203, -197 and -196) and heptabromodiphenyl ether (BDE-183) were generated by debromination.

Subacute oral toxicity of BDE-15, CDE-15, and HODE-15 in ICR male mice: assessing effects on hepatic oxidative stress and metals status and ascertaining the protective role of vitamin E.

The present study examined the effects of oral exposure of 4,4'-dibromodiphenyl ether (BDE-15), 4,4'-dichlorodiphenyl ether (CDE-15), and 4,4'-dihydroxydiphenyl ether (HODE-15) on hepatic oxidative stress (OS) and metal status in Institute of Cancer Research (ICR) male mice. Furthermore, the role of vitamin E in ameliorating potential OS caused by BDE-15, CDE-15, and HODE-15 was investigated. Three groups of mice were exposed to 1.20 mg/kg(body weight)/day of each of the three toxicants for 28 days. Results showed that none of the three toxicants altered growth rates of mice, but significantly increased (P<0.05) relative liver weights and decreased relative kidney weights. Pathological changes including cell swelling, inflammation and vacuolization, and hepatocellular hypertrophy in livers were observed. Significant decreases (P<0.05 and P<0.01) in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and glutathione (GSH) levels, together with increases in malondialdehyde (MDA) content were recorded in all toxicant-treated groups. Hepatic copper levels increased in all toxicant-treated groups. Hepatic zinc levels decreased in the liver of BDE-15-treated mice, whereas they increased in the livers of CDE-15-treated and HODE-15-treated mice. In conclusion, daily exposure to the three toxicants perturbed metal homeostasis and increased OS in mouse liver. Experimental data indicated the hepatic oxidative toxicity of the three toxicants followed the order BDE-15

Field dissipation of oxyfluorfen in onion and its dynamics in soil under Indian tropical conditions.

Oxyfluorfen, a diphenyl-ether herbicide is being used to control annual and perennial broad-leaved weeds and sedges in a variety of field crops including onion. The present study was aimed to investigate the dynamics and field persistence of oxyfluorfen in onion plant, bulb and soil under Indian tropical conditions. Application of four rates of oxyfluorfen viz., 200, 250, 300 and 400 g AI ha(-1) as pre-emergence gave good weed control in field experiment with onion. The oxyfluorfen residue dissipated faster in plant than in soil respectively, with a mean half-life of 6.1 and 11.2 days. Dissipation followed first-order kinetics. In laboratory column leaching experiments, 17 percent of the applied oxyfluorfen was recovered from the soil and indicates its solubility in water and mobility in sandy clay loam soil was low. A sorption study revealed that the adsorption of oxyfluorfen to the soil was highly influenced by the soil organic carbon with the Koc value of 5450. The study concludes that the dissipation of oxyfluorfen in soil and onion was dependent on the physico-chemical properties of the soil and environmental conditions.

Effects of nitrogen and phosphorus concentrations on the bioaccumulation of polybrominated diphenyl ethers by Prorocentrum donghaiense.

The growth, cellular total lipids, bioaccumulation amount, and bioaccumulation factors (BAFs) of 2,4,4'-tribromodiphenyl ether (BDE28), 2,2',4,4'-tetrabromodiphenyl ether (BDE47), and 2,2',4,4',5-pentabromodiphenyl ether (BDE99) in a semi-continuous culture of Prorocentrum donghaiense were studied in relation to nitrate (0, 128, and 512 micromol/L) and phosphate (0, 8, and 32 micromol/L) concentrations. The BDE28, BDE47, and BDE99 content per cell under 0 micromol N/L were 3.77 x 10(-6), 3.95 x 10(-6), and 4.32 x 10-6 ng/cell, respectively, which were significantly higher than those under 128 and 512 micromol N/L. A nearly 5-fold increase in polybrominated diphenyl ether (PBDE) content per algal cell was found between 0 and 8 micromol P/L and between 8 and 32 micromol P/L. With increasing N and P concentrations, the PBDE content per volume of algal culture and the accumulation percentage of available PBDEs declined slightly. The BAFs for the PBDEs based on lipids showed that the logBAF(lip) under 0 micromol N/L was higher than those under 128 and 512 micromol N/L. The logBAF(lip) under 0 micromol P/L was higher than that under 8 micromol P/L but lower than that under 32 micromol P/L. Correlation analysis indicated a significant negative correlation between nutrient concentration and cellular total lipids, as well as the PBDE content per cell. The results indicate that different N and P concentrations change the total lipids content of P. donghaiense, thereby resulting in varying PBDE accumulation.

In vitro biotransformation of PBDEs by root crude enzyme extracts: potential role of nitrate reductase (NaR) and glutathione S-transferase (GST) in their debromination.

In order to investigate the enzyme transformation of PBDEs and to track the key enzymes involved in PBDE degradation in plants, in vivo exposure of plants of ryegrass, pumpkin and maize and in vitro exposure of their root crude enzyme extracts to PBDEs were conducted. Degradation of PBDEs in the root crude enzyme solutions fit well with the first order kinetics (R(2)=0.52-0.97, P<0.05), and higher PBDEs degraded faster than the lower ones. PBDEs could be transformed to lower brominated PBDEs and hydroxylated-PBDEs by the root crude enzyme extracts with debromination as the main pathway which contributed over 90% of PBDE depletion. In vitro and in vivo exposure to PBDEs produced similar responses in root enzyme activities of which the nitroreductase (NaR) and glutathione-transferase (GST) activities decreased significantly, while the peroxidase, catalase and cytochrome P-450 activities had no significant changes. Furthermore, higher enzyme concentrations of NaR and GST led to higher PBDE debromination rates, and the time-dependent activities of NaR and GST in the root crude enzyme extracts were similar to the trends of PBDE depletion. All these results suggest that NaR and GST were the key enzymes responsible for PBDE degradation. This conclusion was further confirmed by the in vitro debromination of PBDEs with the commercial pure NaR and GST.

Polybrominated diphenyl ethers in maternal serum, umbilical cord serum, colostrum and mature breast milk. Insights from a pilot study and the literature.

Human serum and mother's milk are frequently used to assess exposure to polybrominated diphenyl ethers (PBDEs), including transplacental transfer to the foetus. However, little is known about the kinetics of PBDEs, especially the highly brominated BDE congeners. In this pilot study, maternal serum samples were collected from 10 women at delivery and five to six weeks post partum. Umbilical serum was also obtained. Milk was donated two to five days, and five to six weeks after delivery. The amount of PBDEs in these samples was determined using liquid-liquid extraction and GC/MS. Low, moderately and highly brominated diphenyl ethers were present in umbilical cord serum, indicating placental transfer. The lipid-adjusted levels of BDE-47, BDE-207 and BDE-209 were similar in maternal and umbilical cord serum, whereas the cord serum levels for the penta- to octa-BDEs quantified were lower than in maternal serum. Marked changes were seen in the congener pattern in breast milk during the first month of lactation, whereas maternal serum levels did not change significantly. The general pattern was an enrichment of low to moderately brominated congeners (i.e. from BDE-17 to BDE-154, with the exception of BDE-28) in colostrum compared with maternal serum. In contrast, more highly brominated congeners were found at similar, or lower levels in colostrum than in maternal serum. After the transition from colostrum to mature milk, the levels of BDE-153 and BDE-209 were substantially reduced, and BDE-209 was below the limit of detection in 6 out of 9 samples. A literature review on the design and reporting of studies on the transfer of PBDEs from mother to infant revealed a lack of transparency in many cases. The use of the recently published STROBE-ME guidelines is therefore recommended.

Absorption and translocation of polybrominated diphenyl ethers (PBDEs) by plants from contaminated sewage sludge.

Polybrominated diphenyl ethers (PBDEs) are used as additive flame retardants. PBDEs are persistent, bioaccumulative and toxic compounds. They are often detected in sewage sludge which is applied on agricultural soils as fertilizer. The objective of this study was to find out whether plants are able to accumulate and translocate PBDEs. Tobacco (Nicotiana tabacum) and nightshade (Solanum nigrum) were planted in pots containing contaminated sewage sludge and uncontaminated substrate. After 6 months of plant cultivation in sewage sludge up to 15.4 ng g(-1) dw and 76.6 ng g(-1) dw of PBDE congeners--BDE 47, BDE 99 and BDE 100---were accumulated in the nightshade and tobacco tissue, respectively. Corresponding values in plants vegetated in the control garden substrate were 10 times lower. The bioconcentration factors (BCFs) of accumulated congeners were calculated. Tobacco exhibited higher BCFs values and for both plants BCFs values of BDE 47, BDE 99, BDE 100 and BDE 209 negatively correlated with their octanol-water partition coefficients (logK(ow)). The exception was decaBDE (BDE 209) which was accumulated only in tobacco tissue in the concentration of 116.8 ng g(-1) dw. The majority of PBDEs was detected in above-ground plant biomass indicating that both plants have the ability to translocate PBDEs. To our knowledge this is one of the first studies reporting the accumulation of both lower PBDEs and BDE 209 in plants. Our results suggest that absorption, accumulation and translocation of PBDEs by plants and their transfer to the food chain could represent another possible risk for human exposure.

Effects of decontaminated fish oil or a fish and vegetable oil blend on persistent organic pollutant and fatty acid compositions in diet and flesh of Atlantic salmon ( Salmo salar).

The health benefits of seafood are well documented and based on the unique supply of n-3 highly unsaturated fatty acids (HUFA). Aquaculture now contributes about 50 % of food-grade seafood globally and Atlantic salmon (Salmo salar) is a rich source of n-3 HUFA. However, salmon and other oily fish can accumulate lipophilic persistent organic pollutants (POP), including dioxins (PCDD/F), polychlorinated biphenyls (PCB) and polybrominated diphenyl ethers (PBDE), derived largely from feed. In the present study, triplicate groups of salmon, of initial weight 0.78 kg, were fed one of three experimental diets for 11 weeks. The diets were coated with either a northern fish oil (FO) with a high POP content (cNFO), the same oil that had been decontaminated (deNFO) or a blend of southern fish oil, rapeseed and soyabean oils (SFO/RO/SO). Dietary PCDD/F+dioxin-like PCB (DL-PCB) concentrations were 17.36, 0.45 and 0.53 ng toxic equivalents (TEQ)/kg, respectively. After 11 weeks, the flesh concentrations in fish fed the cNFO, deNFO and SFO/RO/SO diets were 6.42, 0.34 and 0.41 ng TEQ/kg, respectively. There were no differences in flesh EPA and DHA between fish fed the cNFO or deNFO diets although EPA and DHA were reduced by 50 and 30 %, respectively, in fish fed the SFO/RO/SO diet. Thus, decontaminated FO can be used to produce salmon high in n-3 HUFA and low in POP. Salmon produced using deNFO would be of high nutritional value and very low in POP and would utilise valuable fish oils that would otherwise be destroyed due to their high pollutant concentrations.