Enantiomerization and enantioselective bioaccumulation of diclofop-methyl in tubifex worms.

In this study, the hydrolysis of diclofop-methyl (DM) in aqueous system and the bioaccumulation of its main metabolite, Diclofop (DA), in the tubifex worms were investigated using enantioselective high-performance liquid chromatography. With the addition of tubifex, rapid hydrolysis was observed for DM. It is revealed that the hydrolysis of DM in the water and the accumulation of DA in the worms were both enantioselective. Meanwhile, either the hydrolysis amount or the levels of enantioselectivity were influenced by the tubifex. After incubated for 24 h, about 94.6% of the DM was hydrolyzed and the enantiomer fraction of metabolite (DA) deviated from 0.5 with R-DA significantly higher than S-DA. The enantiopure S-DM and R-DM and S-DA and R-DA were incubated, and enantiomerizations were detected between the two DM enantiomers with S-form inversing into R-form and vice versa. It was found that the S-DM exhibited a higher tendency to invert than the R-DM.

Congener Variation of Genetic Dependent-Developmental Toxicology in Two Emerging Classes of Dioxin-like Compounds.

Emerging classes of dioxin-like compounds (DLCs) like hydroxylated/methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) and polychlorinated diphenyl sulfides (PCDPSs) could lead to diverse adverse outcomes in humans and wildlife, yet knowledge gaps exist in their molecular mechanisms associated with different structures following early life environmental exposure. This study integrated a genetic knockout technique and concentration-dependent reduced zebrafish transcriptome approach (CRZT) to unravel the toxicological pathways underpinning developmental toxicity of four HO-/MeO-PBDEs and five PCDPSs at environmentally relevant doses. Generally, the dependence of aryl hydrocarbon receptor (AhR) on the embryotoxicity and transcriptomic potencies induced by the HO-PBDEs and PCDPSs varied across different congeners. The knockout of the ahr2 gene led to 1.02- to 76.48-fold decreases of DLC-induced embryotoxicities and reduced the transcriptome-based potencies ranging from 1.38 to 2124.74 folds in the CRZT test. The fold changes denoting AhR-mediated potentials significantly increased with the increasing chlorination degrees of MeO-PBDEs and PCDPSs (p < 0.05). Moreover, ahr2 knockout primarily affected the DLC-induced early molecular responses relevant to DNA damage, enzyme activation, and organ development. Our integrated approach revealed the differential role of AhR in mediating the developmental toxicity of emerging DLCs possessing varied structures at environmentally relevant doses.

Computational Risk Assessment of Persistence, Bioaccumulation, and Toxicity of Novel Flame-Retardant Chemicals.

Novel brominated flame retardants (NBFRs) have emerged as chemicals of environmental concern, as they have been widely used as an alternative to polybrominated diphenyl ethers (PBDEs). Considering the similar structural features of NBFRs and PBDEs necessitates a comprehensive investigation to understand the physicochemical relationships of these compounds and their ability to alter biological functions. In this study, we investigated the persistent nature of NBFRs in terms of thyroid-disrupting potential by understanding the structure-stability aspects using density functional theory (DFT)-based reactivity parameters and interactions via molecular docking and molecular dynamics (MD) simulations. The results indicate that the DFT-based stability descriptor (chemical hardness) is associated with the persistent nature of NBFRs. The computed molecular interaction profile revealed prominent interactions between thyroid receptor-ß (TR-ß) and NBFRs. Stable trajectory and interactions with TR-ß were obtained with ATE, p-TBX, PBT, PBEB, and TBBPA-DBPE during 100 ns of MD simulation. The results of these studies have suggested that the presence of a higher number of halogenated atoms increases the stability vis-à-vis the persistence and endocrine disruption potential of NBFRs.

Study on the Biomolecular Competitive Mechanism of Polybrominated Diphenyl Ethers and Their Derivatives on Thyroid Hormones.

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants. PBDEs and their derivatives, hydroxylated PBDEs (OH-PBDEs), can bind to hormone receptors and impact hormone secretion, transportation, and metabolism, leading to endocrine disruption and the development of various diseases. They have particularly strong interference effects on thyroid hormones. This study used decabromodiphenyl ether (BDE-209); 2,2',4,4'-tetrabromodiphenyl ether (BDE-47); and 6-OH-BDE-47 as representative compounds of PBDEs and their derivatives, OH-PBDEs. A fluorescence probe, fluorescein-isothiocyanate-L-thyroxine (FITC-T4, F-T4), specific for binding to transthyretin (TTR), a thyroid transport protein, was prepared. The binding capacity of PBDEs and their derivatives, OH-PBDEs, to TTR was quantitatively measured using fluorescence spectroscopy. The principle of quenching the fluorescence intensity of F-T4 after binding to TTR was used to analyze the competitive interaction between the probe and BDE-209, BDE-47, and 6-OH-BDE-47, thereby evaluating the toxic effects of PBDEs and their derivatives on the thyroid system. Additionally, AutoDock molecular docking software (1.5.6) was used to further analyze the interference mechanism of OH-PBDEs on T4. The results of the study are as follows: (1) Different types of PBDEs and OH-PBDEs exhibit varying degrees of interference with T4. Both the degree of bromination and hydroxylation affect their ability to competitively bind to TTR. Higher bromination and hydroxylation degrees result in stronger competitive substitution. (2) The competitive substitution ability of the same disruptor varies at different concentrations. Higher concentrations lead to stronger substitution ability, but there is a threshold beyond which the substitution ability no longer increases. (3) When OH-PBDEs have four or more bromine atoms and exhibit the most structural similarity to T4, their binding affinity to TTR is stronger than that of T4.

BDE209-promoted Dio2 degradation in H4 glioma cells through the autophagy pathway, resulting in hypothyroidism and leading to neurotoxicity.

Decabromodiphenyl ether (BDE209), the homologue with the highest number of brominates in polybrominated diphenyl ethers (PBDEs), is one of the most widespread environmental persistent organic pollutants (POPs) due to its mass production and extensive application in recent decades. BDE209 is neurotoxic, possibly related to its interference with the thyroid hormone (TH) system. However, the underlying molecular mechanisms of BDE209-induced TH interference and neurobehavioral disorders remains unknown. Here, we explored how BDE209 manipulated the major enzyme, human type II iodothyronine deiodinase (Dio2), that is most important in regulating local cerebral TH equilibrium by neuroglial cells, using an in vitro model of human glioma H4 cells. Clonogenic cell survival assay and LC/MS/MS analysis showed that BDE209 could induce chronic neurotoxicity by inducing TH interference. Co-IP assay, RT-qPCR and confocal assay identified that BDE209 destroyed the stability of Dio2 without affecting its expression, and promoted its binding to p62, thereby enhancing its autophagic degradation, thus causing TH metabolism disorder and neurotoxicity. Furthermore, molecular docking studies predicted that BDE209 could effectively suppress Dio2 activity by competing with tetraiodothyronine (T4). Collectively, our study demonstrates that BDE209-induced Dio2 degradation and loss of its enzymatic activity in neuroglial cells are the fundamental pathogenic basis for BDE209-mediated cerebral TH disequilibrium and neurotoxicity, providing a target of interest for further investigation using glial/neuronal cell co-culture system and in vivo models.

A mechanistic and kinetic investigation on the oxidative thermal decomposition of decabromodiphenyl ether.

The thermal processes of materials containing decabromodiphenyl ether (BDE-209) normally result in the exposure of BDE-209 to high-temperature environments, generating a series of hazardous compounds. However, the evolution mechanisms of BDE-209 during oxidative thermal processes remain unclear. Thus, this paper presents a detailed investigation on the oxidative thermal decomposition mechanism of BDE-209 by utilizing density functional theory methods at the M06/cc-pVDZ theoretical level. The results show that the barrierless fission of the ether linkage dominates the initial degradation of BDE-209 at all temperatures, with branching ratio over 80%. The decomposition of BDE-209 in oxidative thermal processes is mainly along BDE-209 → pentabromophenyl and pentabromophenoxy radicals → pentabromocyclopentadienyl radicals → brominated aliphatic products. Additionally, the study results on the formation mechanisms of several hazardous pollutants indicate that the ortho-phenyl-type radicals created by ortho-C-Br bond fission (branching ratio reached 15.1% at 1600 K) can easily be converted into octabrominated dibenzo-p-dioxin and furan, which require overcoming the energy barriers of 99.0 and 48.2 kJ/mol, respectively. The O/ortho-C coupling of two pentabromophenoxy radicals also acts as a non-negligible pathway for the formation of octabrominated dibenzo-p-dioxin. The synthesis of octabromonaphthalene involves the self-condensation of pentabromocyclopentadienyl radicals, followed by an intricately intramolecular evolution. Results presented in this study can enhance our understanding of the transformation mechanism of BDE-209 in thermal processes, and offer an insight into controlling the emissions of hazardous pollutants.

Amino Acid Transporter as a Potential Carrier Protein for the Root-to-Shoot Translocation of Polybrominated Diphenyl Ethers in Rice.

As typical persistent organic pollutants, polybrominated diphenyl ethers (PBDEs) tend to accumulate in edible parts of rice, posing great ecological and health risks. The translocation of PBDEs from underground to aboveground parts of rice is a crucial procedure to determine the final bioaccumulation level. Herein, this study aimed to identify the transporter proteins for PBDEs in rice plants in order to strengthen our understanding of the bioaccumulation mechanism and the potential prevention strategy of the PBDE risk. Similar time-dependent patterns were observed among the root-to-shoot translocation factors (TFs) of PBDEs, the expression of lysine histidine transporter (LHT) protein, and the relative levels of LHT substrates (phenylalanine or tyrosine), implying the potential co-transport of PBDEs, phenylalanine, and tyrosine by the carrier LHT. Fluorescence spectra and circular dichroism showed that PBDE congeners interfered with LHT via static fluorescence quenching and changes in the protein's secondary structure. The in vitro sorption fraction of LHT to PBDEs, as revealed by sorption equilibrium analysis, was comparable to the in vivo TF values. Knockout of OsLHT1 in rice using CRISPR/Cas9 technology caused a 48.2-78.4% decrease in PBDE translocation. Molecular docking simulation suggested that PBDEs, phenylalanine, and tyrosine were inserted into the same ligand-binding cavity of LHT, substantiating the potential carrier role of LHT for PBDEs from a conformational perspective. Quantitative structure activity relationship analysis demonstrated that the ether-bond oxygen and the carbons at the site 4 and 4' of PBDE molecules are significant determinants of the binding affinity with the LHT protein and in vivo translocation of PBDEs. In summary, this study discovered that LHT acts as the cellular carrier for PBDEs and offered a comprehensive molecular explanation for the bioaccumulation and translocation of PBDEs in rice plants, covering both biological and chemical perspectives. These findings fill in a knowledge gap on the endogenous transporter proteins for exogenous organic pollutants.

Hydrogen-Donor-Controlled Polybrominated Dibenzofuran (PBDF) Formation from Polybrominated Diphenyl Ether (PBDE) Photolysis in Solutions: Competition Mechanisms of Radical-Based Cyclization and Hydrogen Abstraction Reactions.

Polybrominated dibenzofurans (PBDFs) are characteristic dioxin-like products of polybrominated diphenyl ether (PBDE) photolysis. In this study, competition mechanisms of radical-based cyclization and hydrogen abstraction reactions are proposed in PBDF formation. Commonly, the ortho C-Br bond dissociation during photolysis generates aryl radicals, which undergo intramolecular cyclization to form PBDFs or hydrogen abstraction with hydrogen donors (such as organic solvents and water) to form lower brominated PBDEs. By using 2,4,4'-tribromodiphenyl ether (BDE-28) as the model reactant, the experimental PBDF formation ratios in various solutions are explained quantitatively by the calculated rate constants of cyclization and hydrogen abstraction reactions using the density functional theory (DFT) method. The solvent effect of pure and mixed solvents on PBDF formation is illustrated successfully. The structure-related hydrogen donation ability for hydrogen abstraction controls the bias of competition reactions and influences PBDF formation. Water resulted to be the most significant generation of PBDFs. Fulvic and humic acid display higher hydrogen donation ability than small-molecule organics due to the partitioning effect in aqueous solution. Quantitative structure-activity relationship (QSAR) models of the calculated rate constants for 512 cyclization and 319 hydrogen abstraction reactions using 189 PBDEs as the initial reactants in water are established, revealing the high risk of PBDF formation in aqueous solution.

Bioaccumulation, Trophic Transfer, and Biotransformation of Polychlorinated Diphenyl Ethers in a Simulated Aquatic Food Chain.

Polychlorinated diphenyl ethers (PCDEs) are detected in aquatic environments and demonstrate adverse effects in aquatic organisms. However, data regarding the environmental behavior of PCDEs in aquatic ecosystems are lacking. In the present study, a simulated aquatic food chain (Scenedesmus obliquus-Daphnia magna-Danio rerio) was constructed in a lab setting, and the bioaccumulation, trophic transfer, and biotransformation of 12 PCDE congeners were quantitatively investigated for the first time. The log-transformed bioaccumulation factors (BCFs) of PCDEs in S. obliquus, D. magna, and D. rerio were in the range of 2.94-3.77, 3.29-4.03, and 2.42-2.89 L/kg w.w., respectively, indicating the species-specific bioaccumulation of PCDE congeners. The BCF values increased significantly with the increasing number of substituted Cl atoms, with the exception of CDE 209. The number of Cl atoms at the para and meta positions were found to be the major positive contributing factors for BCFs in the case of the same number of substituted Cl. The lipid-normalized biomagnification factors (BMFs) of S. obliquus to D. magna, D. magna to D. rerio, and the whole food chain for the 12 PCDE congeners ranged at 1.08-2.27, 0.81-1.64, and 0.88-3.64, respectively, suggesting that some congeners had BMFs comparable to PBDEs and PCBs. Dechlorination was the only metabolic pathway observed for S. obliquus and D. magna. For D. rerio, dechlorination, methoxylation, and hydroxylation metabolic pathways were observed. 1H nuclear magnetic resonance (NMR) experiments and theoretical calculations confirmed that methoxylation and hydroxylation occurred at the ortho position of the benzene rings. In addition, reliable quantitative structure-property relationship (QSPR) models were constructed to qualitatively describe the relationships between molecular structure descriptors and BCFs for PCDEs. These findings provide insights into the movement and transformation of PCDEs in aquatic ecosystems.

Comparative evaluation and prioritization of key influences on biodegradation of 2,2',4,4'-tetrabrominated diphenyl ether by bacterial isolate B. xenovorans LB400.

Polybrominated diphenyl ethers (PBDEs) are a class of persistent organic pollutants being widely distributed and harmful to human health and wildlife, and the development of sustainable rehabilitation strategies including microbial degradation is of great concern. Although the increasing number of bacteria, especially the broad-spectrum and potent aerobes have been isolated for the efficient removal of PBDEs, the external influences and the corresponding influential mechanism on biodegradation are not fully understood yet. Given the wide-spectrum biodegradability of aerobic bacterial isolate, B. xenovorans LB400 for PBDEs, the dual impacts of many pivotal factors including pH, temperature, presence of dissolved organic matter (DOM) and cadmium ion etc. were comprehensively revealed on biodegradation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47). Due to the structural resemblance and stimulation of specific enzyme activity in bacteria, the biphenyl as substrates showed the greater capacity than non-aromatic compounds in improving biodegradation. The individual adaptation to neutrality and cultivation at about 30 °C was beneficial for biodegradation since the bacterial cellular viability and enzyme activity was mostly preserved. Although it was possibly good for the induction of hormesis and favorable to enhance the permeability or bioavailability of pollutant, the exceeding increase of Cd2+ or DOM may not give the profitable increase of biodegradation yet for the detrimental effect. For biodegradation, the mechanistic relationship that took account of the integrative correlation with the influential factors was artfully developed using partial least square (PLS) regression technique. Relative to the most significant influence of culture time and initial concentration of BDE-47, the larger relevance of other factors primarily marked as pH and DOM was consecutively shown after the quantitative prioritization. This may not only help understand the influential mechanism but provide a prioritizing regulation strategy for biodegradation of BDE-47. The PLS-derived relationship was validated with the certain predictability in biodegradation, and could be used as an alternative to accelerate a priori evaluation of suitability or improve the feasibility of such bacteria in remediation of PBDEs in the environment.

Investigations on the binding properties of hydroxylated polybrominated diphenyl ethers with lysozyme using the multispectral techniques and molecular modeling.

As a kind of phenolic chemical with endocrine disrupting potency, hydroxylated polybrominated diphenyl ethers (OH-PBDEs) cause a latent threat to human health from their residue in the environment. Their binding efficiency with lysozyme (LYSO) was studied by molecular simulation combined with fluorescence, UV-vis absorption and circular dichroism (CD), so as to assess their toxicity at the molecular level. Molecular docking data indicate that van der Waals force is the principal interaction force between OH-PBDEs and LYSO. The binding site for 5'-OH-BDE-25 in LYSO is ascertained as the active site, which interaction with the TRP63 and TRP108 residues of LYSO to take shape a strong face-to-face stacked rank (F-shaped). Both 4'-OH-BDE-99 and 3'-OH-BDE-154 display a certain degree of deviation from the active site. Nevertheless, their F-shaped interaction with TRP63 conduce to bind LYSO and stabilize the docking conformation. Combined with dynamics simulation and spectral analysis, the secondary structure of LYSO can be induced by the three kinds of OH-PBDEs. CD spectrum shows that the combination of LYSO and OH-PBDEs will make α- Helix content increased. The combination of OH-PBDEs and LYSO touch upon a static quenching mechanism as a result of steady state fluorescence. The energy decomposition analysis exhibited that LYSO-OH-PBDEs binding site was stable by van der Waals and hydrophobic interaction. As enzyme activity experiments demonstrate that OH-PBDEs can inhibit the activity of LYSO, which is helpful to clarify the molecular toxicity mechanism of OH-PBDEs.

Binary toxicity of polystyrene nanoplastics and polybrominated diphenyl ethers to Arctic Cyanobacteria under ambient and future climates.

Cyanobacteria are the predominant biota in the Arctic. Interactive effects on Arctic cyanobacteria between climate-change-shifting parameters and anthropogenic contaminants are largely unknown. We utilized a fractional factorial experiment and Arctic cyanobacteria Pseudanabaena biceps Strain PCCC_O-153 to capture the complexity of interacting climate factors, nano-polystyrene (nano-PS) and 2,2´,4,4´-tetrabromodipenyl ether (BDE-47). The short-term binary toxicity of nano-PS and BDE-47 was then examined through experiments, toxicity units, and reference models. The toxic mechanism was further revealed through biochemical analyses and multivariate statistics. We found that BDE-47 and nano-PS had more hazardous effects than changing climate conditions. The mixture had antagonistic effects on PCCC_O-153, attributing to the aggregation of nano-PS, the adsorption of BDE-47, and the wrapping of both contaminants by released extracellular polymeric substances. Binary toxicity was caused by the chain reactions triggered by combining individual contaminants. Total protein was a sensitive target and positively correlated to chlorophyll pigment. Oxidative stress for the mixture mainly resulted from the presence of nano-PS. This is the first study to access the hazardous effects of a mixture of anthropogenic contaminants on Arctic cyanobacteria under ambient and future climates.

Polybrominated diphenyl ethers as hitchhikers on microplastics: Sorption behaviors and combined toxicities to Epinephelus moara.

Emerging pollutants, such as microplastics (MPs) and polybrominated diphenyl ethers (PBDEs) may pose a serious threat to human health and ecological safety. However, little is known about the MP-mediated PBDEs exposures and their combined toxicities towards farmed fishes. This study investigated the sorption behaviors of two typical PBDEs (BDE-47 and BDE-209) to MPs of different polymer types (PE, PS, PHA and PHB), and examined their combined toxic effects on grouper (Epinephelus moara) by determining the change of oxidative stress markers and comparing gene expression difference through high-throughput sequencing. Our results demonstrated that the sorption of PBDEs on MPs were polymer type-dependent and the sorption capacities were in the order of PHA>PHB>PS>PE. The combined exposures of MPs and PBDEs led to more severe disturbance on the oxidative system compared with individual exposure. The activity of superoxide dismutase (SOD) and the content of glutathione were decreased, while the activity of catalase (CAT) and the content of malondialdehyde were increased. The disorder of oxidative system can influence the growth of groupers. High-throughput sequencing confirmed that pathways of ferroptosis, IL-17 and PPAR expressed differently under combined exposure of MPs and BDE-47. IL-17 pathway related genes were inhibited, while genes in PPAR pathway were upregulated. The combined exposure brought more severe effect on grouper's gene expression compared with individual exposure. GPX-related genes and CAT gene in the liver were up-regulated, while SOD-related genes were down-regulated. Our results demonstrated that the combined toxicity of MPs and PBDEs can pose a non-neglectable threat to aquaculture development and food safety, and gained a primary insight into the potential risk of MPs to farmed fishes.

Understanding the role of biochar in affecting BDE-47 biodegradation by Pseudomonas plecoglossicida: An integrated analysis using chemical, biological, and metabolomic approaches.

Biochar-assisted microbial degradation technology is considered as an important strategy to eliminate organic pollutants, but the mechanism of biochar in affecting biodegradation has not been systematically studied. To address this knowledge gap, the effect of various biochars on biodegradation of different initial concentrations of BDE-47 by Pseudomonas plecoglossicida was investigated. The results showed that biochar exhibited significant promotion to the biodegradation of BDE-47, especially at concentrations of BDE-47 above 100 µg/L. The promotion effect was negatively influenced by the aromaticity and micropore volume of biochar. Biochar alleviated the cytotoxicity of BDE-47 to P. plecoglossicida and promoted cell proliferation based on toxicity assays. Additionally, biochar acted as shelter and stimulated the secretion of extracellular polymeric substances, which might support P. plecoglossicida to struggle with extreme conditions. Metabolomic analysis indicated that biochar resulted in upregulation expression of 38 metabolites in P. plecoglossicida. These upregulated metabolites were mainly related to glyoxylate and dicarboxylate metabolism, citrate cycle, and serial amino acid metabolism, suggesting that biochar could improve the BDE-47 biodegradation via enhancing oxidative metabolism and energy supply of the bacterial cells. This work elucidates how biochar can affect BDE-47 biodegradation and provides insights for the application prospect of biochar-assisted microbial degradation technology in the environment.

Ecological Role of 6OH-BDE47: Is It a Chemical Offense Molecule Mediated by Enoyl-ACP Reductases?

Although hydroxylated polybrominated diphenyl ethers (OH-BDEs) are among the most abundant natural organobromine compounds, the fundamental biological rationale for marine organisms to produce OH-BDEs remains elusive. Herein, we demonstrated that natural OH-BDEs exerted strong antibacterial activities against Escherichia coli by inhibiting enoyl-[acyl-carrier-protein] reductase (FabI), while anthropogenic OH-BDEs were inactive. Distinct from E. coli, OH-BDE-producing marine γ-proteobacteria including Marinomonas mediterranea MMB-1 (MMB-1) and Pseudoalteromonas luteoviolacea 2ta16 (Pl2ta16) exhibited resistance to 6OH-BDE47. An alternative enoyl-[acyl-carrier-protein] (ACP) reductase, FabV, was detected in all three OH-BDE-producing marine γ-proteobacteria. Thermal stability and protein affinity purification studies revealed that 6OH-BDE47 did not bind to recombinant or endogenous FabV of MMB-1 or Pl2ta16, demonstrating that FabV was the primary mechanism for OH-BDE-producing marine γ-proteobacteria to be resistant to 6OH-BDE47. To further confirm if the laboratory results were evidenced in the field, the 16S rRNA sequencing and metagenomics data from seven field-collected marine sponges were analyzed. Notably, the two Clade 4 sponges containing high concentrations of 6OH-BDE47 exhibited a distinct microbiome community structure compared to the other analyzed clades. Correspondingly, FabV was found to be selectively enriched in the same Clade 4 sponges. The merged evidence from the laboratory experiments and field studies demonstrated that 6OH-BDE47 may act as a chemical offense molecule in marine sponges.

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.

Ecological and Pharmacological Activities of Polybrominated Diphenyl Ethers (PBDEs) from the Indonesian Marine Sponge Lamellodysidea herbacea.

Two known Polybrominated Diphenyl Ethers (PBDEs), 3,4,5-tribromo-2-(2',4'-dibromophenoxy)phenol (1d) and 3,4,5,6-tetrabromo-2-(2',4'-dibromophenoxy)phenol (2b), were isolated from the Indonesian marine sponge Lamellodysidea herbacea. The structure was confirmed using 13C chemical shift average deviation and was compared to the predicted structures and recorded chemical shifts in previous studies. We found a wide range of bioactivities from the organic crude extract, such as (1) a strong deterrence against the generalist pufferfish Canthigaster solandri, (2) potent inhibition against environmental and human pathogenic bacterial and fungal strains, and (3) the inhibition of the Hepatitis C Virus (HCV). The addition of a bromine atom into the A-ring of compound 2b resulted in higher fish feeding deterrence compared to compound 1d. On the contrary, compound 2b showed only more potent inhibition against the Gram-negative bacteria Rhodotorula glutinis (MIC 2.1 µg/mL), while compound 1d showed more powerful inhibition against the other human pathogenic bacteria and fungi. The first report of a chemical defense by compounds 1d and 2b against fish feeding and environmental relevant bacteria, especially pathogenic bacteria, might be one reason for the widespread occurrence of the shallow water sponge Lamellodysidea herbacea in Indonesia and the Indo-Pacific.

Oxy-Polybrominated Diphenyl Ethers from the Indonesian Marine Sponge, Lamellodysidea herbacea: X-ray, SAR, and Computational Studies.

Polybrominated diphenyl ether (PBDE) compounds, derived from marine organisms, originate from symbiosis between marine sponges and cyanobacteria or bacteria. PBDEs have broad biological spectra; therefore, we analyzed structure and activity relationships of PBDEs to determine their potential as anticancer or antibacterial lead structures, through reactions and computational studies. Six known PBDEs (1-6) were isolated from the sponge, Lamellodysdiea herbacea; 13C NMR data for compound 6 are reported for the first time and their assignments are confirmed by their theoretical 13C NMR chemical shifts (RMSE < 4.0 ppm). Methylation and acetylation of 1 (2, 3, 4, 5-tetrabromo-6-(3', 5'-dibromo-2'-hydroxyphenoxy) phenol) at the phenol functional group gave seven molecules (7-13), of which 10, 12, and 13 were new. New crystal structures for 8 and 9 are also reported. Debromination carried out on 1 produced nine compounds (1, 2, 14, 16-18, 20, 23, and 26) of which 18 was new. Debromination product 16 showed a significant IC50 8.65 ± 1.11; 8.11 ± 1.43 µM against human embryonic kidney (HEK293T) cells. Compounds 1 and 16 exhibited antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae with MID 0.078 µg/disk. The number of four bromine atoms and two phenol functional groups are important for antibacterial activity (S. aureus and K. pneumoniae) and cytotoxicity (HEK293T). The result was supported by analysis of frontier molecular orbitals (FMOs). We also propose possible products of acetylation and debromination using analysis of FMOs and electrostatic charges and we confirm the experimental result.

Molecular Modifications and Control of Processes to Facilitate the Synergistic Degradation of Polybrominated Diphenyl Ethers in Soil by Plants and Microorganisms Based on Queuing Scoring Method.

In this paper, a combination of modification of the source and regulation of the process was used to control the degradation of PBDEs by plants and microorganisms. First, the key proteins that can degrade PBDEs in plants and microorganisms were searched in the PDB (Protein Data Bank), and a molecular docking method was used to characterize the binding ability of PBDEs to two key proteins. Next, the synergistic binding ability of PBDEs to the two key proteins was evaluated based on the queuing integral method. Based on this, three groups of three-dimensional quantitative structure-activity relationship (3D-QSAR) models of plant-microbial synergistic degradation were constructed. A total of 30 PBDE derivatives were designed using BDE-3 as the template molecule. Among them, the effect on the synergistic degradation of six PBDE derivatives, including BDE-3-4, was significantly improved (increased by more than 20%) and the environment-friendly and functional evaluation parameters were improved. Subsequently, studies on the synergistic degradation of PBDEs and their derivatives by plants and microorganisms, based on the molecular docking method, found that the addition of lipophilic groups by modification is beneficial to enhance the efficiency of synergistic degradation of PBDEs by plants and microorganisms. Further, while docking PBDEs, the number of amino acids was increased and the binding bond length was decreased compared to the template molecules, i.e., PBDE derivatives could be naturally degraded more efficiently. Finally, molecular dynamics simulation by the Taguchi orthogonal experiment and a full factorial experimental design were used to simulate the effects of various regulatory schemes on the synergistic degradation of PBDEs by plants and microorganisms. It was found that optimal regulation occurred when the appropriate amount of carbon dioxide was supplied to the plant and microbial systems. This paper aims to provide theoretical support for enhancing the synergistic degradation of PBDEs by plants and microorganisms in e-waste dismantling sites and their surrounding polluted areas, as well as, realize the research and development of green alternatives to PBDE flame retardants.

Identification of Reductive Dehalogenases That Mediate Complete Debromination of Penta- and Tetrabrominated Diphenyl Ethers in Dehalococcoides spp.

Polybrominated diphenyl ethers (PBDEs) are persistent, highly toxic, and widely distributed environmental pollutants. The microbial populations and functional reductive dehalogenases (RDases) responsible for PBDE debromination in anoxic systems remain poorly understood, which confounds bioremediation of PBDE-contaminated sites. Here, we report a PBDE-debrominating enrichment culture dominated by a previously undescribed Dehalococcoides mccartyi population. A D. mccartyi strain, designated TZ50, whose genome contains 25 putative RDase-encoding genes, was isolated from the debrominating enrichment culture. Strain TZ50 dehalogenated a mixture of pentabrominated diphenyl ether (penta-BDE) and tetra-BDE congeners (total BDEs, 1.48 µM) to diphenyl ether within 2 weeks (0.58 µM Br-/day) via ortho- and meta-bromine elimination; strain TZ50 also dechlorinated tetrachloroethene (PCE) to vinyl chloride and ethene (260.2 µM Cl-/day). Results of native PAGE, proteomic profiling, and in vitro enzymatic activity assays implicated the involvement of three RDases in PBDE and PCE dehalogenation. TZ50_0172 (PteATZ50) and TZ50_1083 (TceATZ50) were responsible for the debromination of penta- and tetra-BDEs to di-BDE. TZ50_0172 and TZ50_1083 were also implicated in the dechlorination of PCE to trichloroethene (TCE) and of TCE to vinyl chloride/ethene, respectively. The other expressed RDase, TZ50_0090 (designated BdeA), was associated with the debromination of di-BDE to diphenyl ether, but its role in PCE dechlorination was unclear. Comparatively few RDases are known to be involved in PBDE debromination, and the identification of PteATZ50, TceATZ50, and BdeA provides additional information for evaluating debromination potential at contaminated sites. Moreover, the ability of PteATZ50 and TceATZ50 to dehalogenate both PBDEs and PCE makes strain TZ50 a suitable candidate for the remediation of cocontaminated sites. IMPORTANCE The ubiquity, toxicity, and persistence of polybrominated diphenyl ethers (PBDEs) in the environment have drawn significant public and scientific interest to the need for the remediation of PBDE-contaminated ecosystems. However, the low bioavailability of PBDEs in environmental compartments typically limits bioremediation of PBDEs and has long impeded the study of anaerobic microbial PBDE removal. In the current study, a novel Dehalococcoides mccartyi strain, dubbed strain TZ50, that expresses RDases that mediate organohalide respiration of both PBDEs and chloroethenes was isolated and characterized. Strain TZ50 could potentially be used to remediate multiple cooccurring organohalides in contaminated systems.