Dioxins, PFOS, and 20 other Persistent Organic Pollutants in Eggs of Nine Wild Bird Species from the Vaal River, South Africa.

The Vaal River catchment drains the largest and most populated industrial and mining region in Southern Africa. Heron, ibis, cormorant, egrets, and darter eggs, representing three habitats and four feeding guilds, were collected at four locations in 2009/10 to identify hotspots and hazards associated with persistent organic pollutants (POPs). The POPs included 21 organochlorine pesticides, five polybrominated diphenyl ether (PBDE) classes, 18 polychlorinated biphenyls (PCBs including six non-dioxin-like PCBs; NDL-PCB), and 12 dioxin-like PCBs (DL-PCBs), 17 polychlorinated dibenzo-p-dioxins and dibenzo-p-furans (PCDD/Fs), and perfluorooctane sulfonate (PFOS). Aquatic predators had higher PFOS and PCDD/F concentrations, while PCBs dominated in terrestrial eggs. Organochlorine pesticides, PBDEs, and PCBs were strongly associated with eggs from the industrial regions, while PCDD/F concentrations were evenly distributed. PCDD/F and PCB toxic equivalency quotient concentrations were low with no adverse effects expected. PFOS peaked at Bloemhof Dam with a maximum of 2300 ng/g wm in an African Darter egg, indicating an unexpected PFOS hotspot, the source of which is unknown. Despite order of differences in compound class concentrations, there was no association with egg size. To the best of our knowledge, this is the only study that analysed all 2010 POPs in bird eggs on a large geographic scale. This study highlighted the importance of multi-species studies sampling from multiple locations to assess the risk that POPs pose to avian populations as hotspots and species at risk may be missed by studies looking at one or few species.

The endocrine disruptor DE-79 alters oxytocinergic transmission and sexual behavior expression in male rats.

Polybrominated diphenyl ethers (PBDEs), used as flame retardants are persistent organic pollutants exerting important health effects. PBDEs with >5 bromide substitutions were considered less harmful and therefore extensively used commercially. DE-79 was a widely used PBDE mixture of hexa-, hepta-, octa- and nona-brominated compounds that increases vasopressin (AVP) production. AVP and oxytocin (OT) are both produced in neurons of the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei projecting to the neurohypophysis and to brain regions involved in copulatory behavior. OT plays an important role in male copulation. Since DE-79 alters AVP expression in the SON and PVN, it might also modify OT content and alter male sexual behavior. We analyzed if repeated DE-79 exposure of adult male rats affected OT content and OT receptor (OTR) density in the SON, PVN, medial preoptic area (mPOA), ventral tegmental area, nucleus accumbens, and amygdala, and if male copulatory behavior was affected. We show that DE-79 exposure produces a generalized decrease in brain OT immunoreactivity, increases OTR density in all brain regions analyzed but the mPOA, and reduces the ejaculatory threshold after a first ejaculation. The documented ejaculation-induced OT release might participate in this last effect. Thus, one-week DE-79 exposure alters the OT-OTR system and modifies male rat sexual performance. Based on the literature it could be speculated that these effects are related to the putative endocrine disrupting actions of DE-79, ultimately altering brain OT levels and OTR expression that might affect copulation and other important OT-mediated brain functions.

Disentangling Source Profiles and Time Trends of Halogenated Flame Retardants in the Great Lakes.

Thirty-five polybrominated diphenyl ethers (PBDEs) and eight other alternative flame retardants were measured in air samples (vapor plus particles) collected at six sites near the North American Great Lakes between 2005 and 2019 as part of the Integrated Atmospheric Deposition Network (IADN). These data were analyzed using a multiple linear regression model to determine spatial and temporal trends. Overall, the levels of flame retardants remain significantly higher in urban sites compared to rural and remote sites except for pentabromoethylbenzene (PBEB), hexabromobenzene (HBB), and total Dechlorane Plus (ΣDP). Here, we report the first findings of decreasing levels of ΣDP at Sturgeon Point, New York. The atmospheric levels of total PBDEs remain unchanged over time near Lakes Michigan and Superior and declined near Lakes Erie and Ontario, with rate constants at the latter two lakes revealing halving times of approximately 7 to 14 years. This work presents results from the first investigation of PBDE source apportionment in the Great Lakes atmosphere. Source apportionment by use of positive matrix factorization (PMF) identified two legacy commercial technical mixtures (i.e., penta-BDE and deca-BDE mixes) and elucidated a factor representing ambient degradation. Our results show that weathered local sources of technical commercial mixtures, and their photolysis contribute most to the total PBDE burden in the Great Lakes atmosphere.

Feed as a source of polybrominated diphenyl ethers (PBDEs).

One of the most important routes for human exposure to polybrominated diphenyl ethers (PBDEs) is the ingestion of contaminated food. Food of animal origin safety is strongly related to feed quality. The aim of the study was the assessment of feeds and feed materials quality associated with ten PBDE congeners (BDE-28, 47, 49, 99, 100, 138, 153, 154, 183 and 209) contamination. The quality of 207 feed samples divided into eight categories (277/2012/EU) was checked using the gas chromatography-high resolution mass spectrometry (GC-HRMS). At least one congener was identified in 73% of the samples. All investigated fish oil, animal fat, and feed for fish were contaminated, and 80% of plant-origin feed samples were free of PBDEs. The highest median content of ∑10PBDE was found in fish oils (2260 ng kg-1) followed by fishmeal (530 ng kg-1). The lowest median was found in mineral feed additives, plant materials excluding vegetable oil and compound feed. BDE-209 was the most frequently detected congener (56%). All congeners except BDE-138 and BDE-183 were detected in 100% of the fish oil samples. Except for BDE-209, the congener detection frequencies did not exceed 20% in compound feed, feed of plant origin, and vegetable oils. Excluding BDE-209, similar congener profiles were found for fish oils, fishmeal and feed for fish, with BDE-47 in the highest concentration, followed by BDE-49 and BDE-100. Another pattern appeared in animal fat, with a higher median concentration of BDE-99 than BDE-47. Time-trend analysis of PBDE concentrations in fishmeal (n = 75) showed a 63% decrease in ∑10PBDE (p = 0.077) and a 50% decrease in the ∑9PBDE (p = 0.008) between 2017 and 2021. It proves the international legislation implemented to reduce PBDE environmental levels has been effective.

Derivation and application of indoor air screening values for inhalation exposure to semi-volatile organic compounds.

Semi-volatile organic compounds (SVOCs) are being increasingly studied in indoor air. The absence of health-based inhalation exposure guidelines for most SVOCs impedes the interpretation of indoor air concentrations from a health risk context. To accelerate the derivation of screening values for a large number of SVOCs, a tiered framework was developed to evaluate and adjust published hazard assessments for SVOCs to calculate benchmarks relevant for evaluation of inhalation risk. Inhalation screening values were derived for 43 SVOCs considered in this study, most of which required extrapolation from oral exposure guidelines. The screening values were compared to published SVOC concentrations in homes in Canada to evaluate the potential health risks of chronic exposure to SVOCs in indoor residential environments. SVOCs that could be prioritized for further evaluation were dibutyl phthalates (DBP), di(2-ethylhexyl) phthalate (DEHP) and polybrominated diphenyl ethers (PBDEs). The framework could be applied more broadly in the future to derive screening values for other non-traditional indoor air contaminants with limited inhalation hazard data or assessments.

BDE-47 Induces Immunotoxicity in RAW264.7 Macrophages through the Reactive Oxygen Species-Mediated Mitochondrial Apoptotic Pathway.

Polybrominated diphenyl ethers (PBDEs) are classic and emerging pollutants that are potentially harmful to the human immune system. Research on their immunotoxicity and mechanisms suggests that they play an important role in the resulting pernicious effects of PBDEs. 2,2',4,4'-Tetrabrominated biphenyl ether (BDE-47) is the most biotoxic PBDE congener, and, in this study, we evaluated its toxicity toward RAW264.7 cells of mouse macrophages. The results show that exposure to BDE-47 led to a significant decrease in cell viability and a prominent increase in apoptosis. A decrease in mitochondrial membrane potential (MMP) and an increase in cytochrome C release and caspase cascade activation thus demonstrate that cell apoptosis induced by BDE-47 occurs via the mitochondrial pathway. In addition, BDE-47 inhibits phagocytosis in RAW264.7 cells, changes the related immune factor index, and causes immune function damage. Furthermore, we discovered a significant increase in the level of cellular reactive oxygen species (ROS), and the regulation of genes linked to oxidative stress was also demonstrated using transcriptome sequencing. The degree of apoptosis and immune function impairment caused by BDE-47 could be reversed after treatment with the antioxidant NAC and, conversely, exacerbated by treatment with the ROS-inducer BSO. These findings indicate that oxidative damage caused by BDE-47 is a critical event that leads to mitochondrial apoptosis in RAW264.7 macrophages, ultimately resulting in the suppression of immune function.

Early exposure to flame retardants is prospectively associated with anxiety symptoms in adolescents: A prospective birth cohort study.

BACKGROUND: Anxiety disorders emerge during childhood and adolescence and are frequently preceded by subsyndromal anxiety symptoms. Environmental toxicants, including gestational polybrominated diphenyl ether (PBDE) exposure, are associated with neuropsychiatric sequelae; however, the role of PBDEs as risk factors for anxiety in adolescence is unclear. METHODS: Using data from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort enrolled from 2003 to 2006, we investigated the relationship between gestational serum PBDE concentrations and anxiety symptoms in adolescents (N = 236). We measured five PBDE congeners (PBDE-28, -47, -99, -100, and -153) at 16 ± 3 weeks of gestation and calculated their sum (∑PBDE). We assessed self-reported anxiety symptoms using the Screen for Child Anxiety Related Emotional Disorders (SCARED) and depressive symptoms using the Children's Depression Inventory (CDI-2) at age 12 years. We estimated the associations of maternal PBDE concentrations with child anxiety and depressive symptoms using multivariable linear regression and modified Poisson regression. Covariates included child sex, maternal race, maternal age at delivery, maternal marital status, maternal education, and household income at the 12-year study visit as well as maternal depressive and anxiety symptoms. Sensitivity analyses were performed to control for maternal lead and mercury at delivery. RESULTS: After adjusting for predetermined covariates, each doubling in maternal PBDE concentrations was associated with increased SCARED scores (e.g., for ∑PBDE, SCARED total score, ß = 1.6 95% confidence interval [CI]: 0.3-2.9, p = .019) and a nonsignificant increase in depressive symptoms (e.g., for CDI total score, ß = .8, 95% CI: -0.2-1.8, p = .11). CONCLUSIONS: Gestational serum PBDE concentrations just before mid-pregnancy and during a period of active cortical and limbic neurogenesis, synaptogenesis and myelogenesis may be a risk factor for developing anxiety symptoms in early adolescence.

Melatonin administration alleviates 2,2,4,4-tetra-brominated diphenyl ether (PBDE-47)-induced necroptosis and secretion of inflammatory factors via miR-140-5p/TLR4/NF-κB axis in fish kidney cells.

2,2,4,4-tetra-brominated diphenyl ether (PBDE-47)-the dominant homologue of polybrominated diphenyl ethers-is a toxic environmental pollutant in the aquatic environment that continuously exists and bioaccumulates in the aquatic food chain. In experimental disease models, melatonin (MEL) has been reported to attenuate necroptosis and inflammatory responses. To further explore the mechanism underlying PBDE-47 toxicity and the mitigative impact of MEL detoxification, in this study, fish kidney cell models of PBDE-47 poisoning and/or MEL treatment were developed. The Ctenopharyngodon idellus kidney (CIK) cell line was treated with PBDE-47 (100 µM) and/or MEL (60 µM) for 24 h. Experimental data suggest that PBDE-47 exposure resulted in the enhancement of cytoplasmic Ca2+ concentration, induction of calcium dysmetabolism, decrease in the miR-140-5p miRNA level, upregulation of Toll-like Receptor 4 (TLR4) and nuclear factor-kappaB (NF-κB), triggering of receptor interacting serine/threonine kinase-induced necroptosis, and NF-κB pathway mediated secretion of inflammatory factors in CIK cells. PBDE-47-induced CIK cell damage could be mitigated by MEL through the regulation of calcium channels and the restoration of disorders of the miR-140-5p/TLR4/NF-κB axis. Overall, MEL relieved PBDE-47-induced necroptosis and the secretion of inflammatory factors through the miR-140-5p/TLR4/NF-κB axis. These findings enrich the current understanding of the toxicological molecular mechanisms of the PBDE-47 as well as the detoxification mechanisms of the MEL.

New Insights into Human Biotransformation of BDE-209: Unique Occurrence of Metabolites of Ortho-Substituted Hydroxylated Higher Brominated Diphenyl Ethers in the Serum of e-Waste Dismantlers.

Extremely high levels of decabromodiphenyl ether (BDE-209) are frequently found in the serum of occupationally exposed groups, such as e-waste dismantlers and firefighters. However, the metabolism of BDE-209 in the human body is not adequately studied. In this study, 24 serum samples were collected from workers at a typical e-waste recycling workshop in Taizhou, Eastern China, and the occurrence and fate of these higher brominated diphenyl ethers (PBDEs) were investigated. The median concentration of the total PBDEs in the serum was 199 ng/g lipid weight (lw), ranging from 125 to 622 ng/g lw. Higher brominated octa- to deca-BDEs accounted for more than 80% of the total PBDEs. Three ortho-hydroxylated metabolites of PBDEs─6-OH-BDE196, 6-OH-BDE199, and 6'-OH-BDE206─were widely detected with a total concentration (median) of 92.7 ng/g lw. The concentrations of the three OH-PBDEs were significantly higher than their octa- and nona-PBDE homologues, even exceeding those of the total PBDEs in several samples, indicating that the formation of OH-PBDEs was a major metabolic pathway of the higher brominated PBDEs in occupationally exposed workers. An almost linear correlation between 6-OH-BDE196 and 6-OH-BDE199 (R = 0.971, P < 0.001) indicates that they might undergo a similar biotransformation pathway in the human body or may be derived from the same precursor. In addition, the occurrence of a series of penta- to hepta- ortho-substituted OH-PBDEs was preliminarily identified according to their unique "predioxin" mass spectral profiles by GC-ECNI-MS. Taken together, the tentative metabolic pathway for BDE-209 in e-waste dismantlers was proposed. The oxidative metabolism of BDE-209 was mainly observed at the ortho positions to form 6'-OH-BDE-206, which later underwent a consecutive loss of bromine atoms at the meta or para positions to generate other ortho-OH-PBDEs. Further studies are urgently needed to identify the chemical structures of these ortho-OH-PBDE metabolites, and perhaps more importantly to clarify the potentially toxic effects, along with their underlying molecular mechanisms.

Method development and application to sediments for multi-residue analysis of organic contaminants using gas chromatography-tandem mass spectrometry.

A method for the determination of four classes of potentially toxic substances (PTSs) was developed and applied in marine sediments, including (i) polycyclic aromatic hydrocarbons (PAHs), (ii) polychlorinated biphenyls (PCBs), (iii) polybrominated diphenyl ethers (PBDEs), and (iv) organochlorinated pesticides (OCPs). The method is based on ultrasonic extraction with a mixture of dichloromethane:methanol (9:1 v/v) and gas chromatography coupled with tandem mass spectrometry analysis (GC-MS/MS) in multiple reaction monitoring (MRM) mode. A total of 89 compounds were identified using two precursor-product ion standards for each analyte. The method detection limit (MDL; 0.001-0.055 ng g-1 dw) and method quantification limit (MQL; 0.002-0.184 ng g-1 dw) are below the usual thresholds of pollution adopted by international sediment quality guidelines. The method proved to be selective, sensitive, accurate, and linear, with the advantage of reducing sample handling time and consumable expenses (solvent, adsorbents). The developed method was successfully applied to surface sediments of Sepetiba Bay, Rio de Janeiro State, Brazil. Total concentrations of PAH (29.20-209.5 ng g-1 dw), PCB (0.06-2.16 ng g-1 dw), OCP (0.03-0.33 ng g-1 dw), and PBDE (0.06-0.21 ng g-1 dw) represent a baseline for these compounds and revealed mild to low levels of contamination in comparison to other coastal bays in SE Brazil. By using the proposed method, we expect this preliminary dataset can be expanded and include other similar coastal systems from developing countries marked by scarcity of information about levels, risk assessment, and specific sediment quality guidelines encompassing multiple classes of regulated and emerging organic contaminants.

PBDEs disrupt homeostasis maintenance and regeneration of planarians due to DNA damage, proliferation and apoptosis anomaly.

Polybrominated diphenyl ethers (PBDEs) are widely used as brominated flame retardants in the manufacturing industry, belonging to persistent organic pollutants in the environment. Planarians are the freshwater worms, with strong regenerative ability and extreme sensitivity to environmental toxicants. This study aimed to evaluate the potential acute comprehensive effects of PBDE-47/-209 on freshwater planarians. Methods to detect the effects include: detection of oxidative stress, observation of morphology and histology, detection of DNA fragmentation, and detection of cell proliferation and apoptosis. In the PBDE-47 treatment group, planarians showed increased oxidative stress intensity, severe tissue damage, increased DNA fragmentation level, and increased cell proliferation and apoptosis. In the PBDE-209 treatment group, planarians showed decreased oxidative stress intensity, slight tissue damage, almost unchanged DNA fragmentation level and apoptosis, proliferation increased only on the first day after treatment. In conclusion, both PBDE-47 and PBDE-209 are dangerous environmental hazardous material that can disrupt planarians homeostasis, while the toxicity of PBDE-47 is sever than PBDE-209 that PBDE-47 can lead to the death of planarians.

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers.

Polybrominated diphenyl ethers (PBDE) are a group of flame retardants used in a variety of artificial materials. Despite being phased out in most industrial countries, they remain in the environment and human tissues due to their persistence, lipophilicity, and bioaccumulation. Populational and experimental studies demonstrate the male reproductive toxicity of PBDEs including increased incidence of genital malformations (hypospadias and cryptorchidism), altered weight of testes and other reproductive tissues, altered testes histology and transcriptome, decreased sperm production and sperm quality, altered epigenetic regulation of developmental genes in spermatozoa, and altered secretion of reproductive hormones. A broad range of mechanistic hypotheses of PBDE reproductive toxicity has been suggested. Among these hypotheses, oxidative stress, the disruption of estrogenic signaling, and mitochondria disruption are affected by PBDE concentrations much higher than concentrations found in human tissues, making them unlikely links between exposures and adverse reproductive outcomes in the general population. Robust evidence suggests that at environmentally relevant doses, PBDEs and their metabolites may affect male reproductive health via mechanisms including AR antagonism and the disruption of a complex network of metabolic signaling.

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes.

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH-BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH-BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK-ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand-protein docking suggested that 6-OH-BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH-BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH-BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body ß-lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK-ERK signaling, and axonal guidance.

A mitogen-activated protein kinase PoxMK1 mediates regulation of the production of plant-biomass-degrading enzymes, vegetative growth, and pigment biosynthesis in Penicillium oxalicum.

Mitogen-activated protein kinase (MAPK) cascades are broadly conserved and play essential roles in multiple cellular processes, including fungal development, pathogenicity, and secondary metabolism. Their function, however, also exhibits species and strain specificity. Penicillium oxalicum secretes plant-biomass-degrading enzymes (PBDEs) that contribute to the carbon cycle in the natural environment and to utilization of lignocellulose in industrial processes. However, knowledge of the MAPK pathway in P. oxalicum has been relatively limited. In this study, comparative transcriptomic analysis of P. oxalicum, cultured on different carbon sources, found ten putative kinase genes with significantly modified transcriptional levels. Six of these putative kinase genes were knocked out in the parental strain ∆PoxKu70, and deletion of the gene, Fus3/Kss1-like PoxMK1 (POX00158), resulted in the largest reduction (91.1%) in filter paper cellulase production. Further tests revealed that the mutant ∆PoxMK1 lost 37.1 to 92.2% of PBDE production, under both submerged- and solid-state fermentation conditions, compared with ∆PoxKu70. In addition, the mutant ∆PoxMK1 had reduced vegetative growth and increased pigment biosynthesis. Comparative transcriptomic analysis showed that PoxMK1 deletion from P. oxalicum downregulated the expression of major PBDE genes and known regulatory genes such as PoxClrB and PoxCxrB, whereas the transcription of pigment biosynthesis-related genes was upregulated. Comparative phosphoproteomic analysis revealed that PoxMK1 deletion considerably modified phosphorylation of key transcription- and signal transduction-associated proteins, including transcription factors Mcm1 and Atf1, RNA polymerase II subunits Rpb1 and Rpb9, MAPK-associated Hog1 and Ste7, and cyclin-dependent kinase Kin28. These findings provide novel insights into understanding signal transduction and regulation of PBDE gene expression in fungi.Key points• PoxMK1 is involved in expression of PBDE- and pigment synthesis-related genes.• PoxMK1 is required for vegetative growth of P. oxalicum.• PoxMK1 is involved in phosphorylation of key TFs, kinases, and RNA polymerase II.

Curcumin hinders PBDE-47-induced neutrophil extracellular traps release via Nrf2-associated ROS inhibition.

Polybrominated diphenyl ethers (PBDE-47), a kind of lipophilic persistent organic pollutants (POPs) brominated flame retardant, has been widely used in various consumer products. However, the toxicity of PBDE-47 on human immune system has not been well elucidated. Neutrophil extracellular traps (NETs) contribute to the innate immune responses, and the release of NETs is recognized as the most important part of the extracellular killing mechanism. The aim of this study was to investigate the effect of PBDE-47 on NETs and its possible molecular mechanism, as well as the intervention effect of curcumin (Cur). In this study, the formation of PBDE-47-induced NETs was observed by fluorescence microscopy and scanning electron microscopy, and was also quantitatively detected by DNA dye SYTOX green. In addition, we used Cur and Nrf2 inhibitor ML385 to explore the role of reactive oxygen species (ROS), extracellular signal regulated kinase (ERK) and p38 signaling pathway in PBDE-47-induced reticular formation. We demonstrated that PBDE-47 could significantly induce the formation of NETs, and its molecular mechanism might be related to ROS burst. Cur reduced ROS and inhibited PBDE-47-induced NETs formation by interfering with Nrf2. In conclusion, this study revealed that Cur hindered PBDE-47-induced NETs via Nrf2-associated ROS inhibition, which enriched the cytotoxicity mechanism of PBDE-47, and provided a new clue for the development of Cur as an antagonist of PBDE-47-related immune injury.

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.

40 Years of Research on Polybrominated Diphenyl Ethers (PBDEs)-A Historical Overview and Newest Data of a Promising Anticancer Drug.

Polybrominated diphenyl ethers (PBDEs) are a group of molecules with an ambiguous background in literature. PBDEs were first isolated from marine sponges of Dysidea species in 1981 and have been under continuous research to the present day. This article summarizes the two research aspects, (i) the marine compound chemistry research dealing with naturally produced PBDEs and (ii) the environmental toxicology research dealing with synthetically-produced brominated flame-retardant PBDEs. The different bioactivity patterns are set in relation to the structural similarities and dissimilarities between both groups. In addition, this article gives a first structure-activity relationship analysis comparing both groups of PBDEs. Moreover, we provide novel data of a promising anticancer therapeutic PBDE (i.e., 4,5,6-tribromo-2-(2',4'-dibromophenoxy)phenol; termed P01F08). It has been known since 1995 that P01F08 exhibits anticancer activity, but the detailed mechanism remains poorly understood. Only recently, Mayer and colleagues identified a therapeutic window for P01F08, specifically targeting primary malignant cells in a low µM range. To elucidate the mechanistic pathway of cell death induction, we verified and compared its cytotoxicity and apoptosis induction capacity in Ramos and Jurkat lymphoma cells. Moreover, using Jurkat cells overexpressing antiapoptotic Bcl-2, we were able to show that P01F08 induces apoptosis mainly through the intrinsic mitochondrial pathway.

BDE-47 exposure modulates cellular responses, oxidative stress and biotransformation related-genes in Mytilus galloprovincialis.

Polybrominated diphenyl ethers (PBDEs) are flame retardants, characterized by elevated stability in the marine environment, where are accumulated by organisms, inducing a wide panel of negative effects. In this study, some biochemical patterns related to toxicity, biotransformation and oxidative stress, were studied in the marine model system, Mytilus galloprovincialis, exposed to BDE-47. Mussels were fed with microalgae, previously treated with increasing concentrations of PBDEs (maximum dose 100 ng L-1 of BDE-47 per day). After 15 days of treatment, mussels were fed with the same diet without BDE-47, for additional 15 days. Gills and digestive glands were analyzed at T 0, at 15 and 30 days. Histopathological lesions were assessed in digestive glands of contaminated mussels, while expression of genes, related to cell cycle, multidrug resistance, oxidative stress and detoxification was evaluated on both gills and digestive glands. After 15 days, BDE-47 exposure significantly affected the cell activity in digestive gland and, at 30 days, only mussels exposed to the lower doses showed a certain recovery. Regarding the gene expression, both gills and digestive glands showed a significant down-regulation of the target genes at 15 days, although most of them were up-regulated at 30 days in digestive gland. The results on BDE-47 accumulation in mussels revealed a dose-dependent concentration in tissues, which remained elevated after further 15 days of depuration. This trend supports the responses of the biomarkers, indicating that exposure, at environmentally realistic concentrations of BDE-47, strongly modulates oxidative stress and related patterns of gene expression, suggesting concerns for long-term effect in the biota.

Hepatic Transcriptomic Patterns in the Neonatal Rat After Pentabromodiphenyl Ether Exposure.

Human exposure to pentabromodiphenyl ether (PBDE) mixture (DE-71) and its PBDE-47 congener can occur both in utero and during lactation. Here, we tested the hypothesis that PBDE-induced neonatal hepatic transcriptomic alterations in Wistar Han rat pups can inform on potential toxicity and carcinogenicity after longer term PBDE exposures. Wistar Han rat dams were exposed to either DE-71 or PBDE-47 daily from gestation day (GD 6) through postnatal day 4 (PND 4). Total plasma thyroxine (T4) was decreased in PND 4 pups. In liver, transcripts for CYPs and conjugation enzymes, Nrf2, and ABC transporters were upregulated. In general, the hepatic transcriptomic alterations after exposure to DE-71 or PBDE-47 were similar and provided early indicators of oxidative stress and metabolic alterations, key characteristics of toxicity processes. The transcriptional benchmark dose lower confidence limits of the most sensitive biological processes were lower for PBDE-47 than for the PBDE mixture. Neonatal rat liver transcriptomic data provide early indicators on molecular pathway alterations that may lead to toxicity and/or carcinogenicity if the exposures continue for longer durations. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation.

Exposure to PBDE47 affects mouse oocyte quality via mitochondria dysfunction-induced oxidative stress and apoptosis.

2, 2', 4, 4'-Tetrabrominated diphenyl ether (PBDE47) is the most abundant homologues in polybrominated diphenyl ethers (PBDEs) and is used widely in daily life as a brominated flame retardant. It has been shown that PBDE47 has neurotoxicity, thyroid toxicity, and also is reported to have reproductive toxicity, which can impair the follicular function of female rats and activate ovarian endoplasmic reticulum stress, leading to ovarian damage. However, the toxicity of PBDE47 to the quality of mammalian oocyte has not been reported. In this study, we reported that PBDE47 exposure affected the mouse ovarian and uterine. We also showed that oocyte number reduced and meiotic maturation competence decreased. Moreover, PBDE47 exposure disrupted actin filaments distribution, and also changed the level of histone methylation. Based on the genome-wide sequencing we showed that PBDE47 altered multiple gene expression in mouse oocytes. PBDE47 exposure caused mitochondria dysfunction, showing with aberrant distribution and mitochondrial membrane potential. In addition, our results suggested that PBDE47 induced early apoptosis, which was caused by oxidative stress, showing with increased ROS level and positive Annexin-V signal. In conclusion, our results indicated that PBDE47 exposure affected the maturation of mouse oocyte via its effects on mitochondria function, ROS level and its related apoptosis.