Slick science: will new BP funds keep Gulf genomics afloat?

Funding injections by British Petroleum this summer are fueling studies in the Gulf Coast, raising hopes that the Deepwater Horizon oil spill might provide answers to long-standing questions on the nature of cellular toxicity. Rebecca Alvania investigates.

Polycyclic aromatic compounds in urban soils of Stockholm City: Occurrence, sources and human health risk assessment.

Polycyclic aromatic compounds (PACs) are ubiquitous pollutants that are found everywhere in our environment, including air, soil and water. The aim of this study was to determine concentrations, distribution, sources and potential health risk of 43 PACs in soils collected from 25 urban parks in Stockholm City, Sweden. These PACs included 21 PAHs, 11 oxygenated PAHs, 7 methylated PAHs, and 4 azaarenes whose concentrations ranged between 190 and 54 500, 30.5-5 300, 14.9-680, and 4.17-590 ng/g soil, respectively. Fluoranthene was found at the highest levels ranging between 17.7 and 9800 ng/g, benzo[a]pyrene between 9.64 and 4600 ng/g, and the highly potent carcinogen dibenzo[a,l]pyrene up to 740 ng/g. The most abundant oxy-PAH was 6H-benzo[cd]pyren-6-one (2.09-2300 ng/g). Primary sources of PAHs were identified by use of diagnostic ratios and Positive Matrix Factorization modelling and found to be pyrogenic including vehicle emissions and combustion of biomass. Estimating the incremental lifetime cancer risks (ILCRS) associated with exposure to PAHs in these soils indicated that the PAH levels in some parks constitute a considerable increased risk level for adults and children (total ILCR > 1 × 10-4). Compared to worldwide urban parks contamination, we conclude that the PAC soil levels in parks of Stockholm City in general are low, but that some parks are more heavily contaminated and should be considered for clean-up actions to limit human health risks.

Effects of dechlorane plus on intestinal barrier function and intestinal microbiota of Cyprinus carpio L.

Dechlorane Plus (DP) is a typical polychlorinated flame retardant that has been emerged in chemical products. Due to its accumulation and amplification effect, the toxicity of DP has become a widespread environmental safety issue. However, whether DP can affect the intestinal tract of teleost fish remains largely unclear. To understand its effects on the intestinal barrier, morphological characteristics and intestinal microbiome of common carp, different concentrations (30, 60 and 120 µg/L) of DP were exposed to common carps for 4 weeks. The results indicated that DP evidently shortened the intestinal folds and damaged the intestinal epithelium layer. In addition, the mRNA expression levels of occludin, claudin-2 and zonula occludens-1 (ZO-1) were significantly decreased with increasing DP concentrations. Furthermore, the relative abundance of some microbiota species were also changed significantly. Our study first demonstrated that DP could cause damage to the intestinal epithelium and destroy the intestinal barrier and increase the relative abundance of pathogenic bacteria, thereby increasing the probability of contact between intestinal epithelium and pathogenic bacteria, which in turn lead to an increased susceptibility to various diseases and poor health. In summary, our findings reveal that chronic DP exposure can have a harmful effect on the intestinal flora balance and is potentially linked to human disease.

Synergistic Effect of a Pleuromutilin Derivative with Tetracycline against Streptococcus suis In Vitro and in the Neutropenic Thigh Infection Model.

Tetracycline (TET) has been widely used in the treatment of Streptococcus suis (S. suis) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was used in combination with TET against 12 S. suis isolates. In the checkerboard assay, the TET/GML-12 combination exhibited synergistic and additive effects against S. suis isolates (n = 12). In vitro time-killing assays and in vivo therapeutic experiments were used to confirm the synergistic effect of the TET/GML-12 combination against S. suis strains screened based on an FICI ≤ 0.5. In time-killing assays, the TET/GML-12 combination showed a synergistic effect or an additive effect against three isolates with a bacterial reduction of over 2.4-log10 CFU/mL compared with the most active monotherapy. Additionally, the TET/GML-12 combination displayed potent antimicrobial activity against four isolates in a mouse thigh infection model. These results suggest that the TET/GML-12 combination may be a potential therapeutic strategy for S. suis infection.

Dechlorane Plus increases adipogenesis in 3T3-L1 and human primary preadipocytes independent of peroxisome proliferator-activated receptor γ transcriptional activity.

BACKGROUND/OBJECTIVES: Polybrominated diphenyl ethers (PBDEs) are chemicals that were added to consumer products to reduce flammability but were deemed toxic and bioaccumulative and were phased out of commerce. Flame retardants (FRs) such as Dechlorane Plus (DP) were introduced as replacements. DP is being produced in high volumes and is detected in the environment, human milk, and human serum. Although human exposure to DP is evident, little is known about its potential effects on human health. We and others have shown that some FRs are potential obesogens, i.e., promote adipogenesis. However, the effects of DP on adipogenesis are not known. METHODS: Murine 3T3-L1 and human primary subcutaneous (Sc) and omental (Om) preadipocytes were differentiated in the presence of DP (0.001-10 µM) and adipogenic effects were measured. Further, the ability of DP to activate the adipogenic transcription factor peroxisome proliferator-activated receptor γ (PPARγ) was also assessed. RESULTS: We show that treatment of murine preadipocytes with DP significantly (p < 0.05) increased lipid accumulation (2.5-fold) and the mRNA expression of adipogenic markers: fatty acid binding protein 4 (Fabp4), lipoprotein lipase (Lpl), perilipin (Plin), adipsin, and adiponectin. DP also significantly (p < 0.05) increased the protein levels of selected mature adipocyte markers. We further show using luciferase reporter assays that DP increased PPARγ transcriptional activity by threefold (p < 0.05). When the PPARγ agonist was replaced by DP in the human preadipocyte differentiation cocktail, DP significantly (p < 0.05) increased the mRNA levels of adipogenic markers, PPARγ, FABP4, and PLIN in human Sc as well as Om cultures. Finally, PPARγ antagonist studies revealed that DP-mediated upregulation of adipogenic markers Fabp4 and Lpl did not occur via PPARγ activation. CONCLUSION: The current study shows that DP can induce adipogenesis of murine and human preadipocytes. We show that, although DP can directly activate PPARγ, its adipogenic effects may be mediated via other pathways.

Changes in thyroid function of nestling tree swallows (Tachycineta bicolor) in relation to polycyclic aromatic compounds and other environmental stressors in the Athabasca Oil Sands Region.

In the Canadian Athabasca Oil Sands Region (AOSR), nestling tree swallows (Tachycineta bicolor) raised near mining-related activities accumulated greater concentrations of polycyclic aromatic compounds (PACs) that contributed to their poorer condition, growth, and reproductive success. Here, we report changes in thyroid function of the same 14 day old (do) nestlings (N ≤ 68) at these mining-related sites (OS1, OS2) compared to reference nestlings (REF1), and in relation to multiple environmental stressors that influence avian thyroid function. Thyroid function was compromised for OS1 nestlings but generally comparable between OS2 and REF1 chicks. In 2012, circulating total triiodothyronine (TT3) and thyroxine (TT4) were similar among all nestlings. The OS1 chicks had more active thyroid glands based on histological endpoints. Hepatic T4 outer-ring deiodinase (T4-ORD) activity was suppressed in OS1 and OS2 chicks. Despite inter-annual differences, OS1 chicks continued experiencing compromised thyroid function with significantly higher circulating TT4 and more active thyroid glands in 2013. The OS2 chicks had less active thyroid glands, which conceivably contributed to their suppressed growth (previously reported) relative to the heavier OS1 nestlings with more active thyroid glands. Thyroid gland activity was more influenced by the chicks' accumulation of (muscle), than exposure (feces) to naphthalene, C2-naphthalenes, and C1-fluorenes. Of four major volatile organic contaminants, sulfur dioxide (SO2) primarily influenced thyroid gland activity and structure, supporting previous findings with captive birds. When collectively considering environmental-thyroidal stressors, chicks had a greater thyroidal response when they experienced colder temperatures, accumulated more C2-naphthalenes, and consumed aquatic-emerging insects with higher PAC burdens than terrestrial insects (carbon (δ13C)). We hypothesize that the more active thyroid glands and higher circulating TT4 of the OS1 chicks supported their growth and survival despite having the highest PAC burdens, whereas the lack of thyroid response in the OS2 chicks combined with high PAC burdens, contributed to their smaller size, poorer condition and poorer survival.

Neurodevelopmental toxicity assessments of alkyl phenanthrene and Dechlorane Plus co-exposure in zebrafish.

Alkyl phenanthrene (A-Phen) and Dechlorane Plus (DP) are ubiquitous environmental pollutants that widely co-exist in the environment. It has been established that both A-Phen and DP elicit neurotoxicity, but the potential interactive toxicity of these contaminants is not well-known. To determine whether a mixture of A-Phen and DP would exhibit interactive effects on neurodevelopment, we co-exposed 3-methylphenanthrene (3-MP), a representative of A-Phen, with DP. Our results illustrated that exposure to 5 or 20 µg/L 3-MP alone or in combination with 60 µg/L DP caused neurobehavioral anomalies in zebrafish. In accordance with the behavioral deficits, 3-MP alone or co-exposed with DP significantly decreased axonal growth of secondary motoneurons, altered intracellular Ca2+ homeostasis and induced cell apoptosis in the muscle of zebrafish. Additionally, 3-MP alone or co-exposed with DP significantly increased reactive oxygen species (ROS) and the mRNA levels of apoptosis-related genes. These findings indicate that 3-MP alone or co-exposed with DP induces neurobehavioral deficits through the combined effects on neuronal connectivity and muscle function. Chemical analysis revealed significant increases in 3-MP and DP bioaccumulation in zebrafish co-exposed with 3-MP and DP. Elevated bioaccumulation resulting from mixture exposure may represent a significant contribution of the synergistic effects observed in combined chemical exposure.

In ovo transformation of two emerging flame retardants in Japanese quail (Coturnix japonica).

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and Dechlorane Plus (DP) are two chlorinated, alternative flame retardants that have been found in wild birds and bird eggs. Little is known about the fate and effect of these compounds in birds, especially during the vulnerable stages of embryonic development. To investigate the ability of birds to biotransform these compounds, an in ovo exposure experiment with Japanese quail eggs was performed. Quail eggs were injected in the yolk sac with 1000ng/g egg of TDCIPP (2.3 nmol/g ww), DP (1.5 nmol/g ww) or a mixture of both and were then incubated at 37.5°C for 17 days. To get a time-integrated understanding of the in ovo transformation of the compounds, one egg per treatment was removed from the incubator every day and analyzed for TDCIPP and its metabolite bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and/or for DP. By the end of the incubation period, TDCIPP was completely metabolized, while simultaneously BDCIPP was formed. The conversion of the parent compound into the metabolite did not occur proportionally and the concentration of BDCIPP showed a tendency to decrease when TDCIPP became depleted, both indicating that BDCIPP was further transformed into compounds not targeted for analysis. Further untargeted investigations did not show the presence of other metabolites, possibly due to the volatility of the metabolites. On the other hand, the DP concentration did not decrease during egg incubation. This study indicates that within the incubation period, avian embryos are able to biotransform TDCIPP, but not DP.

Japanese quail (Coturnix japonica) liver and thyroid gland histopathology as a result of in ovo exposure to the flame retardants tris(1,3-dichloro-2-propyl) phosphate and Dechlorane Plus.

Japanese quails (Coturnix japonica) were exposed in ovo to tris(1,3-dichloro-2-propyl) phosphate (TDCIPP; 500 ng/µl), Dechlorane Plus (DP; 500 ng/µl), or a 1:1 mixture of these two to investigate the effects on liver and thyroid gland morphology. Histological examination of 14-day-old quails showed that exposure to TDCIPP or the mixture induced hepatic sinusoidal dilatation. No marked effects were seen for DP alone. In addition, the mixture produced divergence of thyroid gland follicles and proliferation of follicular cells. Our study is the first demonstrating histopathological alterations as a result of exposure during early development to the flame retardants TDCIPP or a TDCIPP-DP mixture suggesting the need for further research efforts to investigate potential adverse health effects associated with exposure to these environmental chemicals in wild birds.

Mapping Indicators of Toxicity for Polycyclic Aromatic Compounds in the Atmosphere of the Athabasca Oil Sands Region.

Extracts of passive air samples collected from 15 passive sampling network sites across the Athabasca Oil Sands region were used to explore the application of in vitro assays for mutagenicity (Salmonella mutation assays) and cytotoxicity (lactate dehydrogenase assay) to assess the toxicity of the air mixture. The air monitoring of polycyclic aromatic compounds (PACs) and PAC transformation products, including nitrated polycyclic aromatic hydrocarbons (NPAHs) and oxygenated polycyclic aromatic hydrocarbons (OPAHs) was then linked to the potential toxicity of air. The PACs in air during April to May 2014 were elevated near mining activities and declined with distance from the source region, whereas NPAHs and OPAHs exhibited a more variable spatial distribution with the highest levels in Fort McMurray. Overall, the air samples exhibited a weak mutagenicity. The highest indirect-acting mutagenicity was observed for sites closest to mining activities; however, the indirect-acting mutagenicity did not decline sharply with distance from mining areas. Indirect-acting mutagenicity was strongly correlated with levels of total PACs, benzo(a)pyrene equivalent mass, and OPAHs. Most of the samples exhibited cytotoxic potential, but the magnitude of the response was variable across the sample region and did not correlate with levels of target analytes. This indicates that PACs and PAC derivatives were not a major contributor to the cytotoxicity observed in the air samples.

Evaluation of the Genotoxic and Physiological Effects of Decabromodiphenyl Ether (BDE-209) and Dechlorane Plus (DP) Flame Retardants in Marine Mussels (Mytilus galloprovincialis).

Dechlorane Plus (DP) is a proposed alternative to the legacy flame retardant decabromodiphenyl ether (BDE-209), a major component of Deca-BDE formulations. In contrast to BDE-209, toxicity data for DP are scarce and often focused on mice. Validated dietary in vivo exposure of the marine bivalve (Mytilus galloprovincialis) to both flame retardants did not induce effects at the physiological level (algal clearance rate), but induced DNA damage, as determined by the comet assay, at all concentrations tested. Micronuclei formation was induced by both DP and BDE-209 at the highest exposure concentrations (100 and 200 µg/L, respectively, at 18% above controls). DP caused effects similar to those by BDE-209 but at lower exposure concentrations (5.6, 56, and 100 µg/L for DP and 56, 100, and 200 µg/L for BDE-209). Moreover, bioaccumulation of DP was shown to be concentration dependent, in contrast to BDE-209. The results described suggest that DP poses a greater genotoxic potential than BDE-209.

Cryptophane-folate biosensor for (129)xe NMR.

Folate-conjugated cryptophane was developed for targeting cryptophane to membrane-bound folate receptors that are overexpressed in many human cancers. The cryptophane biosensor was synthesized in 20 nonlinear steps, which included functionalization with folate recognition moiety, solubilizing peptide, and Cy3 fluorophore. Hyperpolarized (129)Xe NMR studies confirmed xenon binding to the folate-conjugated cryptophane. Cellular internalization of biosensor was monitored by confocal laser scanning microscopy and quantified by flow cytometry. Competitive blocking studies confirmed cryptophane endocytosis through a folate receptor-mediated pathway. Flow cytometry revealed 10-fold higher cellular internalization in KB cancer cells overexpressing folate receptors compared to HT-1080 cells with normal folate receptor expression. The biosensor was determined to be nontoxic in HT-1080 and KB cells by MTT assay at low micromolar concentrations typically used for hyperpolarized (129)Xe NMR experiments.

The effects of heavy metals and their interactions with polycyclic aromatic hydrocarbons on the oxidative stress among coke-oven workers.

Heavy metals and polycyclic aromatic hydrocarbons (PAHs) are predominate toxic constituents of particulate air pollution that may be related to the increased risk of cardiopulmonary events. We aim to investigate the effects of the toxic heavy metals (arsenic, As; cadmium, Cd; chromium, Cr; nickel, Ni; and lead, Pb), and their interactions with PAHs on oxidative stress among coke-oven workers. A total of 1333 male workers were recruited in this study. We determined their urinary levels of As, Cd, Cr, Ni, Pb, twelve PAH metabolites, 8-hydroxydeoxyguanosine (8-OHdG), and 8-iso-prostaglandin-F2α (8-iso-PGF2α). Multivariate linear regression models were used to analyze the effects of these metals and their interactions with PAHs on 8-OHdG and 8-iso-PGF2α levels. It was found that only urinary As and Ni showed marginal or significant positive linear dose-dependent effects on 8-OHdG in this study population, especially among smokers (ß=0.103, P=0.073 and ß=0.110, P=0.002, respectively). After stratifying all participants by the quartiles of ΣOH-PAH, all five metals showed linear association with 8-OHdG in the highest quartile subgroup (Q4) of ΣOH-PAHs. However, these five urinary metals showed significantly consistent linear associations with 8-iso-PGF2α in all subjects and each stratum. Urinary ΣOH-PAHs can significant modify the effects of heavy metals on oxidative stress, while co-exposure to both high levels of ΣOH-PAHs and heavy metals render the workers with highest 8-OHdG and 8-iso-PGF2α (all P(interaction)≤0.005). This study showed evidence on the interaction effects of heavy metals and PAHs on increasing the oxidative stress, and these results warrant further investigation in more longitudinal studies.

Global and MGMT promoter hypomethylation independently associated with genomic instability of lymphocytes in subjects exposed to high-dose polycyclic aromatic hydrocarbon.

Global hypomethylation, gene-specific methylation, and genome instability are common events in tumorigenesis. To date, few studies have examined the aberrant DNA methylation patterns in coke oven workers, who are highly at risk of lung cancer by occupational exposure to polycyclic aromatic hydrocarbons (PAHs). We recruited 82 PAH-exposed workers and 62 unexposed controls, assessed exposure levels by urinary 1-hydroxypyrene, and measured genetic damages by comet assay, bleomycin sensitivity, and micronucleus assay. The PAHs in coke oven emissions (COE) were estimated based on toxic equivalency factors. We used bisulfite-PCR pyrosequencing to quantitate DNA methylation in long interspersed nuclear element-1 (LINE-1) and O(6)-methylguanine-DNA methyltransferase (MGMT). Further, the methylation alteration was also investigated in COE-treated human bronchial epithelial (16HBE) cells. We found there are higher levels of PAHs in COE. Among PAH-exposed workers, LINE-1 and MGMT methylation levels (with CpG site specificity) were significantly lowered. LINE-1, MGMT, and its hot CpG site-specific methylation were negatively correlated with urinary 1-hydroxypyrene levels (r = -0.329, p < 0.001; r = -0.164, p = 0.049 and r = -0.176, p = 0.034, respectively). In addition, LINE-1 methylation was inversely associated with comet tail moment and micronucleus frequency, and a significant increase of micronucleus in low MGMT methylation group. In vitro study revealed that treatment of COE in 16HBE cells resulted in higher production of BPDE-DNA adducts, LINE-1 hypomethylation, hypomethylation, and suppression of MGMT expression. These findings suggest hypomethylation of LINE-1 and MGMT promoter could be used as markers for PAHs exposure and merit further investigation.

Assessing the mammalian toxicity of high-boiling petroleum substances under the rubric of the HPV program.

In 1998, the US EPA announced the HPV Challenge Program, a voluntary chemical data collection effort. The Petroleum HPV Testing Group (PHPVTG(1)) volunteered to provide data on approximately 110 high boiling petroleum substances (HBPS), i.e. substances with final boiling points ≥ approximately 650°F (343°C). These HBPS are substances of unknown and variable composition (UVCBs) that are composed of numerous individual constituents. Toxicity studies have shown that some HBPS can produce systemic (repeat-dose) and developmental effects, and some are mutagenic under in vitro conditions. The papers in this supplement show that these effects are related to the profiles of aromatic constituents in these substances. Further, it is shown that the effects on selected repeat-dose and developmental toxicity endpoints and mutagenic activity in bacterial assays can be predicted from compositional information using models based on the aromatic-ring class profile, "ARC profile" as defined by gas chromatographic separation of the DMSO-soluble fraction of the starting materials. This chromatographic method and the predictive models provide an efficient means of characterizing for screening purposes the potential for repeat-dose, developmental effects and bacterial mutagenicity of HBPS and can reduce the number of animal tests that would be required if these tests were conducted on all 110 HBPS.

Neglschisandrins E-F: two new lignans and related cytotoxic lignans from Schisandra neglecta.

Phytochemical investigation of an ethanolic extract of stems of Schisandra neglecta led to the isolation and identification of two new dibenzocyclooctadiene lignans, designated neglschisandrins E (1) and F (2), and thirteen known lignans. All structures and stereochemistries were determined by spectroscopic methods, including 2D-NMR techniques. The isolates were evaluated for in vitro cytotoxic activity. Among them, compounds 2-6 exhibited moderate to weak cytotoxicity against the human colorectal carcinoma HCT-8 cell line with EC50 values of 7.33~19.8 µg/mL. In addition, compounds 2-4 also exhibited marginal cytotoxicity against the human lung carcinoma A549 cell line with EC50 values of 11.8~15.0 µg/mL.

Complex polycyclic aromatic compound mixtures in PM2.5 in a Chinese megacity: Spatio-temporal variations, toxicity, and source apportionment.

Polycyclic aromatic compounds (PACs) are important toxic organic components in fine particulate matter (PM2.5), whereas the links between PM2.5 toxicity and associated PACs in ambient air are poorly understood. This study investigated the spatial-temporal variations of PACs in PM2.5 collected from 11 sampling sites across a Chinese megacity and characterized the reactive oxygen species (ROS) generation and cytotoxicity induced by organic extracts of PM2.5 based on cellular assays. The extra trees regression model based on machine learning and ridge regression were used to identify the key toxicants among complex PAC mixtures. The total concentrations of these PACs varied from 2.12 to 71.7 ng/m3 across the study city, and polycyclic aromatic hydrocarbons (PAHs) are the main PACs. The spatial variations of the toxicological indicators generally resembled those of the PAC concentrations, and the PM2.5 related to waste treatment facilities exhibited the strongest toxic potencies. The ROS generation was highly correlated with high molecular weight PAHs (MW302 PAHs), followed by PAHs with MW<302 amu and oxygenated PAHs, but not with nitrated PAHs and the plastics additives. The cell mortality showed weak correlations with these organic constituents. The associations between the biological endpoints and these PM2.5-bound contaminants were further confirmed by exposure to authentic chemicals. Four primary sources of PACs were identified, among which coal and biomass combustion sources (30.2% of the total PACs) and industrial sources (31.0%) were predominant. PACs emitted from industrial sources were highly associated with ROS generation in this city. Our findings highlight the potent ROS-generating potential of MW302 PAHs and the importance of industrial sources contributing to PM2.5 toxicity in this megacity, raising public concerns and further administration.

Responses of mouse liver to dechlorane plus exposure by integrative transcriptomic and metabonomic studies.

Dechlorane plus (DP), a chlorinated flame retardant, has been widely detected in different environmental matrices and biota. However, toxicity data for DP have seldom been reported. In the present study, we investigated hepatic oxidative stress, DNA damage, and transcriptomic and metabonomic responses of male mice administered 500 mg/kg, 2000 mg/kg, and 5000 mg/kg of DP by gavage for 10 days. The results showed that DP exposure increased the level of superoxide dismutase (SOD) and 8-hydroxy-2-deoxyguanosine (8-OHdG). The microarray-based transcriptomic results demonstrated that DP exposure led to significant alteration of gene expression involved in carbohydrate, lipid, nucleotide, and energy metabolism, as well as signal transduction processes. The NMR-based metabonomic analyses corroborated these results showing changes of metabolites associated with the above altered mechanisms. Our results demonstrate that an oral exposure to DP can induce hepatic oxidative damage and perturbations of metabolism and signal transduction. These observations provide novel insight into toxicological effects and mechanisms of action of DP at the transcriptomic and metabonomic levels.

Dechlorane Plus and related compounds in aquatic and terrestrial biota: a review.

Dechlorane Plus, dechlorane 602, dechlorane 603 and dechlorane 604 are flame retardants that have been used for a long time as a substitute for mirex, but they have not been noticed as environmental contaminants until recently (2006). Regardless of their large molecular size and very high lipophilicity (log K(OW) > 9), Dechlorane Plus and related compounds have been detected in different aquatic and terrestrial species, supporting their bioaccumulation and biomagnification. Moreover, some studies showed different behaviour of the syn-Dechlorane Plus and anti-Dechlorane Plus isomers in the environment and different biomagnification factors in biota. This review describes the different analytical approaches applied to the determination of Dechlorane Plus and related compounds. Moreover, a summary of their levels in aquatic and terrestrial biota, as well as in humans, is presented, showing also current research results on their bioaccumulation and biomagnification potential. Finally, isomer-specific bioaccumulation of Dechlorane Plus is also discussed.

Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response.

ATM and ATR protein kinases play a crucial role in cellular DNA damage responses. The inhibition of ATM and ATR can lead to the abolition of the function of cell cycle checkpoints. In this regard, it is expected that checkpoint inhibitors can serve as sensitizing agents for anti-cancer chemo/radiotherapy. Although several ATM inhibitors have been reported, there are no ATR-specific inhibitors currently available. Here, we report the inhibitory effect of schisandrin B (SchB), an active ingredient of Fructus schisandrae, on ATR activity in DNA damage response. SchB treatment significantly decreased the viability of A549 adenocarcinoma cells after UV exposure. Importantly, SchB treatment inhibited both the phosphorylation levels of ATM and ATR substrates, as well as the activity of the G2/M checkpoint in UV-exposed cells. The protein kinase activity of immunoaffinity-purified ATR was dose-dependently decreased by SchB in vitro (IC(50): 7.25 muM), but the inhibitory effect was not observed in ATM, Chk1, PI3K, DNA-PK, and mTOR. The extent of UV-induced phosphorylation of p53 and Chk1 was markedly reduced by SchB in ATM-deficient but not siATR-treated cells. Taken together, our demonstration of the ability of SchB to inhibit ATR protein kinase activity following DNA damage in cells has clinical implications in anti-cancer therapy.