Widespread Pesticide Distribution in the European Atmosphere Questions their Degradability in Air.

Risk assessment of pesticide impacts on remote ecosystems makes use of model-estimated degradation in air. Recent studies suggest these degradation rates to be overestimated, questioning current pesticide regulation. Here, we investigated the concentrations of 76 pesticides in Europe at 29 rural, coastal, mountain, and polar sites during the agricultural application season. Overall, 58 pesticides were observed in the European atmosphere. Low spatial variation of 7 pesticides suggests continental-scale atmospheric dispersal. Based on concentrations in free tropospheric air and at Arctic sites, 22 pesticides were identified to be prone to long-range atmospheric transport, which included 15 substances approved for agricultural use in Europe and 7 banned ones. Comparison between concentrations at remote sites and those found at pesticide source areas suggests long atmospheric lifetimes of atrazine, cyprodinil, spiroxamine, tebuconazole, terbuthylazine, and thiacloprid. In general, our findings suggest that atmospheric transport and persistence of pesticides have been underestimated and that their risk assessment needs to be improved.

Development of a supramolecular solvent-based extraction method for application to quantitative analyses of a wide range of organic contaminants in indoor dust.

This study investigates the efficacy of supramolecular solvent (SUPRAS) in extracting a diverse spectrum of organic contaminants from indoor dust. Initially, seven distinct SUPRAS were assessed across nine categories of contaminants to identify the most effective one. A SUPRAS comprising Milli-Q water, tetrahydrofuran, and hexanol in a 70:20:10 ratio, respectively, demonstrated the best extraction performance and was employed for testing a wider array of organic contaminants. Furthermore, we applied the selected SUPRAS for the extraction of organic compounds from the NIST Standard Reference Material (SRM) 2585. In parallel, we performed the extraction of NIST SRM 2585 with conventional extraction methods using hexane:acetone (1:1) for non-polar contaminants and methanol (100%) extraction for polar contaminants. Analysis from two independent laboratories (in Norway and the Czech Republic) demonstrated the viability of SUPRAS for the simultaneous extraction of twelve groups of organic contaminants with a broad range of physico-chemical properties including plastic additives, pesticides, and combustion by-products. However, caution is advised when employing SUPRAS for highly polar contaminants like current-use pesticides or volatile substances like naphthalene.

Replacement Flame-Retardant 2-Ethylhexyldiphenyl Phosphate (EHDPP) Disrupts Hepatic Lipidome: Evidence from Human 3D Hepatospheroid Cell Culture.

The present study aims to evaluate the effects of repeated exposure to 2-ethylhexyldiphenyl phosphate (EHDPP) on human liver cells. In vitro three-dimensional (3D) hepatospheroid cell culture was utilized to explore the potential mechanisms of EHDPP-mediated metabolic disruption through morphological, transcriptional, and biochemical assays. Lipidomics analysis was performed on the individual hepatospheroids to investigate the effects on intracellular lipid profiles, followed by hepatospheroid morphology, growth, functional parameters, and cytotoxicity evaluation. The possible mechanisms were delineated using the gene-level analysis by assessing the expression of key genes encoding for hepatic lipid metabolism. We revealed that exposure to EHDPP at 1 and 10 µM for 7 days alters the lipid profile of human 3D hepatospheroids. Dysregulation in several lipid classes, including sterol lipids (cholesterol esters), sphingolipids (dihydroceramide, hexosylceramide, ceramide, sphingomyelin), glycerolipids (triglycerides), glycerophospholipids, and fatty acyls, was noted along with alteration in genes including ACAT1, ACAT2, CYP27A1, ABCA1, GPAT2, PNPLA2, PGC1α, and Nrf2. Our study brings a novel insight into the metabolic disrupting effects of EHDPP and demonstrates the utility of hepatospheroids as an in vitro cell culture model complemented with omics technology (e.g., lipidomics) for mechanistic toxicity studies.

Spatial and Temporal Trends of Persistent Organic Pollutants across Europe after 15 Years of MONET Passive Air Sampling.

The Global Monitoring Plan of the Stockholm Convention on Persistent Organic Pollutants (POPs) was established to generate long-term data necessary for evaluating the effectiveness of regulatory measures at a global scale. After 15 years of passive air monitoring (2003-2019), MONET is the first network to produce sufficient data for the analysis of continuous long-term temporal trends of POPs in air across the entire European continent. This study reports long-term concentrations of 20 POPs monitored at 32 sites in 27 European countries. As of January 1, 2019, the concentration ranges (pg/m3) were 1.1-52.8 (∑6PCB), 0.3-8.5 (∑12dl-PCB), 0.007-0.175 (∑17PCDD/F), 0.02-2.2 (∑9PBDE), 0.4-24.7 (BDE 209), 0.5-247 (∑6DDT), 1.7-818 (∑4HCH), 15.8-74.7 (HCB), and 5.9-21.5 (PeCB). Temporal trends indicate that concentrations of most POPs have declined significantly over the past 15 years, with median annual decreases ranging from -8.0 to -11.5% (halving times of 6-8 years) for ∑6PCB, ∑17PCDD/F, HCB, PeCB, and ∑9PBDE. Furthermore, no statistically significant differences were observed in either the trends or the concentrations of specific POPs at sites in Western Europe (WEOG) compared to sites in Central and Eastern Europe (CEE), which suggests relatively uniform compound-specific distribution and removal at the continental scale.

Personal care product use and lifestyle affect phthalate and DINCH metabolite levels in teenagers and young adults.

Humans are widely exposed to phthalates and their novel substitutes, and considering the negative health effects associated with some phthalates, it is crucial to understand population levels and exposure determinants. This study is focused on 300 urine samples from teenagers (aged 12-17) and 300 from young adults (aged 18-37) living in Czechia collected in 2019 and 2020 to assess 17 plasticizer metabolites as biomarkers of exposure. We identified widespread phthalate exposure in the study population. The diethyl phthalate metabolite monoethyl phthalate (MEP) and three di (2-ethylhexyl) phthalate metabolites were detected in the urine of >99% of study participants. The highest median concentrations were found for metabolites of low-molecular-weight (LMW) phthalates: mono-n-butyl phthalate (MnBP), monoisobutyl phthalate (MiBP) and MEP (60.7; 52.6 and 17.6 µg/L in young adults). 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) metabolites were present in 68.2% of the samples with a median of 1.24 µg/L for both cohorts. Concentrations of MnBP and MiBP were similar to other European populations, but 5-6 times higher than in populations in North America. We also observed large variability in phthalate exposures within the study population, with 2-3 orders of magnitude differences in urinary metabolites between high and low exposed individuals. The concentrations varied with season, gender, age, and lifestyle factors. A relationship was found between high levels of MEP and high overall use of personal care products (PCPs). Cluster analysis suggested that phthalate exposures depend on season and multiple lifestyle factors, like time spent indoors and use of PCPs, which combine to lead to the observed widespread presence of phthalate metabolites in both study populations. Participants who spent more time indoors, particularly noticeably during colder months, had higher levels of high-molecular weight phthalate metabolites, whereas participants with higher PCP use, particularly women, tended to have higher concentration of LMW phthalate metabolites.

Proteomic analysis of the bone marrow microenvironment in extramedullary multiple myeloma patients.

Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by the uncontrolled clonal proliferation of bone marrow (BM) plasma cells. The poor prognosis of patients is associated with the presence of extramedullary disease (EMD). Previously, different mechanisms involved in the colonization of BM niches by MM cells and their escape during EMD have been described. Thus, we aimed to investigate the expression of selected cytokines in the BM plasma of MM patients as well as EMD patients to reveal novel molecules involved in EMD pathogenesis. Expression of 120 different cytokines was measured in BM plasma of 13 MM and 11 EMD patients using Proteome Profiler Antibody Arrays. The correlation between statistically significant cytokines and clinicopathological parameters of patients was determined using the Spearman correlation analysis. Finally, protein-protein interactions were analyzed, and GO and KEGG pathways enrichment analysis was performed. In total, 27 cytokines were found to be differently expressed between MM and EMD patients. After the Benjamini-Hochberg correction for multiple testing, the statistical significance of two cytokines downregulated in EMD (EGF, BDNF) and six cytokines upregulated in EMD (NAP-2, ADIPOQ, CRP, MIG, BAFF, and THBS1) was maintained. Correlation analysis proved a significant association between the expression of these molecules and selected clinical-pathological features of MM/EMD patients. Protein association network analysis revealed important protein-protein interactions between THBS1/EGF, MIG/NAP-2, THBS1/NAP-2, EGF/NAP-2, and ADIPOQ/CRP. Finally, identified cytokines were proved to be significantly involved in focal adhesion, PI3K/AKT, and MAPK signaling pathways, and regulation of cell development, localization, proliferation, migration, differentiation, immune system processes, and stress response. Obtained results confirm the key function of the BM microenvironment in the pathogenesis of MM and indicate the essential role of numerous cytokines in disease progression and EMD development. However, the exact mechanisms need to be further clarified.

Temporal Trends of Persistent Organic Pollutants across Africa after a Decade of MONET Passive Air Sampling.

The Global Monitoring Plan of the Stockholm Convention on Persistent Organic Pollutants (POPs) was established to generate long-term data necessary for evaluating the effectiveness of regulatory measures at a global scale. After a decade of passive air monitoring (2008-2019), MONET is the first network to produce sufficient data for the analysis of long-term temporal trends of POPs in the African atmosphere. This study reports concentrations of 20 POPs (aldrin, chlordane, chlordecone, DDT, dieldrin, endrin, endosulfan, HBCDD, HCB, HCHs, heptachlor, hexabromobiphenyl, mirex, PBDEs, PCBs, PCDDs, PCDFs, PeCB, PFOA, and PFOS) monitored in 9 countries (Congo, Ghana, Ethiopia, Kenya, Mali, Mauritius, Morocco, Nigeria, and Sudan). As of January 1, 2019, concentrations were in the following ranges (pg/m3): 0.5-37.7 (∑6PCB), 0.006-0.724 (∑17PCDD/F), 0.05-5.5 (∑9PBDE), 0.6-11.3 (BDE 209), 0.1-1.8 (∑3HBCDD), 1.8-138 (∑6DDT), 0.1-24.3 (∑3endosulfan), 0.6-14.6 (∑4HCH), 9.1-26.4 (HCB), 13.8-18.2 (PeCB). Temporal trends indicate that concentrations of many POPs (PCBs, DDT, HCHs, endosulfan) have declined significantly over the past 10 years, though the rate was slow at some sites. Concentrations of other POPs such as PCDD/Fs and PBDEs have not changed significantly over the past decade and are in fact increasing at some sites, attributed to the prevalence of open burning of waste (particularly e-waste) across Africa. Modeled airflow back-trajectories suggest that the elevated concentrations at some sites are primarily due to sustained local emissions, while the low concentrations measured at Mt. Kenya represent the continental background level and are primarily influenced by long-range transport.

Legacy and novel flame retardants from indoor dust in Antarctica: Sources and human exposure.

The air humidity in Antarctica is very low and this peculiar weather parameter make the use of flame retardants in research facilities highly needed for safety reasons, as fires are a major risk. Legacy and novel flame retardants (nFRs) including polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), Dechlorane Plus (DP), and other nFRs were measured in indoor dust samples collected at research Stations in Antarctica: Gabriel de Castilla, Spain (GCS), Julio Escudero, Chile (JES), and onboard the RRS James Clark Ross, United Kingdom (RRS JCR). The GC-HRMS and LC-MS-MS analyses of dust samples revealed ∑7PBDEs of 41.5 ± 43.8 ng/g in rooms at GCS, 18.7 ± 11.6 ng/g at JES, and 27.2 ± 37.9 ng/g onboard the RRS JCR. PBDE pattern was different between the sites and most abundant congeners were BDE-183 (40%) at GCS, BDE-99 (50%) at JES, and BDE-153 (37%) onboard the RRS JCR. The ∑(4)HBCDs were 257 ± 407 ng/g, 14.9 ± 14.5 ng/g, and 761 ± 1043 ng/g in indoor dust collected in rooms at GCS, JES, and RRS JCR, respectively. The ∑9nFRs were 224 ± 178 ng/g at GCS, 14.1 ± 13.8 ng/g at JES, and 194 ± 392 ng/g on the RRS JCR. Syn- and anti-DP were detected in most of the samples and both isomers showed the highest concentrations at GCS: 163 ± 93.6 and 48.5 ± 61.1 ng/g, respectively. The laboratory and living room showed the highest concentration of HBCDs, DPs, BTBPE. The wide variations in FR levels in dust from the three research facilities and between differently used rooms reflect the different origin of furnishing, building materials and equipment. The potential health risk associated to a daily exposure via dust ingestion was assessed for selected FRs: BDEs 47, 99, and 153, α-, ß-, and γ-HBCD, BTBPE, syn- and anti-DP. Although the estimated exposures are below the available reference doses, caution is needed given the expected increasing use of novel chemicals without a comprehensive toxicological profile.

Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia.

Casein kinase 1δ/ε (CK1δ/ε) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1δ/ε inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.

Stable-isotope dilution LC-MS/MS method for quantitative determination of microcystin conjugates with cysteine and glutathione in biotic matrices.

Microcystins are cyclic peptide toxins with hepatotoxic and tumor-promoting properties, which are produced in significant quantities (up to tens of µg/L) in freshwater cyanobacterial water blooms. Several studies reported microcystin accumulation in fish with possible food transfer to humans. These compounds are further metabolized to cysteine and glutathione conjugates which can be present in tissues in significant concentrations. In this study, we focused on the development and evaluation of robust and highly sensitive SPE-LC-MS/MS method for the analysis of microcystin conjugates in fish tissue samples. For the first time, we demonstrate the use of isotopically labeled internal standards which are essential for accurate and precise determination of analytes in complex biotic matrices. LLOQs of respective microcystin conjugates (signal-to-noise ratio; S/N > 10, peak-to-peak method) ranged from 3.3 to 5.0 ng/g of tissue fresh weight (FW). The calibration was linear within a range of concentrations from 1 to 70 ng/mL for all analyzed conjugates. The precision and repeatability of the method were very good with recoveries in the range of 88.5-107.6% and relative standard deviations between 8.8 and 13.2% for all analytes. In the follow-up study, fully validated method was used for the determination of microcystin conjugate levels in common carp exposed to microcystin-containing cyanobacterial biomass under controlled conditions. Significant amounts of microcystin conjugates (up to 55 ng/g) were found in the tissues of fish after 7 weeks of exposure. Our method was shown to be robust, sensitive, selective, and suitable for the determination of trace levels of microcystin conjugates in fish tissues.

The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes.

Various cyclin-dependent kinase (Cdk) complexes have been implicated in the regulation of transcription. In this study, we identified a 70-kDa Cyclin K (CycK) that binds Cdk12 and Cdk13 to form two different complexes (CycK/Cdk12 or CycK/Cdk13) in human cells. The CycK/Cdk12 complex regulates phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and expression of a small subset of human genes, as revealed in expression microarrays. Depletion of CycK/Cdk12 results in decreased expression of predominantly long genes with high numbers of exons. The most prominent group of down-regulated genes are the DNA damage response genes, including the critical regulators of genomic stability: BRCA1 (breast and ovarian cancer type 1 susceptibility protein 1), ATR (ataxia telangiectasia and Rad3-related), FANCI, and FANCD2. We show that CycK/Cdk12, rather than CycK/Cdk13, is necessary for their expression. Nuclear run-on assays and chromatin immunoprecipitations with RNA polymerase II on the BRCA1 and FANCI genes suggest a transcriptional defect in the absence of CycK/Cdk12. Consistent with these findings, cells without CycK/Cdk12 induce spontaneous DNA damage and are sensitive to a variety of DNA damage agents. We conclude that through regulation of expression of DNA damage response genes, CycK/Cdk12 protects cells from genomic instability. The essential role of CycK for organisms in vivo is further supported by the result that genetic inactivation of CycK in mice causes early embryonic lethality.

Early inflammatory profiling of schwannoma cells induced by lipopolysaccharide.

Inflammatory profiling of Schwann cells manifested as an upregulation of cytokines is present after traumatic or disease injury of the peripheral nerves. Inflammatory activation of Schwann cells via Toll-like receptors (TLRs) can be triggered by exogenous pathological molecules or endogenous ligands produced during Wallerian degeneration. We investigated the early period of inflammatory reactions by following the levels of TLR4, NFκB, IL-1ß, pSTAT3, and IL-6 proteins after LPS treatment of RT4 schwannoma cells under in vitro conditions. Significantly increased levels of NFκB, IL-1ß, pSTAT3, and IL-6 proteins were found 1 h after LPS action indicating their involvement in the initiation of the inflammatory reaction of schwannoma cells. This initiation was induced without increased TLR4 protein expression, but was accompanied by the appearance of TLR4 in early endosomes. The protein levels decreased within the next 6 h of treatment with a subsequent increase of NFκB, IL-1ß, and pSTAT3 after 24 h of LPS treatment. In contrast, continuous decrease of IL-6 over time following LPS treatment was unexpected. Levels of soluble IL-6 protein in the culture medium also decreased with decreasing levels of LPS over 24 h.

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors.

A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination-mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.

Butyrate alters expression of cytochrome P450 1A1 and metabolism of benzo[a]pyrene via its histone deacetylase activity in colon epithelial cell models.

Butyrate, a short-chain fatty acid produced by fermentation of dietary fiber, is an important regulator of colonic epithelium homeostasis. In this study, we investigated the impact of this histone deacetylase (HDAC) inhibitor on expression/activity of cytochrome P450 family 1 (CYP1) and on metabolism of carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP), in colon epithelial cells. Sodium butyrate (NaBt) strongly potentiated the BaP-induced expression of CYP1A1 in human colon carcinoma HCT116 cells. It also co-stimulated the 7-ethoxyresorufin-O-deethylase (EROD) activity induced by the 2,3,7,8-tetrachlorodibenzo-p-dioxin, a prototypical ligand of the aryl hydrocarbon receptor. Up-regulation of CYP1A1 expression/activity corresponded with an enhanced metabolism of BaP and formation of covalent DNA adducts. NaBt significantly potentiated CYP1A1 induction and/or metabolic activation of BaP also in other human colon cell models, colon adenoma AA/C1 cells, colon carcinoma HT-29 cells, or in NCM460D cell line derived from normal colon mucosa. Our results suggest that the effects of NaBt were due to its impact on histone acetylation, because additional HDAC inhibitors (trichostatin A and suberanilohydroxamic acid) likewise increased both the induction of EROD activity and formation of covalent DNA adducts. NaBt-induced acetylation of histone H3 (at Lys14) and histone H4 (at Lys16), two histone modifications modulated during activation of CYP1A1 transcription, and it reduced binding of HDAC1 to the enhancer region of CYP1A1 gene. This in vitro study suggests that butyrate, through modulation of histone acetylation, may potentiate induction of CYP1A1 expression, which might in turn alter the metabolism of BaP within colon epithelial cells.

Effect of arsenic and cyanobacterial co-exposure on pathological, haematological and immunological parameters of rainbow trout (Oncorhynchus mykiss).

OBJECTIVES: Under environmental conditions, fish are simultaneously exposed to multiple stressors. This study provides new knowledge on the effects of controlled exposure to multiple stressors, namely cyanobacterial biomass and food contaminated with arsenic. METHODS: Rainbow trout were divided into six groups of 25 fish and exposed to different contaminant combinations for 30 days: 1) control group, 2) cyanobacterial biomass, 3 & 4) two groups exposed to arsenic at concentrations of 5 mg.kg(-1) and 50 mg.kg(-1) fish feed, and 5 & 6) two groups exposed to cyanobacterial biomass and arsenic combined. We then evaluated pathological, haematological and immunological parameters at 10, 20 and 30 days after exposure. RESULTS: Marked gross pathological findings were present in groups exposed to arsenic and arsenic/cyanobacteria after 30 days. A strong decrease in haemoglobin concentration was observed in all experimental groups receiving arsenic after 10 days exposure. Total leukocyte count increased markedly in fish exposed to cyanobacterial biomass, and to higher arsenic concentrations by the end of the experiment. Neutrophils decreased significantly at the end of exposure. Similarly, exposure to cyanobacteria and/or arsenic led to suppression of opsonised zymosan particle-induced neutrophil respiratory bursts. CONCLUSIONS: Our results demonstrate that the effects of exposure to toxic cyanobacterial biomass and arsenic on fish are enhanced when the contaminants are combined. In particular, long-term exposure led to disturbances in the white blood-cell count. Modulation of phagocytosis, which is the first line of defence against invading pathogens, suggests that the combined action leads to a decreased ability to control infection.

Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway.

Cytochrome P450 1B1 (CYP1B1) is an enzyme that has a unique tumor-specific pattern of expression and is capable of bioactivating a wide range of carcinogenic compounds. We have reported previously that coordinated upregulation of CYP1B1 by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and the aryl hydrocarbon receptor ligands, may increase bioactivation of promutagens, such as benzo[a]pyrene (BaP) in epithelial cells. Here, we extend those studies by describing a novel mechanism participating in the regulation of CYP1B1 expression, which involves activation of the p38 mitogen-activated protein kinase (p38) and mitogen- and stress-activated protein kinase 1 (MSK1). Using inhibitors of p38 and MSKs, as well as mouse embryonic cells derived from p38α-deficient and MSK1/2 double knockout mice, we show here that TNF-α potentiates CYP1B1 upregulation via the p38/MSK1 kinase cascade. Effects of this inflammatory cytokine on CYP1B1 expression further involve the positive transcription elongation factor b (P-TEFb). The inhibition of the P-TEFb subunit, cyclin-dependent kinase 9 (CDK9), which phosphorylates RNA polymerase II (RNAPII), prevented the enhanced CYP1B1 induction by a combination of BaP and inflammatory cytokine. Furthermore, using chromatin immunoprecipitation assays, we found that cotreatment of epithelial cells with TNF-α and BaP resulted in enhanced recruitment of both CDK9 and RNAPII to the Cyp1b1 gene promoter. Overall, these results have implications concerning the contribution of inflammatory factors to carcinogenesis, since enhanced CYP1B1 induction during inflammation may alter metabolism of exogenous carcinogens, as well as endogenous CYP1B1 substrates playing role in tumor development.

Particle size distribution of halogenated flame retardants and implications for atmospheric deposition and transport.

This study investigates the distribution of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD) and a group of novel flame retardants (NFRs) on atmospheric aerosols. Two high volume cascade impactors were used to collect particulate fractions of ambient air over a one year period at urban and rural sites. The majority of FRs were found on the finest aerosols (<0.95 µm). Concentrations of HBCD were higher than those of ΣPBDEs. Moreover, we noted seasonality and spatial differences in particle size distributions, yet a large portion of the observed differences were due to differences in particulate matter (PM) itself. When normalized by PM, the size distributions of the FRs exhibited much greater heterogeneity. Differences existed between the FR distributions by molecular weight, with the higher molecular weight FRs (e.g., BDE-209, Dechlorane Plus) distributed more uniformly across all particulate size fractions. The seasonal, spatial, and compound-specific differences are of crucial importance when estimating dry and wet deposition of FRs as smaller aerosols have longer atmospheric residence times. Estimated wet and dry deposition of four representative FRs (BDE-47, BDE-209, HBCD, and Dechlorane Plus) using size-segregated aerosol data resulted in lower deposition estimates than when bulk aerosol data were used. This has implications for estimates of long-range atmospheric transport and atmospheric residence times, as it suggests that without size-specific distributions, these parameters could be underestimated for FRs.

Assessment of bioavailable fraction of POPS in surface water bodies in Johannesburg City, South Africa, using passive samplers: an initial assessment.

In this study, the semipermeable membrane device (SPMD) passive samplers were used to determine freely dissolved concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in selected water bodies situated in and around Johannesburg City, South Africa. The devices were deployed for 14 days at each sampling site in spring and summer of 2011. Time weighted average (TWA) concentrations of the water-borne contaminants were calculated from the amounts of analytes accumulated in the passive samplers. In the area of interest, concentrations of analytes in water ranged from 33.5 to 126.8 ng l(-1) for PAHs, from 20.9 to 120.9 pg l(-1) for PCBs and from 0.2 to 36.9 ng l(-1) for OCPs. Chlorinated pesticides were mainly composed of hexachlorocyclohexanes (HCHs) (0.15-36.9 ng l(-1)) and dichlorodiphenyltrichloromethane (DDT) with its metabolites (0.03-0.55 ng l(-1)). By applying diagnostic ratios of certain PAHs, identification of possible sources of the contaminants in the various sampling sites was performed. These ratios were generally inclined towards pyrogenic sources of pollution by PAHs in all study sites except in the Centurion River (CR), Centurion Lake (CL) and Airport River (AUP) that indicated petrogenic origins. This study highlights further need to map up the temporal and spatial variations of these POPs using passive samplers.

Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered cranial neurogenesis.

CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD) is associated with mutations in the CDK13 gene encoding transcription-regulating cyclin-dependent kinase 13 (CDK13). Here, we focused on the development of craniofacial structures and analyzed early embryonic stages in CHDFIDD mouse models, with one model comprising a hypomorphic mutation in Cdk13 and exhibiting cleft lip/palate, and another model comprising knockout of Cdk13, featuring a stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically expressed at high levels in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13 deficiency leads to development of hypoplastic branches of the trigeminal nerve including the maxillary branch. Additionally, we detected significant changes in the expression levels of genes involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes in the expression pattern of other key face-specific genes (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in the regulation of craniofacial morphogenesis.

Child exposure to organophosphate and pyrethroid insecticides measured in urine, wristbands, and household dust and its implications for child health in South Africa: A panel study.

Background: Children in agricultural areas are exposed to organophosphate (OP) and pyrethroid (PYR) insecticides. This explorative study investigated child exposure to OPs and PYRs, comparing temporal and spatial exposure variability within and among urine, wristbands, and dust samples. Methods: During spraying season 2018, 38 South African children in two agricultural areas (Grabouw/Hex River Valley) and settings (farm/village) participated in a seven-day study. Child urine and household dust samples were collected on days 1 and 7. Children and their guardians were wearing silicone wristbands for seven days. Intraclass correlation coefficients (ICCs) evaluated temporal agreements between repeated urine and dust samples, Spearman rank correlations (Rs) evaluated the correlations among matrices, and linear mixed-effect models investigated spatial exposure predictors. A risk assessment was performed using reverse dosimetry. Results: Eighteen OPs/PYRs were targeted in urine, wristbands, and dust. Levels of chlorpyrifos in dust (ICC = 0.92) and diethylphosphate biomarker in urine (ICC = 0.42) showed strong and moderate temporal agreement between day 1 and day 7, respectively. Weak agreements were observed for all others. There was mostly a weak correlation among the three matrices (Rs = -0.12 to 0.35), except for chlorpyrifos in dust and its biomarker 3,5,6-trichloro-2-pyridinol in urine (Rs = 0.44). No differences in exposure levels between living locations were observed. However, 21% of the urine biomarker levels exceeded the health-risk threshold for OP exposure. Conclusions: Observed high short-term variability in exposure levels during spraying season highlights the need for repeated sampling. The weak correlation between the exposure matrices points to different environmental and behavioral exposure pathways. Exceeding risk thresholds for OP should be further investigated.