No description available.

No description available.

Diethylstilbestrol (DES) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been identified as immunotoxicants causing thymic atrophy, thymocyte hypocellularity, phenotypic changes detected by CD4 and CD8 surface antigens, and progenitor T-cell targeting in the fetal mouse. We hypothesized that gestational exposure to these two compounds may lead to comparable histologic and gene expression alterations in the fetal mouse thymus and liver. Treatment of pregnant C57Bl/6 mice with doses of 5 or 10 ug/kg TCDD or 48 ug/kg DES by oral gavage on gestation days (gd) 14 and 16 severely depressed day 18 thymic cellularity. Histologic evaluation of day 18 fetal thymuses showed disruption of normal cortico-medullary architecture after TCDD or DES. Decreased thymocyte density was noted primarily in cortical zones where pyknotic cells were increased by either TCDD or DES treatment. Using day 18 thymocyte suspensions and flow cytometry, 7-AAD showed decreases in viable thymocytes from TCDD- or DES-treated fetal mice, and concomitant increases in thymocytes in early apoptosis. When thymocytes were co-identified with CD4 and CD8 cell surface antigen expression, enhanced apoptosis occurred in CD4+CD8+ phenotype after TCDD treatment. After DES exposure, increased apoptosis occurred in CD4-CD8- and CD4-CD8+thymocytes. Both TCDD and DES increased liver to body weight ratios and decreased ratios of hematopoietic to hepatic cells present. Cytomegaly was seen in hepatocytes of TCDD and DES treated animals, and these cells had more variable features, such as increased cytoplasmic basophilia and more prominent nucleoli. Real time quantitative PCR demonstrated that DES decreased c-jun, Bcl-2, and PKCalpha mRNA expression. These results suggest a shift away from proliferative activity and may reflect alterations noted predominantly in the hematopoietic population. TCDD increased c-jun mRNA expression with modest decreases in PKCalpha, and marked decreases in p53 also noted. Decreases in p53 suggest a pro-proliferative status of hepatic cells, while decreases in PKCalpha may indicate decreases in phosphorylation of substrates required for normal cell cycle progression. The increased c-jun suggests that this gene may play a role in the hepatocyte hyperplasia, as well as the diminution of hematopoiesis. / Ph. D.

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are two structurally related groups of chemicals, generally referred to as `dioxins´. These are of great concern due to their high toxicity and global spread. Other groups of compounds with similar chemical structure and toxicity mechanisms are the brominated analogues polybrominated dibenzo-p-dioxins (PBDDs) and polybrominated dibenzofurans (PBDFs), and the dioxin-like polychlorinated biphenyls (PCBs). Numerous studies have been undertaken to investigate sources and transport routes of dioxins. However, much remains to be done, including analytical, inventories of dioxin-like compounds, such as PBDD/Fs, and the development of more convenient analytical methods. The currently standard procedure for analyzing dioxins (and dioxin-like compounds) is to use Soxhlet extraction followed by multi-step clean-up and gas chromatography - high resolution mass spectrometry (GC- HRMS) for detection. Unfortunately, this method is very solvent, labor and time-consuming, making it very expensive. The main aim of the studies this thesis was to develop pressurized liquid extraction (PLE) with integrated clean up techniques for fast, convenient preparation of dioxin samples. PLE with integrated clean-up has previously been used for extracting dioxins from biological samples, but in these studies the possibility of extending its use to abiotic samples was explored. The results show that PLE with an integrated carbon trap is suitable for analyzing dioxins in various types of soil samples, sediment and flue gas samples. The results also showed that it has potential for analyzing dioxins in fly ash. The thesis focuses on developments of the methodology for dioxin analysis, but also includes results obtained from PBDDs and dioxin-like PCB analyses. In addition, the possibility of using various other kinds of detection techniques rather than GC-HRMS, such as enzyme-linked immunosorbent assays (ELISAs) or two-dimensional gas chromatography with micro electron capture detection (GCxGC-µECD) was explored. The results indicate that ELISA and GCxGC-µECD could serve as complementary detection systems in some cases. However, it is not yet possible to fully replace GC-HRMS. A further refinement of the PLE with in-cell clean-up technique is the modular approach developed in these studies. With this technique it is possible to include various steps for both clean-up and fractionation. For example, sulphuric acid impregnated silica could be combined with active carbon for the simultaneous removal of lipids (along with other interferences) and fractionation of PCBs and PCDD/Fs. It was shown that the method could provide data that agreed reasonably well with both reference values and values obtained using traditional methods. In general PLE proved to have high extraction efficiency and to yield very similar congener profiles to the reference method. In addition, it was shown that it allowed one-step extraction and clean-up of a salmon sample. Such single-step procedures are the ultimate goals for any extraction technique, and it would be highly desirable to develop one-step methods that could be extended to other types of samples. For the rest of the matrices tested (soil, sediment, mussel and crab tissue and flue gas) the method was successful, however a final polishing step is currently required, involving either dilution or clean-up using miniaturized multilayer silica columns, to obtain extracts that are pure enough for GC-HRMS analysis. Using the developed modular-PLE system substantial costs could be saved. It was estimated that the method could reduce the cost of preparing samples by up to 90%, which would greatly facilitate large-scale inventories.

Detta examensarbete syftade till att ta fram ett underlag för en regional åtgärdsplan avseende dibenso-p-dioxiner och dibensofuraner, gemensamt benämnda som PCDD/F eller dioxiner, i Gävleborgs län. Länet har historiskt varit ett av de mest utsatta områdena i Sverige beträffande dessa föroreningar och höga koncentrationer i bland annat strömming har medfört att denna inte får saluföras i övriga EU.   I arbetet har resultaten från den rådande forskningen på området studerats för att få kunskap om nuvarande källor och möjliga förklaringar till de fortsatt förhöjda koncentrationerna av dioxiner. Därefter har data från tidigare undersökningar av dioxinkoncentrationer i Gävleborgs län samlats in, sammanställts och använts för att studera hur koncentrationerna varierar geografiskt inom länet. Principalkomponentanalys (PCA) av specifika dioxinkongeners koncentrationer har sedan använts för att försöka identifiera verksamhetstyper som potentiellt kan ha bidragit till föroreningarna på olika platser - en analys som dock är behäftad med stora osäkerheter. De insamlade provresultaten har även använts för att genom massbalansmodellering undersöka återhämtningen i två känt förorenade fjärdar i länet; Norrsundet och Gårdsfjärden. Utifrån resultaten av ovanstående analyser diskuterades även nyttan av att genomföra eventuella åtgärder för att reducera halterna i kraftigt förorenade områden.   Proverna som sammanställts visade klara geografiska skillnader i sedimentkoncentration, och till viss del även i koncentration i muskel från abborre, vilket visar på en stark betydelse av lokala källor i vissa områden. Bland strömmingsproverna kunde inget liknande samband ses. Detta kan förklaras av att det migrerande beteendet hos strömming gör att fisken under sin livstid exponeras för varierande föroreningsnivåer i olika områden, medan abborren är mer stationär även som vuxen. Principalkomponentanalysen gav, för vissa prover, indikationer kring vilken typ av verksamhet som bidragit till de uppmätta koncentrationerna. Dessa resultat är dock mycket osäkra och bör inte på egen hand användas som underlag för att fastställa föroreningskällor. Massbalansmodelleringen visade att PCDD/F-koncentrationen i sediment inte har någon betydelse för koncentrationen i vattenmassan utan att inflödet från omgivande hav dominerar även i avgränsade fjärdar. De modellerade jämviktskoncentrationerna mellan sediment och vattenmassa indikerade även att koncentrationerna i sediment kommer fortsätta överskrida somliga gränsvärden tills koncentrationen i vattenmassan reducerats, vilket även stöds av att dessa gränsvärden överskreds i majoriteten av de sammanställda proverna.   Baserat på samtliga ovannämnda resultat drogs slutsatsen att lokala saneringsåtgärder sannolikt inte ger någon effekt på PCDD/F-koncentrationerna i strömming, samt att de inte är tillräckliga för att erhålla sedimentkoncentrationer under samtliga gränsvärden. De kan däremot effektivt minska den exponering som mer stationära organismer som abborre utsätts för i områden med kraftigt förorenade sediment, och kan även ha positiva effekter på förekomsten av andra miljöfarliga ämnen i området. För- och nackdelar måste således övervägas i varje enskilt fall. / The aim of this Master’s Thesis was to provide a basis for a regional plan of action regarding dibenzo-p-dioxins and dibenzofurans, commonly referred to as PCDD/F or dioxins, in Gävle-borg County. This region has historically been one of the Swedish areas most affected by these pollutants, and high concentrations in for example Atlantic herring (Clupea harengus) have resulted in restrictions where some fish species cannot be sold in other EU countries.   In this work, results of current research on the subject were studied in order to gain knowledge about current sources and possible explanations to the continued high concentrations of dioxins. Thereafter, data from earlier investigations of dioxin levels in Gävleborg County have been gathered, compiled and used to study the regional geographic variation of the concentrations. Principal component analysis (PCA) was then used on the concentrations of specific congeners in an attempt to identify source types that might have contributed to the contamination in various sites; this analysis is however marred by uncertainties. The gathered data have also been used to investigate the recovery in two bays with known contaminations, Norrsundet and Gårdsfjärden, using mass balance modelling. The benefits of implementing measures to reduce the PCDD/F-concentrations in highly polluted areas were then discussed based on the results of the above-mentioned analyses.   The measured sediment concentrations, and partly also the concentrations in European perch (Perca fluviatilis), of the compiled samples showed distinct geographic differences, which indicates a strong influence from local sources in some areas. Among the herring samples, no such connection could be seen. This could be explained by the migrating behaviour of adult herring, resulting in an exposure to various levels of contamination in different areas as they migrate, while adult perch has a more stationary behaviour. For some samples, the principal component analysis gave indications on source types that might have contributed to the local contamination levels. These results are however very uncertain and they should not be used as the sole basis when determining emission sources. The mass balance modelling showed that the PCDD/F-concentrations in sediments have no influence on the concentrations in the water body; the inflow from the surrounding sea is predominant also in enclosed bays. The modelled equilibrium concentrations between sediments and water body also indicated that the sediment concentrations will continue to exceed the guideline values until the water concentrations have decreased. This is also supported by the fact that the majority of the samples showed concentrations exceeding these guideline values.   Based on all of the abovementioned results it was concluded that local remediation measures would most likely not affect the PCDD/F-concentrations in herring. It was also concluded that such measures would not suffice to obtain sediment concentrations that fall below all guideline values. They can however be used to lessen the exposure that stationary organisms are subjected to in areas with highly contaminated sediments, and can also have positive effects on the levels of other hazardous substances in the area. Thus, the benefits and disadvantages need to be considered in each specific case.

This thesis contributes to an increased understanding of the formation of dioxins and dioxin-like compounds in combustion processes. Although emissions to air from waste incineration facilities have been greatly reduced by the use of efficient air pollution control measures, the resulting residues (ashes and filters) are highly toxic and are classified as hazardous waste. The main objective of the work underlying this thesis was to elucidate the formation and chlorination pathways of dioxins and dioxin-like compounds in waste combustion flue gases in the temperature range 640-200°C in a representative, well-controlled laboratory-scale reactor using artificial municipal solid waste. This could contribute to the reduction of harmful emissions to air and also reduce the toxicity of waste incineration residues, thus reducing or even eliminating the need for costly and potentially hazardous after-treatment. A comparison of four different quenching profiles showed that the formation of polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDF) was rapid and mainly occurred in the 640-400°C temperature region, with high dependency on sufficient residence time within a specific temperature region. Prolonged residence time at high temperatures (450/460°C) reduced the PCDD yields, even at lower temperatures along the post-combustion zone. PCDD, PCDF and PCN (polychlorinated naphthalene) isomer distribution patterns indicated contributions from chlorophenol condensation as well as chlorination reactions for all three classes of compounds. The formation of PCDDs was largely influenced by chlorophenol condensation and to some extent by chlorination reactions. For the PCDFs, chlorine substitution adjacent to the oxygen bridges was unfavoured, as demonstrated by the notably lower abundance of 1,9-substituted congeners. This was supported by bidirectional orthogonal partial least squares (O2PLS) modelling. The variable with the greatest influence on the distribution of PCDD congeners was the relative free energy (RΔGf). The O2PLS models displayed distinct clusters, dividing most of the homologues into two or three sub-groups of congeners which seemed to correspond to the probability of origination from chlorophenol condensation. The effects of injection of aromatic structures into the flue gas differed for each class of compounds. Injection of naphthalene increased the formation of monochlorinated naphthalene but the remaining homologues appeared to be unaffected. This was probably due to insufficient residence time at temperatures necessary for further chlorination. Injected dibenzo-p-dioxin was decomposed, chlorinated and re-condensated into PCDDs and PCDFs, whereas injection of dibenzofuran and fluorene reduced the PCDD levels in the flue gas. / Denna avhandling fokuserar på olika aspekter som kan bidra till en ökad förståelse av bildning av dioxiner och dioxin-lika föreningar i förbränningsprocesser. Även om utsläppen till luft från sopförbränningsanläggningar har minskat kraftigt tack vare effektiva rökgasreningsmetoder, så återstår problemet med mycket giftiga rökgasreningsprodukter (askor och filter), vilka klassificeras som farligt avfall. Det huvudsakliga syftet med arbetet bakom denna avhandling var att klarlägga bildnings- och kloreringsvägarna för dioxiner och dioxin-lika föreningar i temperaturintervallet 640-200°C i rökgaser från sopförbränning. Detta kan möjliggöra lösningar för ytterligare emissionsminskningar och en avgiftning av biprodukterna från avfallsförbränning, vilket minskar eller till och med eliminerar behovet av kostsam och riskfylld efterbehandling. Realistiska och välkontrollerade försök har utförts i en lab-skalereaktor där en artificiell hushållssopa har förbränts. En jämförelse av fyra olika temperatur- och uppehållstidsprofiler visade att bildning av polyklorerade dibenso-p-dioxiner (PCDD) och dibensofuraner (PCDF) sker snabbt och huvudsakligen inom temperaturintervallet 640-400°C. Bildningen var starkt beroende av en tillräckligt lång uppehållstid inom ett visst temperaturområde. En förlängd uppehållstid vid höga temperaturer (>450°C) resulterade i minskade halter av PCDD, vilka förhöll sig låga även senare i efterförbränningszonen. Isomermönstren av PCDD, PCDF och PCN (polyklorerade naftalener) visade alla tecken på att härröra från både klorfenolkondensation och kloreringsreaktioner. PCDD-mönstret visade tydliga indikationer på bildning från klorfenoler, och till mindre grad bildning via klorering. För PCDF var klorsubstitution i positioner angränsande till syrebryggan missgynnad, vilket bekräftades av multivariat modellering (O2PLS). Den variabel som starkast påverkade bildningen av PCDD var relativa fria energin (RΔGf). Modellerna visade på en distinkt gruppering av PCDD- och PCDF-kongenerna i två eller tre grupper för varje kloreringsgrad, och föreslås vara relaterad till sannolikheten för respektive kongen att bildas via klorfenolkondensation. Injektion av aromatiska kolstrukturer i rökgaskanalen gav upphov till skilda effekter. Injektion av naftalen ökade bildningen av monoklorerad naftalen medan resterande homologer inte verkade påverkas, sannolikt på grund av för kort uppehållstid för ytterligare klorering. Dibenso-p-dioxin spjälkades sannolikt till fenoliska fragment som klorerades och sedan återkondenserades till PCDD och PCDF, medan dibensofuran och fluoren kraftigt reducerade PCDD-koncentrationerna.

During the US – Vietnam War (1961 – 1972), Vietnam was subjected to widespread spraying of the chemical herbicide that is also called Agent Orange containing the most toxic dioxin congener, of 2,3,7,8-Tetrachlorodibenzo(p)dioxin (2,3,7,8-TCDD). A Luoi district belongs to Thua Thien- Hue province, located in the western part of the North Central coast region of Vietnam. During the Ranch Hand campaign (1965 -1970), A Luoi was heavily sprayed with this herbicide. In order to assess potential human health risks for people due to 2,3,7,8-TCDD exposure from contaminated soil, more than 50 soil samples were collected in A Luoi district area in 2013 and 2014 to determine dioxin concentrations by HRGC/HRMS. Human health risk assessment was applied using internationally recognized approaches. Hazard Quotient (HQ) values, assuming 2,3,7,8-TCDD to be a threshold contaminant, were calculated to be 13.2 and 6.1; and Incremental Lifetime Cancer Risk (ILCTR) values, assuming 2,3,7,8-TCDD to be carcinogenic non threshold, were 0.00314 and 0.00627 for adults and children, respectively. These results from exposures in A Luoi show risk values, which are several hundred times higher than acceptable TRVs. The results of this study indicate that, although the war ended nearly 50 years ago, communities living in A Luoi are still at risk of residual dioxin exposure from soils contaminated. Therefore, risk management and mitigation measures are needed, including targeted soil remediation and provision of improved medical and health systems. To our knowledge, this is the first human health risk assessment (HRRA) study in areas sprayed by herbicides during the war in Vietnam. / Trong thời kỳ chiến tranh giữa Mỹ và Việt Nam (1961 - 1972), Việt Nam phải hứng chịu một lượng lớn chất diệt cỏ còn gọi là chất Da cam, trong đó chứa chất hóa học siêu độc 2,3,7,8- Tetrachlorodibenzo (p) dioxin (2,3,7,8-TCDD). Huyện A Lưới thuộc tỉnh Thừa Thiên-Huế, nằm ở phía tây của vùng duyên hải Bắc Trung Bộ Việt Nam. Trong chiến dịch Ranch Hand (1965-1970), huyện A Lưới đã nhiều lần bị phun rải chất diệt cỏ này. Trong 2 năm 2013 và 2014, hơn 50 mẫu đất và thực phẩm đã được thu thập ở khu vực huyện A Lưới và phân tích xác định nồng độ dioxin nhằm đánh giá rủi ro về sức khỏe đối với người dân sống trong vùng bị phun rải chất diệt cỏ trong chiến tranh. Nếu giả định chất 2,3,7,8-TCDD là chất độc có ngưỡng, giá trị HQ (hệ số rủi ro) tính được là 13,2 và 6,1; và nếu giả định 2,3,7,8-TCDD là chất độc gây ung thư không ngưỡng, các giá trị ILCR (nguy cơ ung thư tăng dần suốt đời) tìm được là 0,00314 và 0,00627, tương ứng đối với người lớn và trẻ em sống ở A Lưới. Khi so sánh với các giá trị TRVs (rủi ro chấp nhận được) cho thấy các giá trị rủi ro ở A Lưới cao hơn vài trăm lần. Từ kết quả này chỉ ra mặc dù chiến tranh đã kết thúc gần 50 năm trước, cộng đồng ở A Lưới vẫn có nguy cơ phơi nhiễm dioxin. Cần thiết phải sớm có các biện pháp quản lý rủi ro và giảm thiểu phơi nhiễm dioxin cho người dân, bao gồm việc xử lý đất và cung cấp các hệ thống bảo vệ môi trường, y tế và cải thiện sức khỏe. Đây là bài báo đầu tiên về đánh giá rủi ro sức khỏe cộng đồng dân cư do phơi nhiễm dioxin ở những vùng bị phun rải chất diệt cỏ trong chiến tranh.

This thesis is concerned with measurements of persistent organic pollutants (POPs) in environmental samples. The POPs consist of several groups of compound with many isomers, hence analysing POPs in a complex environment is a This thesis is concerned with measurements of persistent organic pollutants (POPs) in environmental samples. The POPs consist of several groups of compound with many isomers, hence analysing POPs in a complex environment is a challenging task. Studies of the abundance or dynamics of such substances in the environment require careful consideration of several key steps. The environmental and analytical problems must be correctly defined, suitable analytes, sampling strategies and techniques must be selected, the chemical analyses must be reproducible and accurate, and the data evaluation protocols must be rigorous and appropriate. The aim of this thesis was to evaluate the use of pollutant profiles in order to assess complex patterns of environmental exposure. When combined with multivariate data analysis (MVDA) a maximum of information may be extracted from analytical data. Nevertheless, good quality data is essential for correct evaluation of the environmental phenomena under investigation. The precision and accuracy of a solid phase assisted liquid extraction method was therefore assessed by comparison to a reference method. The validated method was used in two human exposure studies. The concentrations of PCBs and dioxins were determined in human tissues from general populations in Sweden and Spain. Although it was concluded that the populations were exposed to similar degree to PCBs and dioxins, principal component analysis (PCA) showed that the compound profiles differed between the populations. PCA was also used to differentiate between occupationally exposed workers and matched controls and between exposed workers with recent and earlier exposure. In addition, the analysis indicated that the differences in PCB patterns in workers with recent and earlier exposure were related to differences in the metabolic degradation rates of individual PCBs. The PCA model was further used to select PCB congeners that were representative of each group. Finally, the emission of polycyclic aromatic hydrocarbons (PAHs) in a traffic tunnel was estimated by measuring 29 individual PAHs. The sampling periods were chosen to reflect a maximum variation in the traffic composition. An excellent prediction of the percentage of heavy-duty vehicles was obtained using partial least squares (PLS) regression. It was shown by PCA that it might be possible to predict source compositions at other locations with the aid of multivariate statistical tools. Thus, properly gathered pollutant profiles and MVDA may be combined to extract a large amount of significant information from environmental source and exposure data.

<p>Dioxins and poly-chlorinated biphenyl (PCB) compounds are high priority organic pollutants which are similar in structure and well known for their toxicity, bioaccumulation and persistence in the environment. Dioxins and PCBs have a high affinity for certain types of clay minerals. However, the molecular mechanism for the observed high affinity of these compounds to clay minerals is not well understood and has been the main focus of this research work. The mechanisms that govern dioxin-clay and PCB-clay interactions were investigated from two perspectives. First, the influence of selected properties clay minerals on dioxin sorption was investigated via in-situ spectroscopic techniques (ATR-FTIRand Raman) structural (XRD) and macroscopic batch sorption methods using dibenzo-p-dioxin (DD) as a model solute. Second, the influence of solute properties, especially position and degree of chlorination and molecular planarity, on sorption was investigated.</p> <p> Smectites, especially, Cs-saponite effectively adsorbs dibenzo-p-dioxin (DD) from water with values reaching 10,000 mg kg^-1, or one weight percent which greatly exceeds that by other naturally occurring sorbents such as soil organic matter. Adsorption was promoted by clay interlayer exchangeable cations with low hydration energies, and by smectites in which negative charge in the smectite originate from the tetrahedral siloxane sheets. IR-active bands of DD sorbed to saponite in the 1280 to 1500 cm^-1region were perturbed compared to the ‘reference’ IR spectra. Combined batch sorption, XRD and spectroscopic data confirm that the intercalation of DD occurred in the clay interlayer and site specific interactions occur between DD molecule and Cs⁺ cation. </p> <p> Sorption of 1-chloro-dibenzo-p-dioxin (1-ClDD) and 2-chloro-dibenzo-p-dioxin (2-ClDD) on homoionic (Na⁺, K⁺, Rb⁺, and Cs⁺) smectites was evaluated to explore the effect of chlorine substitution position (and steric hindrance) of dioxin on sorption mechanisms. Similar to DD, adsorption was influenced by the hydration energy of exchangeable cations and the origin of negative charge in the smectite. XRD measurements revealed that 1-ClDD molecules were oriented nearly parallel to the siloxane surface of the clay while 2-ClDD adopted a tilted orientation, similar to DD. The location of the chlorine constituent in 1-ClDD prevents the molecule from its apparent energetically more favorable orientation. In-situ ATR-FTIR spectra revealed that sorption of 1-ClDD to Cs-saponite resulted in the loss of interfacial H₂O and suggested that the sorption 1-ClDD displaces interlayer H₂O and 2-ClDD is less sterically restricted in the clay interlayer. </p> <p> Sorption of three dioxins (DD, 1-ClDD and 2-ClDD) was compared to three PCBs (PCB-1, PCB-4, and PCB47) with similar octanol-partition coefficients (log K_ow) but varying molecular planarity and degree of chlorination onto Cs-saponite, which was shown to be representative of other smectites, revealed that despite having similar structure and hydrophobicity, dioxins have higher affinity for smectites than PCBs. Sorption studies also showed that sorption of PCBs is influenced by molecular planarity and hydrophobicity. Polarizability and dipole-moment were identified as important solute properties that affect the sorption behavior of dioxins and PCBSs. Linear relationships between these properties and log K_f’(subcooled liquid solubility normalized Freundlich sorption coefficient) values suggest that high sorption affinity of planar dioxins could be due to a combination of <i>Van der Waals</i> interactions with the siloxane surface, steric effects, and site-specific interactions between dioxin and exchangeable cations. In contrast, the sorption of PCBs was highly influenced by their molecular orientation.</p>

Recently, persistent organic pollutants such as polychlorinated biphenyls (PCBs) were classified as “metabolic disruptors” for their suspected roles is altering metabolic and energy homeostasis through bioaccumulation in liver and adipose tissues. Among PCBs, a specific congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), is a potent arylhydrocarbon receptor (AhR) agonist and elicits toxicity similar to the classic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). PCB126 levels found in human blood are particularly associated with diabetes and nonalcoholic fatty liver disease (NAFLD) in humans, however the mechanisms are unclear. We hypothesized that the accumulation of PCB126 disrupts carbohydrate and lipid metabolism by altering the functions of liver and adipose tissues. Hence, our objective was to characterize PCB126 induced-metabolic disruption and the underlying molecular mechanisms that cause toxicity. Separate animal studies were performed using a rat model to understand the time- and dose-dependent effects after PCB126 administration. The chronology of PCB126 toxicity showed early decreases in serum glucose level at 9 h, worsened in a time-dependent way until the end of the study at 12 d. Lipid accumulation and the liver pathology also worsened over time between 3 d and 12 d post administration. These observed effects in the liver were also found to be dose-dependent. The decrease in serum glucose was a result of a decrease in the transcript levels of gluconeogenic and glycogenolytic enzymes, necessary for hepatic glucose production and hence the maintenance of steady glucose levels in the blood. Phosphoenolpyruvate carboxykinase (PEPCK-C), the rate limiting enzyme of gluconeogenesis, was found to be significantly decreased upon exposure to PCB126. The expression levels of peroxisome proliferator-activated receptor alpha (Pparα) and some of its targets involved in fatty acid oxidation were also found to be time and dose-dependently decreased upon exposure to PCB126. In an attempt to understand the molecular targets that may cause these dual effects on both gluconeogenic and fatty acid oxidation, we found that PCB126 significantly decreases phosphorylation of the cAMP response element-binding protein (CREB). CREB is a nuclear transcription factor that is activated in the liver through phosphorylation; to switch-on the transcription of enzymes that catalyze gluconeogenesis and fatty acid oxidation, in order to meet energy demands, especially during fasting. Further, to understand the toxicity of PCB126 on adipose tissue, a human pre-adipocyte model that can be differentiated into mature adipocytes was used. In these studies, we found that exposure of preadipocytes to PCB126 resulted in a significant reduction in their ability to differentiate into adipocytes. This results in decreased lipid accumulation in the adipocyte. Reduction in the differentiation by PCB126 was associated with down regulation in transcript levels of a key adipocyte transcription factor, PPARγ and its transcriptional targets necessary for adipogenesis and adipocyte function. These inhibitory effects of PCB126 on the regulation of PPARγ and the initiation of adipogenesis were mediated through activation of AhR. Overall, this work shows that PCB126 disrupts nutrient homeostasis through its effects on the function of target tissues; liver and adipose. PCB126 significantly alters the nutrient homeostasis through its effects on gluconeogenesis and fatty-acid oxidation necessary for glucose and energy regulation during fasting. In addition, PCB126 interrupts the storage functions of adipose tissue by inhibiting adipogenesis and thus disrupts lipid storage and distribution