Thesis (Ph.D.)--Uppsala Universitet, 2009. / This website links to the complete document in PDF format. Title from title screen (viewed on November 21, 2009). Includes bibliographical references.

Os retardantes de chama bromados são substâncias utilizadas nos mais variados bens de consumo para aumentar sua resistência ao fogo e/ou altas temperaturas em casos de incêndio, aumentando assim, as chances de escape e reduzindo a gravidade das queimaduras. Para este fim os éteres difenílicos polibromados (PBDEs) representam a classe mais utilizada tendo em vista sua eficiência no controle da propagação da chama e seu baixo custo. Estes compostos se incluem entre os recentemente denominados contaminantes ambientais emergentes que apresentam uma carência de dados toxicológicos, principalmente em relação aos efeitos danosos e aos biomarcadores de exposição, além do potencial dano ao ambiente, sendo esta uma preocupação recente da comunidade científica. Pelo fato da mitocôndria ser reconhecida como a principal organela produtora de energia celular, além de exercer um papel fundamental na manutenção de inúmeras funções celulares, ela foi utilizada como modelo experimental para avaliar os efeitos dos congêneres de BDE- 100; -153; -154 e -209 na faixa de concentração de 0,1 ?mol/L a 50 ?mol/L. Nossos resultados mostram que os efeitos em mitocôndrias isoladas podem ocorrer em menores concentrações para os congêneres BDE-153; -154 (Hexa-BDE) e -209 (Deca-BDE) e em maiores concentrações para o BDE-100 (Penta-BDE). Desta forma, foi observado que os compostos possuem capacidade de interagir com membrana mitocondrial, induzir inchamento mitocondrial, desregular a homeostase cálcica e dissipar o potencial de membrana mitocondrial em concentrações diferentes, entretanto não são capazes de induzir estresse oxidativo na mitocôndria. Assim, os resultados indicam que a ação dos PBDEs sobre mitocôndrias pode ser um dos mecanismos de toxicidade desta classe de compostos. / The brominated flame retardants are substances used in various consumer goods to increase their fire resistance and / or higher temperatures in case of fire, thus increasing the chances of escape and reducing the severity of burns. To this end polybrominated diphenyls ethers (PBDEs) are the most used class in view of its efficiency in controlling the spread of flame and its low cost. These compounds are among the newly emerging environmental contaminants known to exhibit a lack of toxicological data, especially regarding the harmful effects and biomarkers of exposure and potential harm to the environment, which is a recent concern of the scientific community. Because the mitochondrion is recognized as the main energy-producing cell organelles, as well as play a vital role in the maintenance of many cellular functions, it was used as an experimental model to evaluate the effects of the congeners BDE-100 (Penta- BDE), -153, -154 (Hexa-BDE) and -209 (Deca-BDE), in concentration range ranging from 0.1 ?mol/L to 50 ?mol/L. The results show that the effects on isolated mitochondria may occur at lower concentrations for the BDE-153, -154 and -209 and high concentrations to the BDE-100. Thus, it was observed that the compounds have the ability to interact with mitochondrial membrane, inducing swelling, dysregulation of calcium homeostasis and dissipation of membrane potential at different concentrations, however they cannot change factors related to oxidative stress in mitochondria. Furthermore, the induction of mitochondrial swelling, and added significant depletion of ATP levels may contribute to the toxic effects observed. Thus, we conclude that the action of PBDESS on mitochondria is one of the mechanisms of toxicity of this class of compounds.

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Polybrominated diphenyl ethers belong among the persistent compounds, which have been classified as priority organic pollutants. In environmental compartments are observed in the past decade. Polybrominated diphenyl ethers are detected in abiotic and biotic matrices. For this dissertation were chosen the matrixes from seats of fire, taken in various localities of the Czech Republic and Slovakia. Their analysis should demonstrate whether they in these specific matrices remain. There were examined following polybrominated diphenyl ether congeners: BDE- 28, 47, 99, 100, 153, 154, 183. For their isolation from the matrix were used three different extraction techniques, namely ultrasonic extraction, microwave extraction and pressurized solvent extraction. For the determination was chosen method of GC / ECD. In this dissertation are also described basic chemical, physical and environmental properties of BDE, including other analytical methods that can be used to determine polybrominated diphenyl ethers in environmental compartments.

We also investigated whether BDE-47 exposure could worsen PD situation by applying transgenic Drosophila (fly) model in which human α-synuclein (α-syn) was overexpressed in wide-type fly to simulate PD. BDE-47 (0, 2, 10 and 50 µM) was fed to flies continuously for 30 days. Integrated LC-MS and GC-MS profiling indicated metabolic changes in tryptophan, phenylalanine, purine, and alanine, aspartate and glutamate pathways, similar to those from mouse experiment. After quantified metabolites of interest by LC-triple quadrupole MS, we confirmed the slowed-down formation of KYNA (kynurenic acid, a neuro-protector) and speeded-up formation of 3HKYN (3-hydroxykynurenine, a neurotoxin) in all BDE-47 exposed groups on the 20th exposure day. The levels of SAM/SAH (methylation biomarker) and GSH/GSSG (oxidative stress biomarker) were found to decrease on the 30th exposure day. Collectively, we propose that BDE-47 could induce imbalance of kynurenine metabolism, insufficient methylation and oxidative stress, which might contribute to the PD progression. To further explore the underlying mechanism of 6-OH-BDE-47 induced neurotoxicity, we conducted omics study of metabolic changes induced by 6-OH-BDE-47 on N2a cells. Cells were exposed to 6-OH-BDE-47 (0, 0.5 and 1 μM) for 24 hours. Considerable metabolic changes in pyrimidine and purine metabolism were observed in high exposure condition while oxidative stress was appeared under low exposure condition. Moreover, 6-OH-BDE-47 was found to affect the dopamine production. iTRAQ proteomics was carried out and pinpointed the dysregulation of ribosome, proteasome, RNA metabolism, aminoacyl-tRNA biosynthesis, vesicular trafficking, purine pathway, and mitochondria electron transport. Immunocytochemistry and Western blot analysis further confirmed that 6-OH-BDE-47 could inhibit autophagy flux, which might result in the aberrant protein aggregation, a pathological hallmark of PD. We further investigated whether 6-OH-BDE-47 exposure could directly induce PD pathology in Sprague Dawley rat. 6-OH-BDE-47 (0.1, 1 and 10 µg) was stereotaxically injected into the right VTA and SNc regions in the midbrain of rat where there are abundant dopaminergic neurons. The apomorphine-induced rotation test indicated significant deterioration in motor function in the group receiving injection of 10 µg. Striatal dopamine was found to decline in a dose-dependent manner. Notably, 6-OH-BDE-47 also promoted the formation of α-syn aggregate, an important pathological hallmark of PD. Proteomics study revealed that protein degradation processes were crucial rather than oxidative stress in 6-OH-BDE-47 induced neurotoxicity in vivo. Mechanistic study based on Western blot further confirmed that 6-OH-BDE-47 could inhibit ubiquitination and autophagy. Collectively, the rat experiment demonstrated that 6-OH-BDE-47 administration could induce motor defect by impairing dopaminergic system and promote α-syn aggregation by inhibiting ubiquitination and autophagy, suggesting that 6-OH-BDE-47 could be a novel risk factor of PD.;Polybrominated diphenyl ethers (PBDEs), as one typical persistent organic pollutants (POPs), are widely spread in the environment and pose potential adverse impacts on human health. As a predominant congener of PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) has been reported to affect habituation capability, synaptic plasticity, and vesicular neurotransmitter release. As an important in vivo metabolite derived from BDE-47, 6-hydroxy-BDE-47 (6-OH-BDE-47) was also reported as a neurotoxin. However, the possible linkages between BDE-47/6-OH-BDE-47 exposure and typical neurodegenerative diseases such as Parkinson's disease (PD) are still unclear. Mass spectrometry (MS) based omics integrated with bioinformatics is emerging as a powerful tool to evaluate metabolic changes occurred after different exposures. Here we developed non-targeted metabolomics, lipidomics, and isobaric tag for relative and absolute quantitation (iTRAQ) proteomics methods based on liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) to depict BDE-47/6-OH-BDE-47 induced metabolic changes and to explore the possible contribution of their exposure to PD pathology/pathogenesis. BDE-47 dissolved in corn oil (0, 1, 10 and 100 mg/kg bwt) was orally administered to adult male C57BL/6 mice for 30 consecutive days. Results of global metabolomics and lipidomics studies of PD-related brain regions based on LC-orbitrap MS revealed significant metabolite changes between the exposed and control groups in purine pathway, glutathione pathway, tryptophan pathway, phenylalanine pathway, alanine, aspartate and glutamate pathway, and lipid composition, mainly involved in oxidative stress and neurotransmitter production. By further quantifying metabolites involved in tryptophan and phenylalanine pathways in mice serum, colon and brain samples by using LC-triple quadrupole MS, dysregulation of PD linked neurotransmitters dopamine and serotonin were confirmed. iTRAQ proteomics study of the striatum, the part of the brain that is most intensively studied in PD pathogenesis, revealed that BDE-47 could induce neurotransmitter system disturbance, mitochondrial dysfunction, oxidative stress and abnormal phosphorylation. Oxygen consumption rate after BDE-47 treatment (0, 1 and 10 μM) in mouse neuroblastoma (N2a) cells was measured for the confirmation. BDE-47 was demonstrated to impair mitochondrial function.

The target of my diploma thesis is evaluation of soil load by polybrominated diphenylethers. This is the soils, which were affected by fire and comparsion with load by soils, which were not affected by fire. In teoretical part available informations about BDE from various sources are processed. Target of practical part is find the optimal method for determination BDE, verification of her yield a determination of reals samples with using this method. In the end this thesis contains measured results, its interpetation in tables, graphes and evaluation of load by individual congeners. Key is comparsion load of soils, which were affected and which were not affected by fire. BDE are released during the fire and we can decide that soils which were caused by fire should be contaminated more, than soils, which were not caused by fire.

Flame retardants (FRs) are widely used in a variety of consumer products, including electronics, textiles, vehicles, furniture foams, and children’s toys. Many of these chemicals are halogenated compounds that are persistent in the environment over long periods of time and are known or suspected endocrine disruptors. As a result, FRs may have a variety of negative health effects on humans and wildlife. Following the discontinuation of commercial polybrominated diphenyl ether (PBDE) mixtures, a variety of alternative FRs have been developed and employed. In comparison with legacy FRs, relatively little is known about the ability of these emerging FRs to bioaccumulate and biomagnify in various systems. The primary objective of my dissertation was to better understand the contamination status of both legacy and emerging FR in the biota of the northwestern Atlantic Specifically my objectives were to (1) identify and quantify legacy and emerging FRs in high trophic level predator species (sharks) of the northwestern Atlantic, (2) determine Tropic Magnification Factors (TMFs) for legacy and emerging FRs within the same food web, and (3) evaluate the maternal transfer of a variety of brominated and chlorinated FRs in viviparous Atlantic sharks.

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