| 1. |
- Andersson, Helén, 1982-
(författare)
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Experimental Studies of Endocrine Disrupting Compounds in Vascular Cells and Tissues
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epidemiological evidence suggest that exposure to endocrine disrupting compounds (EDCs) is a risk factor for diseases that involves the cardiovascular system but we know little about the mechanisms whereby these compounds can cause injury in the vasculature. The aim of this thesis was to characterize the effects and mechanisms of some EDCs in vascular cells and highly vascularized tissues. Elevated exposure to environmental EDCs is associated with an increased risk for cardiovascular diseases. In vitro studies demonstrated that the environmental EDCs, 1-nitropyrene, PCB126 and bisphenol A, caused distinct changes in primary human endothelial cells. 1‑Nitropyrene induced cell stress and DNA damage, PCB126 caused changes that indicate endothelial dysfunction and vasoconstriction, and BPA induced changes that indicate angiogenesis and vasoconstriction. Further studies demonstrated that long-term exposure of rats to BPA induced changes in rat cardiac tissues in vivo similar to those observed in human endothelial cells in vitro. The type of cellular alterations that were demonstrated is known to play to play a role in cardiovascular disease in humans. These findings suggest that environmental EDCs can cause damage to the human endothelium that may contribute to the development of cardiovascular disease. The beneficial effects of the pharmaceutical EDC tamoxifen in breast cancer treatment are compromised by an increased risk for bleedings, hyperplasia, and cancer in the endometrium. Ex vivo studies identified the glandular and surface epithelia as potential target sites for tamoxifen adduct formation and tamoxifen-induced cell stress the human endometrium. No signs of tamoxifen-induced changes were detected in the blood vessels. The results suggest that bioactivation of tamoxifen and subsequent cell injury in endometrial epithelial cells may play a role for tamoxifen’s side effects in the endometrium. Taken together, this thesis provide evidence that may help understanding how exposure to EDCs can increase the risk for diseases in that involves the cardiovascular system.
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| 2. |
- Bengtsson, Johanna, 1985-
(författare)
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The impact of cytochrome P4501-inhibitors on aryl hydrocarbon receptor signaling
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aryl hydrocarbon receptor (AHR) best known as a ligand-activated transcription factor that mediates toxic responses to xenobiotics such as dioxins, is also activated by certain endogenous compounds. Activation of the AHR up-regulates transcription of a large number of genes, including those encoding members of the cytochrome P450 1 family of enzymes (CYP1s). Although the AHR has been shown to be involved in several normal processes, its physiological role remains elusive. The endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ), formed from tryptophan, is present in cell culture media and biological specimens. FICZ is an excellent substrate for CYP1 enzymes and together FICZ/AHR/CYP1A1 interactions constitute an auto regulatory feedback loop that controls AHR signaling. A vast number of compounds that inhibit CYP1 enzymes have been reported to be AHR activators, even though they have little or no affinity for the receptor. We hypothesized, that their agonistic effects are dependent on the presence of background levels of FICZ. To test this, AHR signaling in different cell systems exposed to FICZ and/or inhibitors was assessed by measuring EROD activity and CYP1A1 transcription. In addition to a commercial culture medium, a medium free of background levels of FICZ was used. Activation of AHR by of a diverse set of CYP1A1 inhibitors did require FICZ in the culture medium. Furthermore, the compounds tested both prolonged and potentiated FICZ-induced receptor signaling. On the basis of these observations we propose that a compound may activate AHR signaling indirectly by inhibiting CYP1A1 and thereby attenuating the metabolism of FICZ. This mechanism was confirmed for certain polyphenols and pharmaceuticals. Surprisingly, the activating capacity and potentiating effect of two pharmaceuticals on AHR signaling could not be explained by the mechanism proposed, and we speculated that in these cases the agonistic effect might involve interactions of the cellular antioxidant response with the basic transcription machinery. Together, our observations provide a mechanistic explanation as to how compounds that inhibit CYP1A1 can activate AHR signaling. They also indicate that the general perception of the binding pocket of AHR as promiscuous, is probably wrong. The fact that indirect activation of AHR may cause sustained signaling requires further studies in vivo not least, in order to prevent toxicity.
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| 3. |
- Nilén, Greta, 1989-
(författare)
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Molecular and phenotypical toxicological effects of environmental pollutants and their mixtures : A mechanistic approach
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Current environmental risk assessment of polluted sites primarily relies on single compound evaluation. However, in the environment, organisms are often exposed to complex mixtures of pollutants. To further develop risk assessment of polluted sites and evaluate the risks that mixtures pose to humans and wildlife, a mechanistic understanding of mixture toxicity is needed.The overall aim of this thesis was to increase our knowledge of the toxic effects caused by chemical mixtures and to develop new approaches to investigate the molecular mechanisms underlying such effects. To reach this aim, a comprehensive set of methods was applied, considering molecular and phenotypical alterations as well as chemical analyses.The investigations revealed that the acute toxicity caused by mixtures of the pollutants B[a]P, PFOS, PCB126, and Arsenate is mainly predictable by concentration addition. The results also showed some specific sublethal effects of the various mixtures that were not observed for the single components. In addition, each mixture caused very specific patterns of behavioral alterations, gene expression changes, altered lipid content, and altered organ growth. A complex environmental mixture from soil contaminated with PACs caused for instance behavioral alterations in zebrafish, in addition to dysfunction of genes that are critical for eye development.In summary, this thesis contributes to an increased understanding of the mechanistic pathways underlying the mixture toxicity of selected pollutants and environmental samples. In addition, it provides insights for the development of new approaches that may be included in risk assessment, such as image analysis and effect-directed analysis.
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