Wirkung von Mono(2-ethylhexyl)phthalat auf die Genexpression in Alveolarmakrophagen im allergischen Mausmodell

Seit mehr als 40 Jahren werden Phthalate als Weichmacher für Kunststoffe eingesetzt und in großer Menge produziert. Die Phthalate und insbesondere Di(2-Ethylhexyl)Phthalat (DEHP) und sein Hauptmetabolit Mono(2-ethylhexyl)phthalat (MEHP) stehen seit Jahren im Mittelpunkt kontroverser Diskussionen zur...

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Bibliographic Details
Main Author: Keil, Christian
Contributors: Wahl, Hans-Günther (Dr. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2009
Online Access:PDF Full Text
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Phtalates have been used as plasticisers of plastics for more than 40 years. Phtalates and Di(2-Ethylhexyl)Phthalat (DEHP) with its main metabolite Mono(2-ethylhexyl)phthalat (MEHP) have been a focal point of controversies regarding their toxicity in human beings. They are primarily used in medical supplies such as hemodialysis tubings, bloodbags or respiratory equipment, but also in toys and teethers. The European Community passed an emergency decree in December 1999 which was transformed into a directive of the European parliament in July 2005 prohibiting the use of most phtalates in children’s toys. Whereas the toxic effects of MEHP on gonads and liver are well researched, little is known about effects of MEHP on the respiratory sytem. The research conducted in this thesis has analysed in vivo and in vitro effects of MEHP on the respiratory system.The effects of MEHP in an allergical murine modell were triggered by exposition to aerosols of MEHP. Plethysmographic measurements showed the development of airway hyperreactivity connected to a significant alteration of pulmonary cellular infiltrate. Cells that were washed out consisted only of macrophages. The murine cell-line J774 closely resembling macrophages was stimulated with MEHP and analysed by transcriptome measurements using DNA-microarrays. Exposure to MEHP led to regulation of genetic expression in various genes. Adipose differentiation related protein (ADRP) was upregulated, whereas chemokinereceptor 4 (CXCR4) showed a downregulation, both being certified with a quantitative real-time PCR analysis. Both in cell lines of endothel and hepatocytes, phthalates play a major role as possible ligands of peroxisome proliferator-activated receptors (PPAR). The results of research conducted in this thesis demonstrate an up-regulation of the PPAR-isoform PPARγ in murine macrophages when exposed to MEHP. Furthermore a significant up-regulation of PPARδ could be accounted for in alveolar macrophages and lung tissue. The concentration of PPARα in murine macrophages of the study was too low for a valid analysis of genetic expression. In another investigation alveolar-macrophages from animal experiments were tested for their genetic expression. The in vitro test results could be traced only partly in alveolar macrophages. Nevertheless, a significant up-regulation of ADRP which also showed in alveolar macrophages seems to play a crucial role in the exchange of regulatory mechanisms after exposition to aerosol MEHP.Results of the present work show that an exposition to MEHP in aerosol form leads to pathological alterations of the murine respiratory tract. The apparently very complex processes and mechanisms resulting from an exposition to an aerosol of MEHP should give rise to further studies with the individual genes.