Silva, Elisabete Alexandra Ferreira; (2003) Understanding the mechanisms underlying the joint action of xenoestrogens. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Abnormal sexual development in man and wildlife and the rise in the incidence of testicular and breast cancers are causing widespread concern. It has been suggested that these effects might be related to environmental chemicals which are able to mimic endogenous oestrogens. However, the low potency of many of these so-called xenoestrogens has suggested that they pose negligible health risks when considered individually. We became interested in testing whether weakly oestrogenic chemicals in combination were able to produce an effect significantly different from the one observed for the isolated compounds. The oestrogenic effects of eight chemicals of environmental relevance were recorded using a recombinant yeast oestrogen screen (YES). All agents were combined at a mixture ratio proportional to their potency. The combination effects of this mixture were predicted on the basis of the concentration- response curves of all the components by using the concepts of concentration addition, independent action, effect summation and the toxicity equivalency factor approach. The experimental data confirmed the combination effect predicted by concentration addition, showing a clear additive effect. Crucially, there were substantial mixture effects even though each chemical was present at levels that were, individually, insignificant. Although the action of many of the known oestrogenic compounds is well explained by their ability to bind and activate the oestrogen receptor (ER), there are still uncertainties concerning the mode-of-action of some others. Studies were undertaken to clarify the mechanism by which compounds such as the organochlorine pesticide β-HCH exert their oestrogenic activity. This chemical promotes proliferation of breast cancer cells, but does not bind to the ER. In order to delineate between cell proliferation via ER activation and other possible pathways, we measured the action of this compound on the expression of the TFF1 gene (which is dependent on activation of the ER) in MCF-7 and MDA-MB-231 breast cancer cells, by reverse transcription- competitive polymerase chain reaction (RT-cPCR). Furthermore, we evaluated its influence over important cell signalling pathways such as the mitogen activated protein kinase (MARK) cascade. Our results suggest that β-HCH is capable of activating the nuclear ER, by ligand independent activation via the MAPK cascade.

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