Abstract
(Englisch)
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Scientific objectives and approach:
Molecular and cell biological experiments as well as research in animals and in the human indicate that ED´s with estrogenic actions exist, which are present in either cosmetics (such as UV-absorbers and stabilisers) or pesticides / fungicides. Little research has been done as to whether these substances interact with other steroid receptors or act in non-reproductive organs like the neuroendocrine brain, the cardiovascular, skeletal or urogenital system during development and adult life. Hence, risk assessment for organs known to be estrogen-, androgen-, progestin-, glucocorticoid- or thyroid hormone-receptive following exposure to the above mentioned endocrine disrupters cannot be made on the basis of the present data. To study such effects with basic experimental and clinical tools represents the fundamental objective of this RTD proposal.
Many ED´s have been defined as ligands to a variety of steroid hormone receptors, their effects being studied in a multitude of cell lines. Many diseases have been related to pre- or postnatal exposure to ED´s and long-lasting effects need to be studied. In-vivo experiments in rats and mice will be performed, in which dams and newborn pups receive substances known to be either estrogenic or antiandrogenic or to have anithyroid hormonal effects, namely 2 UV-absorbers used in the production of sunscreens, 1 stabiliser used in cosmetics, 1 fungicide used in fruit plantations, 1 pesticide and 1 synthetic flavone with antithyroid effects. In addition, adult gonadectomised, thyroidectomised or adrenalectomised rats and gene-targeted mice will also be fed with the substances (steroid receptor knock-out mice). Estrogenic, androgenic, progestational, glucocorticoid, and thyroidal effects will be studied with genomic and proteomic tools in the brain and in the cardiovascular, skeletal and uro-genital systems. Experiments with steroid-receptor knock-out mice (ERa and b, AR, GR and thyroid hormone receptor k.o. mice) will prove ultimately as to whether the substances of interest have steroid hormone receptor mediated activities in the intact organism. We will study 5 of the 18 substances with known ED activity on the OECD list released recently, incorporating those displaying multisteroidal effects into the main study. Clinical trials will be performed with phytoestrogens instead of conventional hormone replacement therapy and to study the effects of these phyotestrogens on the cardiovascular system (including the lipid profiles) and the bone. UV absorbers-exposed patients will be available particularly during summer. Transdermal resorption of UV-absorbers and their temporal presence in the body may be determined in the blood using tools such as reporter cells and HPLC/UV detection.
This project is part of the cluster for Endocrine Disrupter research in Europe.
Problems to be solved:
ED´s with steroidal or anti-steroidal effects may be of great importance during embryonic development and later for metabolic, brain, cardiovascular, reproductive and bone function. The effects of UV-absorbing chemicals (4-MDC, homosalate), characterised recently as estrogenic, and of Benzophenone D, a chemical used in cosmetics, as well as the fungicide Procymidone and the pesticide Linuron will be studied in rats and gene-targeted mice.
Expected Impacts:
The experiments will allow risk assessment in developing and adult animals not only in reproductive but also in other steroid-receptive organs. (Milestone 1). The molecular mechanisms behind these actions will be elaborated in the brain, the cardiovascular system and the bone (Milestone 2). Risk assessment for the non-reproductive organs will also be possible in the human (Milestone 3).
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