Projects
17: Environmental disruptor actions in live cells and animals: Elucidating molecular mechanisms of PPAR pathway alterations.
Elucidating molecular mechanisms of PPAR pathways.
Environmental endocrine disruptors may exert adverse effects on wildlife and on humans. Here, the activation of Peroxisome Proliferator Activated Receptors (PPARS)1 will be investigated, in an attempt to clarify the understanding of the molecular action of these disruptors.
Wahli Walter, Université de Lausanne
e-mail: walter.wahli@unil.ch
Background
For a number of years now, it has been believed that endocrine disruptors in the environment may be exerting an adverse effect on the reproductive capacity of wildlife and man. For many endocrine disruptors, the understanding of the molecular mechanism of action remains unsatisfactory.
Mounting evidence demonstrates that PPAR and estrogens regulated pathways are cross-regulated. Therefore, interactions of endocrine disruptors with one of these two receptors, Estrogen Receptor (ER) or PPAR, most likely interferes with the pathways controlled by the other receptor resulting in very complex phenotypes that are difficult to decipher.
Aim
This proposal concerns activation of PPARs by environmental endocrine disruptors as compared with normal regulation. This activation will be studied with respect to the perturbation of metabolic pathways, possible xenobiotic interference via (CYP450) gene regulation, and the consequences of PPAR activation via pollutants during the embryonic development of aquatic animals such as Xenopus. Consequences of PPAR polymorphisms found in human genes will be assessed with respect to the response to endocrine disruptors.
Significance
The endocrine disruption hypothesis asserts that the exposure to small amounts of endocrine disruptors in the environment may interfere with the endocrine system and lead to harmful effects in wildlife and humans. It is of high interest to understand the molecular bases of the signalling pathways involving these receptors and to assess whether, even relatively weak pollutants disrupt them even in a subtle manner. In this case, compounds, although not having overt adverse health effects, could generate mild abnormalities in the regulatory pathways that are weak enough to escape our attention, but nevertheless become manifest after 10,20 or more years.
1) The Peroxisome Proliferator Activated Receptors (PPARS) constitute a sub-group of the Nuclear Hormone Receptor superfamily. Peroxisome Prolifarators (PP) may be endogenous substances or environmental chemicals inducing proliferation of peroxisomes in rodents. Peroxisomes are small cell organelles specialized primarily to oxidative eactions with molecular oxygen.