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Molecular Responses to Estrogenic Endocrine disrupters

Applicant Rusconi Sandro
Number 66582
Funding scheme NRP 50 Endocrine Disruptors
Research institution Division de Biochimie Département de Biologie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Clinical Endocrinology
Start/End 01.02.2002 - 31.01.2007
Approved amount 252'185.00
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Lay Summary (English)

Lead
Lay summary
Molecular responses to estrogenic endocrine disruptors.
Several endocrine-disrupting compounds have been shown to act via estrogen receptor pathways, causing interference in ecosystems and in human fertility and health. Here, the molecular action of these substances working through the estrogen receptor pathway will be investigated.

Background
Endocrine disruption by many environmental pollutants has been shown basically to occur through interaction with nuclear receptors, and in particular via the sex-steroid receptors such as the androgen receptor and the estrogen receptor.
The reported environmental and medical implications of such compounds are rather alarming, and a better understanding of their mode of action could help in assessing their true impact and in envisaging strategies for remedying the situation.

Aim
This research project intends to investigate the molecular action of natural and artificial endocrine-disrupting compounds working via the estrogen receptor (ER) pathway. In the first phase, we will analyze individual regulatory pathways which control the feedback of ER and pathways that are believed to mediate cell proliferation and cell death. This is an aspect that is relevant to the suspected enhanced tumour susceptibility caused by exposure to endocrine disruptors. In our initial experiments we already demonstrated that the recently proposed estrogenic and androgenic activity of cadmium ions can be distinguished from the action exerted by bona fide physiological ligands.
In the second phase, we intend to employ an improved functional genomics approach to distinguish whether the effects of natural and artificial ligands occur at the level of gene transcription or at the level of mRNA stability. Different xenoligands will be subdivided into 'functional groups' according to their genomic effect.
In the third phase, we will be generating reporter animal systems (transgenic mouse lines carrying ER-responsive reporter genes) for the quantitative assessment of biological effects of endocrine disruptors. The transgenic construct is designed to permit non-invasive analysis in the living animal. This allows a better appreciation of the spatial-temporal reactions generated by various compounds.

Significance
This project could play an important role in characterizing the molecular action of endocrine disruptors. A better understanding of the molecular players may lead to more concrete hypotheses about the final impact of those substances, and may even suggest suitable strategies for a meaningful remediation policy.

Direct link to Lay Summary Last update: 21.02.2013

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