Projects
27: Role of environmental endocrine disruptors in the aetiology of Intrauterine Growth Retardation and its later consequences such as disorders in brain development and adult-onset obesity.
Endocrine disruptors as a cause for altered growth and development and uncontrolled obesity.
This program will compare the consequences of Intrauterine Growth Retardation (IUGR) generated either by exposure to Endocrine Disruptor Chemicals (EDCs) or excessive glucocorticoid during gestation, or maternal caloric restriction. The impact of such metabolic insults will be evaluated on pancreas and brain development and on the occurrence of obesity in the rat.
Michel L. Aubert, University of Geneva Medical School
e-mail: michel.aubert@medecine.unige.ch
Background
Several stressful situations during gestation are known to induce low birth weight associated with occurrence of metabolic problems later in life. Exposure to Endocrine Disruptor Chemicals (EDC) could result in occult lesions taking place during sensitive developmental windows inducing errors in tissue development and organization.
Aim
We will examine the possibility that intrauterine exposure to different EDCs (Nicotine, Bisphenol A, or other compounds), could contribute to the occurrence of adult metabolic diseases known to derive from adverse events during intrauterine life. Potential noxious effects due to EDCs will be compared to those known from either maternal caloric restriction or prenatal glucocorticoid exposure. We hope to identify new molecular targets implicated in the altered metabolism seen in IUGR looking at different tissue levels.
Pancreas: the consequences of permanently altered development of pancreatic beta cell function during gestation could represent the most critical cause for the prevalence of adult-onset metabolic problems resulting from any type of intrauterine metabolic insults including exposure to EDCs. We will perform multiple genes analysis on pancreatic islets responsible for insulin secretion during the first month of life. Furthermore we will follow the expression of beta cell specific factors (genes) like Pdx1, Pax6 and Nkx6.1, which are involved in pancreatic development and maintenance of adult, functional beta cells.
Liver and adipose tissue: we would like to identify obvious early genetic markers relevant for adult-onset metabolic problems in order to attempt explaining the cause of adult pathologies known as programmed diseases.
Brain: brain imaging of pups will be performed during the first month of life by Magnetic Resonance Imaging (MRI) at the EPFL. We will aim at assessing delay in development and/or alterations of structures that could be attributed to the prenatal insult. Morphological examination of brain slices will be done after MRI examination. Finally, alterations in expression of a variety of genes involved in brain development, mostly in the hippocampus, will be performed.
Significance
The incidence of uncontrolled obesity in the juvenile age is increasing dramatically. The causes for such an obesity epidemic are not clear. The recent exposure to EDCs coincides with this obesity epidemic, an observation that prompted us to examine whether EDCs could trigger or amplify the lesions responsible for adult-onset metabolic syndromes.