Workpackage 2: Toxicology
The second work package (WP2) of OBELIX is dedicated to hazard characterization and unravelling the underlying mechanisms of early exposure.
In vivo toxicity studies with mice will be performed, in which dams are exposed to the test chemical during gestation and lactation, and offspring are followed to adulthood. Anticipated candidates are selected representatives from the classes phthalates, brominated flame retardants, dioxins or dioxin-like (DL)-PCBs, non-dioxin-like (NDL)-PCBs, organochlorine pesticides and perfluorinated alkyl acids, covering a range of endocrine disruptive mechanisms such as anti-androgenic, estrogenic, anti-thyroidal, as well as agonism of the Aryl Hydrocarbon receptor (AhR), Constitutive Androstane Receptor (CAR), Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor (PPAR). Endpoints examined include biochemical parameters, transcriptome and epigenetic analysis of obesity-related targets. The experimental design using 6 dose groups enables dose-response analysis and benchmark calculation. This approach will deliver hazard characterization information highly suitable for risk assessment for human health (WP3), thus supporting the Community Environment and Health Policy.
In vivo animal studies will provide a wealth of information on the effects of prenatal EDC exposure on body weight and obesity-related target tissues and pathways. This information will pinpoint target tissues and pathways implicated in obesity, which will be further researched for underlying mechanisms using gene expression analysis focussed on both genes that are already known to be involved in the development of obesity as well as novel genes that appear to be differentially regulated by EDC exposure in suspected target tissues. To determine the role of altered epigenetic programming as an underlying mechanism of obesity, genomic methylation status will be analysed. Supplemental in vitro epigenetic studies will be carried out with a selection of candidate cell lines from mice and humans and will include determination of the effects of obesogenic EDCs on in vitro differentiation.