Résumé des résultats (Abstract)
(Anglais)
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The goal of the proposal is to elucidate the effects of developmental exposure of animals to flame retardants Polybrominated Diphenyl Ethers (PBDE) on CNS.
Epidemiological studies indicate a marked increase of PBDE levels in breast milk. In contrast, effects of PBDEs on the developing CNS are largely unknown. Therefore, the aims of the proposal are:
i.) to assess several neurobehavioral endpoints after perinatal treatment of animals for characterisation of possible impairments;
ii.) to relate neurobehavioral effects to electrophysiological effects in the different brain areas;
iii.) to compare perinatal with adult exposure in order to examine if the developing CNS is particularly susceptible to PBDEs;
iv.) to compare different animal species for generalisation of the findings;
v.) to characterise mechanisms of PBDE neural toxicity at cellular and molecular levels including neurotransmitters, receptors and intracellular signal transduction pathways
vi.) to examine if exposure alters sexual differentiation of the brain.
Different dose levels of PBDEs will be studied. PBDE exposure will be compared with PCB-induced effects to relate findings to a better examined substance group.
Scientific approach
For the examination of developmental neurotoxicity of PBDEs the congener 2,2',4,4',5-pentaBDE (PBDE 99) will be studied since this congener is the one of the most abundant PBDEs. Research will be conducted in rats and in mice as well as in vitro models for the characterisation of underlying mechanisms. Animals will be exposed perinatally at different dose levels of PBDE 99. In addition, a PCB-exposed group will be used to compare effects of PBDE exposure to the known effects of PCB exposure. Several neurobehavioral tests will be conducted in different laboratories. These are active and passive avoidance, catalepsy, social and sexual interaction, spatial learning and memory, sleep/wake cycle, and circadian rhythms. Alterations in these behavioural tests should result in a profile of effects which can be related to effects on different parts of the brain, e.g.: passive avoidance is dependent on the amygdala and spatial learning on the hippocampus. Behavioural results will be related to neurophysiological functions in different brain areas, in particular, to long-term potentation which is an electrophysiological correlate of neuronal plasticity. Underlying effects of PBDEs on glutamatergic and dopaminergic neurotransmitters and receptors will be studied ex vivo and in vitro. In addition, cholinergic receptor density and binding will be examined ex vivo. Several signal transduction pathways in neurons and glia cells will be investigated in an ex vivo approach. Sexual differentiation of the brain will be studied ex vivo by determination of enzymatic targets of steroids and anti steroid-dependent gene regulation. The outcome will be related to sex-behaviour. All groups will supply blood and tissues samples which will be collected by the coordinating institute for chemical analysis to determine internal exposure to PBDEs in dams and offspring.
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