Polybrominated Diphenyl Ethers, Aspects of the mechanism of action

Abstract

Polybrominated diphenylethers (PBDEs) are used as flame-retardant additives in a wide range of commercial products. Some PBDEs congeners are persistent in the environment, have lipophilic properties and consequently bioaccumulate. During the last decades, PBDE concentrations increased biota and abiota, more recently these concentrations are levelling off. Structural similarity of certain PBDE congeners to other polyhalogenated aromatic hydrocarbons such as PCBs has raised concerns that these could act as agonists for the Ah receptor (AhR). Studies in this thesis have indicated that the most common environmentally relevant PBDEs (BDE-47, -77, -99, -100, -153, -154, -183) do not act as AhR agonists in both mammalian cell lines as well as primary cultures of cynomolgus monkey (Macaca fascicularis) hepatocytes, measured as induction of CYP1A1 activity. However, PBDEs were able to inhibit TCDD-induced CYP1A1 activity. In transfected mouse and rat cell lines, this inhibitory effect was confirmed at the level of AhR for the lower brominated PBDEs, higher brominated PBDEs seem to work through a different mechanism of action, for instance catalytic inhibition. Besides possible dioxin-like effects, phenobarbital (PB)-like effects were observed in transiently transfected human hepatocytes (HepG2). PBDEs were able to induce CYP3A4, which concurred with activation of the human pregnane X receptor (hPXR). Our results indicate that PBDEs are able to interfere with AhR- and hPXR mediated processes in cell lines. These effects were observed at concentrations that exceed the current human background situation in Europe but in the USA these levels have been reported. This could mean that the findings have implications for human health, further supporting that the exact mechanism of action of PBDEs should be investigated further.