Exposure to mixtures of Persistent Organic Pollutants (POPs) can reduce the transactivation activities of Aryl hydrocarbon Receptor (AhR) in vitro

Human exposure to persistent organic pollutants (POPs) is well documented nowadays, but most available scientific data usually focus on the effect of one single compound at a time and do not address the cocktail effect of mixtures of POPs. This study aims to determine in vitro the cocktail effect of a mixture of POPs in reporter cell lines, at the level of aryl hydrocarbon receptor (AhR) function. This is a key receptor controlling the metabolism of xenobiotic compounds including POPs. Three different luciferase reporter gene transformed cell lines (rat hepatoma Dioxine Responsive (DR)-H4IIE, human mammary gland carcinoma DR-T47-D and human hepatoma DR-Hep G2 cells) were used to screen AhR transactivation activities (both agonistic and antagonistic) of a mixture of 29 compounds listed as POPs under the Stockholm Convention. The mixture was constructed according to the concentration of these selected POPs in human blood. When tested individually, it was found that only 5 out of the 29 compounds showed AhR agonistic activities. PBDE 99, PBDE 153, PCB 138, and PCB 118 were active in the DR-H4IIE while PBDE 99 and gamma HCH were active in the DR-T47D cells. In contrast, 19 out of 29 compounds showed AhR antagonistic activities on DR-H4IIE cells. Not surprisingly, the mixture effect was also AhR antagonistic. Moreover, this AhR antagonistic activity was visible on the dose-response curve with the concentrations of the POP mixture corresponding to 75 times the blood level, and above. Extrapolating from in vitro to in vivo, we could say that, after an incident leading to an increase of the POP mixture blood concentration up to 75 times the background level, there could be an inhibition of AhR transactivation activities. The calculated IC50 of the total mixture, using an additive model, was 16.8 µM, which is 3 times higher than the measured one (5.07 ± 2.02 µM). Therefore, it can be concluded that the compounds in the POP mixture could act additively or even synergically as AhR antagonists in DR-H4IIE cells.