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

All living organisms are exposed to persistent organic pollutants (POPs) not as individual compounds but as mixtures of chemicals. However, to assess the toxicity of POPs, scientific studies usually focus on the effect of one single compound at a time and do not address the cocktail effect of the mixtures, where different chemicals can act additively, antagonistically or synergically to produce a possible adverse effect. This study aims to determine, in vitro, the effect of a mixture of POPs at the level of the Aryl hydrocarbon Receptor (AhR) function. Regardingly, AhR is a key receptor involved in organism’s response to xenobiotics, including POPs. In this study, three different luciferase reporter cell lines (rat hepatoma H4IIE, human mammary gland carcinoma T47-D and human hepatoma Hep G2 cells) were used to screen AhR transactivation activities (both agonistic and antagonistic) of 29 compounds listed as POPs under the 2001 Stockholm Convention. Their mixture, which was prepared according to their individual concentrations found in human blood, was also tested for the same activities. The results showed that these compounds have species and tissue-specific effects and that the rat cells DR (Dioxin responsive)-H4IIE are more sensitive than the two human cell lines (DR-T47-D and DR-Hep G2 cell lines). Only 6 out of the 29 compounds showed AhR agonistic activities. PBDE 153, PBDE 154, PCB 138, and PCB 118 were able to activate the AhR in DR-H4IIE cells only, γHCH was active in DR-T47-D cells only, while PBDE 99 was found to be an AhR agonist in both of the cell lines. No agonistic effect has been seen for DR-Hep G2. In contrast, 19 out of the 29 compounds showed AhR antagonistic activities in DR-H4IIE cells, while 10 and 6 compounds displayed an AhR antagonistic activity in DR-T47D and DR-Hep G2 cells, respectively. Not surprisingly, the mixture of the 29 compounds also showed an AhR antagonistic activity in all cell lines. In DR-H4IIE cells, the AhR inhibition was recorded with concentrations of the POP mixture corresponding to 75 times the blood level and above, which could be plausibly reached in human after a food contamination incident. The calculated IC50 of the total mixture, using an additive model, was 16.8 µM, which is 3 times higher than the measured IC50 (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.