S7: Polybrominated Diphenyl Ethers
Searching for the Adverse Outcome Pathways of Polybrominated Diphenyl Ethers
Research Center for Eco-environmental Science
Polybrominated diphenyl ethers (PBDEs) are a class of persistent organic pollutants which have been detected at relatively high concentrations in human bodies worldwide. Epidemiological studies have revealed statistic associations between PBDEs human expsoure and many adverse health effects including thyroid function disruption, developmental and reproductive diseases. These effects have also been confirmed on experimental animals. However, in mechanistic studies with cellular models the biological pathways examined so far only showed adaptive responses to PBDEs exposure, with no relevant adverse outcome at human exposure levels.
We explored the adverse outcome pathways (AOP) of PBDEs in the following three directions. (1) Competitive binding with TH transport proteins: Hydroxylated PBDEs (OH-PBDEs) were found to bind with isolated transthretin, the primary transport protein of thyroid hormone (TH) with high affinity. Although at current human exposure levels the impct of this binding is insignificant, further increase would lead to disruption of TH transport in vivo. (2) Activating TR-mediated transcriptional pathways: Low bominated OH-PBDEs were found to bind with the ligand-binding domain of thyroid hormone nuclear receptor (TR), and also exhibited TH activity in GH3 cell proliferation assays. Their potency is lower than T4 by orders of magnitude, suggesting this pathway is unlikely to be AOP of PBDEs. (3) Activating GPER-mediated non-genomic pathways: Some OH-PBDEs were found to bind to the membrance receptor, GPER with affinity 20% of E2. By detecting calcium mobilization and cAMP production in SKBR3 cells, we found the OH-PBDEs activated the GPER pathway with the lowest effective concentration (LOEC) of 10 nM. Furthermore, they exhibited activity in SKBR3 cells migration with LOEC of 100 nM. Overall, some OH-PBDEs activated GPER pathway at low concentrations, suggesting this pathway could be the AOP of PBDEs.