posted on 2020-01-13, 13:11authored byJi-Hee Hwang, Kurunthachalam Kannan, Thomas J. Evans, Hisato Iwata, Eun-Young Kim
Polar
bear (Ursus maritimus) populations accumulate
dioxins and related compounds (DRCs) at levels that are of health
concern. The toxicities of DRCs are primarily mediated via aryl hydrocarbon
receptor (AHR) signaling pathway. To evaluate the sensitivity and
responses to DRCs in polar bears, we assessed the activation potencies
of polar bear-specific AHR (pbAHR) by DRCs through in vitro and in
silico approaches. In vitro assays showed that the pbAHR was as sensitive
to DRCs as C3H/lpr mouse AHR, which is well-known
to be highly sensitive to DRCs. Comparison of pbAHR transactivation
potencies indicated that TCDF, 2,3,4,7,8-PeCDF, and BaP exhibited
high induction equivalency factors (IEFs). Considering the accumulation
levels of DRCs in polar bears, PCB126 was found to be the most active
inducer of pbAHR. The in vitro transactivation potencies of ligands
of pbAHR showed a significant relationship with in silico ligand docking
energies in a pbAHR homology model. The protein ligand interaction
fingerprint (PLIF) analysis showed different interaction patterns
depending on the ligands. Several amino acids which are highly conserved
among mammals may be involved in species-specific responses via backbone
interactions with neighboring amino acid residues which are specific
to pbAHR. We document high susceptibility of polar bears to DRCs,
through a mechanistic approach, for the first time.