Developing tools for risk assessment in protected species: Relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse

Abstract

Persistent organic pollutants such as halogenated aromatic hydrocarbons (HAHs) biomagnify in food webs and accumulate to high concentrations in top predators like odontocete cetaceans (toothed whales). The most toxic HAHs are the 2,3,7,8-substituted halogenated dibenzo-p-dioxins and furans, and non-ortho-substituted polychlorinated biphenyls (PCBs), which exert their effects via the aryl hydrocarbon receptor (AHR). Understanding the impact of HAHs in wildlife is limited by the lack of taxon-specific information about the relative potencies of toxicologically important congeners. To assess whether Toxic Equivalency Factors (TEFs) determined in rodents are predictive of HAH relative potencies in a cetacean, we used beluga and mouse AHRs expressed in vitro from cloned cDNAs to measure the relative AHR-binding affinities of ten HAHs from five different structural classes. The rank order of mean IC50s for competitive binding to beluga AHR was: TCDD<TCDF<PCB-126< PCB-169< PCB-77< PCB-81≪< PCB-156~PCB-128< PCB-105< PCB-118. The rank order of mean IC50s for binding to the mouse AHR was TCDD<TCDF< PCB-126< PCB-169< PCB-81< PCB-77< PCB-156≪ PCB-128~PCB-105~PCB-118. Ki values for binding of HAHs to beluga and mouse AHRs were highly correlated (r2= 0.96). Comparison of Ki values suggested that the beluga AHR had a higher affinity than the mouse AHR for most of the HAHs tested, consistent with the ~2-fold higher [3H]TCDD-binding affinity determined previously. These results are consistent with the World Health Organization mammalian TEFs for non- and mono-ortho PCB congeners. The comparatively high HAH binding affinities of the beluga AHR relative to those of an AHR from a dioxin-responsive mouse suggests that beluga, and perhaps cetaceans in general, may be particularly sensitive to the toxic effects of AHR agonists. Further study is warranted in order to more fully address this important question affecting protected and endangered species.

PCB 126 and Other Dioxin-Like PCBs Specifically Suppress Hepatic PEPCK Expression via the Aryl Hydrocarbon Receptor

“…First, the greatest overall induction of EROD was observed with 500 nM PCB 81 as opposed to any dose of PCB 126. Also, EROD activation by PCB 169 was notably weaker than that of the other dioxin-like PCBs, despite it having the second highest TEF of the dioxin-like PCBs screened and a relative AhR binding potency equivalent to that of PCB 81 [37] .…”

“…In addition to PCB 126, three other non-ortho-substituted coplanar dioxin-like PCBs were selected for testing: PCB 169, PCB 81, and PCB 77 ( Table 1 ). PCB 105 was included to represent a mono-ortho-substituted coplanar dioxin-like PCB with a significantly lower TEF relative to the other dioxin-like PCBs [8] , [37] . PCB 153 served as a negative PCB control, as it is both non-coplanar and non-dioxin-like, and as such, has no TEF [8] .…”

Long-term dietary-exposure to non-coplanar PCBs induces behavioral disruptions in adult zebrafish and their offspring

“…Differential expression of the clock gene was detected in a brain microarray analysis of rats exposed to Aroclor 1254 [72]. Aroclor contains the dioxin-like CB-126 congener which is also able to trigger AhR mediated response [35]. The diet mixture used in this experiment contains no coplanar dioxin-like compounds (the detection limit for non-ortho substituted planar dioxin-like congeners was 0.64 pg/µl) [12,38].…”

Assessment of Risks of Dioxins for Aryl Hydrocarbon Receptor-Mediated Effects in Polar Bear (Ursus maritimus) by in Vitro and in Silico Approaches

“…This is because of the difficulties in evaluating interspecies differences in sensitivity to DRCs. Great interspecies differences have been observed in the sensitivity of mammals to CYP1A induction by TCDD and other DRCs. − The molecular basis for the differential sensitivity to DRCs across mammals is not fully understood, but AHR has been considered to play a key role in underlying sensitivity.…”