A Cross-species Quantitative Adverse Outcome Pathway for Activation of the Aryl Hydrocarbon Receptor Leading to Early Life Stage Mortality in Birds and Fishes

Abstract

Dioxin-like compounds (DLCs) elicit adverse effects through activation of the aryl hydrocarbon receptor (AHR). Prior investigations demonstrated that sensitivity to activation of AHR1 in an in vitro AHR transactivation assay is predictive of early life stage mortality among birds. The present study investigated the link between sensitivity to activation of AHR1s and AHR2s and early life stage mortality among fishes. A significant, linear relationship was demonstrated between sensitivity to activation of AHR2 and early life stage mortality among nine fishes, while no relationship was found for AHR1. The slope and y-intercept for the linear relationship between sensitivity to activation of AHR1 and early life stage mortality in birds was not statistically different from the same relationship for AHR2 in fishes. Data for fishes and birds across DLCs were expanded into four significant, linear regression models describing the relationship between sensitivity to activation of AHR and the dose to cause early life stage mortality of 0%, 10%, 50%, or 100%. These four relationships were combined to form a quantitative adverse outcome pathway which can predict dose-response curves of early life stage mortality for DLCs to any bird or fish from species- and chemical-specific responses in an in vitro AHR transactivation assay.

Adverse Outcome Pathway on aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2

“…• The correlation between AHR-mediated reporter gene activity and embryo death has been demonstrated in species of birds and fishes (Doering et al 2018).…”

“…Therefore, this AOP has utility towards the mechanistic understanding of adverse effects of agonists of the AhR with regard to cross-chemical, cross-species, and cross-taxa extrapolations. This utility has led to the development of a qAOP that has demonstrated utility in guiding more objective ecological risk assessments of native species to agonists of the AhR, particularly assessments of threatened or endangered species that often cannot be investigated in laboratory toxicity testing (Doering et al 2018…”

“…• Among fishes, great differences in sensitivity to DLCs are known both for AhRs and for embryos among species that have been tested 2018).…”

“…• AhR2-mediated transactivation measured using luciferase reproter gene (LRG) assays have been demonstrated in 8 species of freshwater and marine fishes to strongly correlate with early life stage mortality (Doering et al 2018). However, AhR1-mediated transactivation does not (Doering et al 2018).…”

“…• AhR2-mediated transactivation measured using luciferase reproter gene (LRG) assays have been demonstrated in 8 species of freshwater and marine fishes to strongly correlate with early life stage mortality (Doering et al 2018). However, AhR1-mediated transactivation does not (Doering et al 2018). Further, the slope and y-intercept for the relationship between AhR2-mediated transactivation and early life stage mortality in fishes are not statistically different from the slope and y-intercept for the relatoinship between AhR1-mediated transactivatoin and embryotoxicity (Doering et al 2018).…”