Relationship: 1492



Activation, AhR leads to Increased, Mortality

Upstream event


Activation, AhR

Downstream event


Increased, Mortality

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
AhR activation leading to early life stage mortality non-adjacent High High

Taxonomic Applicability


Term Scientific Term Evidence Link
chicken Gallus gallus High NCBI
Japanese quail Coturnix japonica High NCBI
Ring-necked pheasant Phasianus colchicus High NCBI
rainbow trout Oncorhynchus mykiss High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability


Sex Evidence
Unspecific High

Life Stage Applicability


Term Evidence
Development High
Embryo High

Key Event Relationship Description


  • This Key Event Relationship describes the indirect link between the Molecular Initiating Event (activation of the AhR) and the Adverse Outcome (increased mortality).
  • Despite decades of research into the molecular initiating event (i.e., binding of chemicals to the AhR) and resulting adverse outcomes (i.e. mortality), less is known about the cascade of key events that link activation of the AhR to the adverse outcome (Doering et al 2016).
  • Current evidence supports a cyclooxygenase-2 (COX-2) mediated mechanism linking activation of the AhR to early life stage mortality (Dong et al 2010; Teraoka et al 2008; 2014).
  • However, hundreds to thousands of different genes are regulated, either directly or indirectly, by activation of the AhR, which presents major uncertainties in the precise pathway of key events or whether perturbation to multiple pathways is the cause of mortality (Brinkmann et al 2016; Doering et al 2016; Huang et al 2014; Li et al 2013; Whitehead et al 2010).
  • Despite these uncertainties in the AOP, considerable research has investigated the indirect relationship between activation of the AhR and increased mortality among different chemicals, species, and taxa (Doering et al 2013).


Evidence Supporting this KER


Biological Plausibility


  • The AhR has key functions in critical physiological and developmental processes, including regulation of the cell cycle, cellular proliferation and differentiation, and cell-to-cell communications, angiogenesis, regulation of the immune system, neuronal processes, metabolism, development of the heart and other organ systems, and detoxification  (Duncan et al., 1998; Hahn et al 2002; Lahvis and Bradfield, 1998; Emmons et al., 1999). 
  • Chemicals that bind to and activate the AhR are known to cause early life stage mortality in vertebrates (Van den Berg et al 1998).

Empirical Evidence



  • AhR deficient strains of mice (Mus musculus) are unaffected by exposure to agonists of the AhR (Fernandez-Salguero et al 1996).
  • Strains of mice that express AhRs with lesser affinity for agonists are more tolerant to adverse effects of exposure relative to strains of mice that express AhRs with greater affinity for agonists (Bisson et al 2009; Ema et al 1993).


  • Species of birds that are sensitive to adverse effects of exposure to agonists of the AhR express AhR1s with greater affinity for agonists relative to AhR1s expressed by species of birds that are tolerant to adverse effects of exposure to agonists (Karchner et al 2006).


  • Knockdown of the AhR2 prevents mortality following exposure to agonist of the AhR in fishes (Clark et al 2010; Hanno et al 2010; Prasch et al 2003; Van Tiem & Di Giulio 2011).


  • AhR1s of amphibians studied to date are insensitive to activation by dioxin-like compounds in vitro, while amphibians studies to date are extremely tolerant to adverse effects of exposure to dioxin-like compounds in vivo (Jung et al 1997; Lavine et al 2005; Shoots et al 2015).


  • Chemicals that activate the AhR of vertebrates are not known to bind AhRs of invertebrates and increased mortality in invertebrates has never been observed as a result of exposure to these agonists (Hahn 2002; Hahn et al 1994).

Uncertainties and Inconsistencies



  • Only limited AhR activation information is currently available for fishes.
  • Only limited AhR activation information and mortality information is currently available for reptiles and amphibians.


  • There are no currently known inconsistencies between AhR activation and increased mortality among vertebrates.

Quantitative Understanding of the Linkage



A quantitative model has been developed linking in silico activation of the AhR with acute lethality (measured as dose to cause 50 % lethality; LD50) among 7 species of mammals with an R2 of 0.99 (Wang et al 2013). The model is described in detail by Wang et al (2013). The model is described as:

If steric (LJ12-6) < 0 then Log (LD50) = 13.273Log(NOQ) + 5.167Log(-Steric(PLP))-0.157Log(-steric(LJ12-6))-1.799Log(-(H-bond))-24.625

If steric (LJ12-6) > 0 then Log (LD50) = 13.273Log(NOQ) + 5.167Log(-Steric(PLP))+0.157Log(-steric(LJ12-6))-1.799Log(-(H-bond))-24.625


A quantitative model has been developed linking in vitro activation of the AhR1 in transfected COS-7 cells (measured as concentration to cause 50 % effect; EC50) with early life stage mortality (measured as dose to cause 50 % lethality; LD50) among three species of birds across 3 chemicals with an R2 of 0.81 (Farmahin et al 2012). This model has been demonstrated to be applicable across all species of birds and for all dioxin-like compounds (Farmahin et al 2012; 2013; Manning et al 2012). The model is described in detail by Farmahin et al (2012). The model is described as:

LD50 = 0.7276*(EC50)+0.2248


Limited information is currently available across fishes. However, a quantitative model has been developed linking in vitro activation of the AhR2 alpha in transfected COS-7 cells (meaured as concentration to cause 50 % effect; EC50) with early life stage mortality (measured as dose to cause 50 % lethality; LD50) for rainbow trout (Oncorhynchus mykiss) across 6 chemicals with an R2 of 0.81 (Abnet et al 1999). The model is described in detail by Abnet et al (1999). The model is described as:

LD50 = 1.57*(EC50)-0.2418

Amphibians and reptiles:

No quantitative models are currently available for amphibians or reptiles.

Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


  • This KER is believed to be applicable to all vertebrates based on mortality as a result of exposure to known agonists of the AhR (Buckler et al 2015; Cohen-Barnhouse et al 2011; Elonen et al 1998; Johnson et al 1998; Jung et al 1997; Kopf & Walker 2009; Park et al 2014; Tillitt et al 2016; Toomey et al 2001; Walker et al 1991; Wang et al 2013; Yamauchi et al 2006; Zabel et al 1995).



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