Upstream eventActivation, AhR
Increase, Early Life Stage Mortality
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF||non-adjacent||High||Moderate|
|Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2||non-adjacent||High||Moderate|
|Japanese quail||Coturnix japonica||High||NCBI|
|Ring-necked pheasant||Phasianus colchicus||High||NCBI|
|bobwhite quail||Colinus virginianus||High||NCBI|
|American kestrel||Falco sparverius||High||NCBI|
|Double-crested cormorant||Double-crested cormorant||High||NCBI|
|Eastern bluebird||Eastern bluebird||High||NCBI|
|Fundulus heteroclitus||Fundulus heteroclitus||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Oncorhynchus mykiss||Oncorhynchus mykiss||Moderate||NCBI|
|Xenopus laevis||Xenopus laevis||Low||NCBI|
Life Stage Applicability
Key Event Relationship Description
The aryl hydrocarbon receptor is commonly known for its involvement in xenobiotic metabolism and clearance, but it also regulates a number of endogenous processes including angiogenesis, immune responses, neuronal processes, metabolism, and development of numerous organ systems (Duncan et al., 1998; Emmons et al., 1999; Hahn et al 2002; Lahvis and Bradfield, 1998). Strong AHR agonists that cause sustained AHR activation interfere with the receptor's endogenous role in embryogenesis, which causes numerous developmental abnormalities and ultimately leads to embryonic death (Kopf and Walker 2009; Carreira et al 2015).
It's important to note that his relationship only applies to AHR agonists that cause sustained AHR activation. Strong AHR agonists that are rapidly metabolized, such as polycyclic aromatic hydrocarbons, only cause transient AHR activation leading to an alternate mode of toxicity.
This Key Event Relationship describes the indirect link between the Molecular Initiating Event (activation of the AhR) and the Adverse Outcome (increased early life stage mortality).
Evidence Supporting this KER
AHR Ligand Binding Domain
- Mammalian and avian sensitivity to DLCs ultimately comes down to the identity of two particular amino acids in the ligand binding domain (LBD) of the AHR: positions 375 and 319 in mice and 380 and 324 in birds.
- A 10-fold difference between two strains of mice (non-responsive DBA/2 mouse, and responsive C57BL/6 14 mouse) in CYP1A induction, lethality and teratogenicity following TCDD exposure (Poland et al. 1976), was attributed to a single nucleotide polymorphism at position 375 (Ema et al. 1994; Poland et al. 1994; Poland and Knutson 1982).
- Several other studies reported the importance of this amino acid in birds and mammals (Backlund and Ingelman-Sundberg 2004; Ema et al. 1994; Karchner et al. 2006; Murray et al. 2005; Pandini et al. 2007; Pandini et al. 2009; Poland et al. 1994; Ramadoss and Perdew 2004).
- The amino acid at position 319 plays an important role in ligand-binding affinity to the AHR and transactivation ability of the AHR, due to its involvement in LBD cavity volume and its steric effect (Pandini et al. 2009).
- Mutation at position 319 in the mouse eliminated AHR DNA binding (Pandini et al. 2009).
Using AHR LBD Constructs to Determine Avian Sensitivity
- Using chimeric AHR1 constructs combining three AHR1 domains (DBD, LBD and TAD) from the chicken (highly sensitive to DLC toxicity) and common tern (resistant to DLC toxicity), Karchner and colleagues (2006), showed that amino acid differences within the LBD were responsible for differences in TCDD sensitivity between the chicken and common tern.
- They specifically attributed positions 324 and 380 with differences in TCDD binding affinity and transactivation between the chicken (Ile324_Ser380) and common tern (Val324_Ala380) receptors.
- The LBD of over 85 bird species have since been analyzed to find that 6 amino acid residues differed among species (Farmahin et al. 2013; Head et al. 2008), but only positions 324 and 380 in the AHR1 LBD were associated with differences in DLC toxicity in ovo and AHR1-mediated gene expression in vitro (Farmahin et al. 2013; Head et al. 2008; Manning et al. 2012).
- Based on these results, avian species can be divided into one of three AHR1 types based on the amino acids found at positions 324 and 380 of the AHR1 LBD: type 1 (Ile324_Ser380; most sensitive), type 2 (Ile324_Ala380; moderately sensitive) and type 3 (Val324_Ala380; least sensitive) (Farmahin et al. 2013; Head et al. 2008; Manning et al. 2012).
- A sampling of bird species and their AHR LBD category is described in table 1. A list of 86 species and their subtype can be found in Farmahin et al. (2013).
- 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).
Binding of dioxin-like compounds (DLCs) to avian AHR1 (Farmahin et al. 2014; Karchner et al. 2006) and AHR1-mediated transactivation measured using luciferase reporter gene (LRG) assays have been demonstrated in domestic and wild species of birds (Farmahin et al. 2012; Farmahin et al. 2013b; Fujisawa et al. 2012; Lee et al. 2009; Manning et al. 2012; Mol et al. 2012), and binding affinity was found to be strongly correlated with embryotoxicity (Manning et al. 2012) .
- 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). Relative potencies of dioxin-like compounds for activation of AHR2 alpha of rainbow trout (Oncorhynchus mykiss) is predictive of relative potencies for early life stage mortality (Abnet et al 1999).
- 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).
- 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
Interestingly, interference with endogenous AHR functions, either by knock-out or by agonist exposure during early development, causes similar cardiac abnormalities (Carreira et al 2015). Although this is counterintuitive, it demonstrates that the AHR has an optimal window of activity, and deviation either above or below this range results in toxicity.
- Only limited AhR activation information and mortality information is currently available for reptiles and amphibians.
- 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 precise cascade of key events that link activation of the AhR to the adverse outcome (Doering et al 2016).
- 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).
- There are no currently known inconsistencies between AhR activation and increased mortality among vertebrates.
Quantitative Understanding of the Linkage
The predictive ability of an LRG assay measuring induction of AHR1-mediated gene expression in cells transfected with different avian AHR1 expression vectors was demonstrated by linear regression analysis comparing log-transformed LD50 values obtained from the literature to log-transformed PC20 values from the LRG assay (Farmahin et al. 2013b; Manning et al. 2012). PC20 values represent the concentration of DLC that elicited 20% of the TCDD maximal response, and were calculated according to the procedure described in OECD guideline 455 (OECD 2009). LD50 values used in regression analyses were obtained from the literature. As shown in the linear regression analysis (Figure 1), logLD50 values were associated with logPC20 and a significant relationship (R2 = 0.93, p < 0.0001) was observed. Thus, to predict the in ovo LD50 for a given species and DLC, one could use the species’ AHR1 LBD sequence to design an AHR1 expression vector, measure the PC20 of the DLC in the LRG assay, and use the regression to obtain an LD50 value.
Figure 1. Linear regression analysis comparing LD50 values with PC20 (logLD50 = 0.79logPC20 + 0.51) values derived from luciferase reporter gene (LRG) assay concentration-response curves. Open symbols represent LRG data from wild-type chicken, ring-necked pheasant or Japanese quail AHR1 expression vectors. Closed symbols represent LRG data from mutant AHR1 (Source: Manning, G. E. et al. (2012). Toxicol. Appl. Pharmacol. 263(3), 390-399.)
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
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.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Overall, 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).
- The correlation between AHR-mediated reporter gene activity and embryo death has been demonstrated in species of birds and fishes (Doernig et al 2018).
- Less is known about differences in binding affinity of AhRs and how this relates to sensitivity in reptiles or amphibians.
- Low binding affinity for DLCs of AhR1s of African clawed frog (Xenopus laevis) and axolotl (Ambystoma mexicanum) has been suggested as a mechanism for tolerance of these amphibians to DLCs (Lavine et al 2005; Shoots et al 2015).
- Among reptiles, only AhRs of American alligator (Alligator mississippiensis) have been investigated and little is known about the sensitivity of American alligator or other reptiles to DLCs (Oka et al 2016).
- Among fishes, great differences in sensitivity to DLCs are known both for AhRs and for embryos among species that have been tested (Doering et al 2013; 2014; 2018).
- Differences in binding affinity of the AhR2 have been demonstrated to explain differences in sensitivity to DLCs between sensitive and tolerant populations of Atlantic Tomcod (Microgadus tomcod) (Wirgin et al 2011).
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