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AOP Title

AhR activation leading to embryo toxicity in fish
Short name: AhR activation leading to embryo toxicity in fish



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OECD Project 1.7: The Adverse Outcome Pathways for Sustained Activation of the Aryl Hydrocarbon Receptor

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The AhR, which is a ligand-activated transcription factor that mediates expression of a suite of pleiotropic responses, including biotransformation enzymes, regulates all known effects of exposure to dioxin-like compounds (DLCs) [1]. The AhR is a member of the Per-Arnt-Sim (PAS) family of proteins and shares some structural similarities with other PAS proteins, including ARNT, aryl hydrocarbon receptor repressor (AhRR), and hypoxia inducible factor 1 (HIF1alpha). Activation of the AhR by dioxin-like chemicals has been shown to cause a range of adverse effects in vertebrates, including hepatotoxicity, immune suppression, reproductive and endocrine impairment, teratogenicity, carcinogenicity, and loss of weight [2]. Upon binding and activation by a ligand the AhR dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT). This complex then binds to specific xenobiotic response elements (XREs) on the DNA of an organism, which results in the transcription of certain genes in fish including those encoding for Phase I metabolic enzymes (i.e. CYP1A1, CYP1B1) [3],[4].

The toxicity of DLCs including PCDDs, PCDFs, and selected PCBs has been demonstrated for a large number of different fish species with some fishes being among the vertebrates of greatest sensitivity to adverse effects from exposure to DLCs [5],[6]. Interestingly, compared to birds and mammals, most fishes are relatively insensitive to mono-ortho PCBs [7]. Thus, while the molecular initiating events and first key steps of AhR-mediated toxicity seems to be highly preserved among vertebrates, the manifestation of these effects resulting in differential sensitivities varies greatly both among different vertebrate groups but also among different species within a group.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
AHR, Activation

Key Events

Event Support for Essentiality
CYP1A1, Up Regulation
AHR nuclear translocator (ARNT)-dependent pathways, Altered regulation
Oxidative Stress, Increase
CYP1B1, Up Regulation

Adverse Outcome

Adverse Outcome
Embryotoxicity, N/A
Pericardial edema, Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
AHR, Activation Directly Leads to AHR nuclear translocator (ARNT)-dependent pathways, Altered regulation Strong
AHR nuclear translocator (ARNT)-dependent pathways, Altered regulation Directly Leads to CYP1A1, Up Regulation Strong
CYP1A1, Up Regulation Directly Leads to Oxidative Stress, Increase Moderate
Oxidative Stress, Increase Directly Leads to Pericardial edema, Increase Moderate
Oxidative Stress, Increase Directly Leads to Embryotoxicity, N/A Moderate

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Life Stage Applicability

Life Stage Evidence Links
Embryo Very Strong
Juvenile Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
Atlantic killifish Fundulus heteroclitus Strong NCBI
zebrafish Danio rerio Strong NCBI
rainbow trout Oncorhynchus mykiss Very Strong NCBI
medaka Oryzias latipes Strong NCBI
fathead minnow Pimephales promelas Strong NCBI
channel catfish Ictalurus punctatus Moderate NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

Consider the following criteria (may include references to KE Relationship pages): 1. concordance of dose-response relationships; 2. temporal concordance among the key events and adverse effect; 3. strength, consistency, and specificity of association of adverse effect and initiating event; 4. biological plausibility, coherence, and consistency of the experimental evidence; 5. alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP. It should be noted that alternative mechanisms of action, if supported, require a separate AOP; 6. uncertainties, inconsistencies and data gaps.

Weight of Evidence Summary

Summary Table
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Quantitative Considerations

Summary Table
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Applicability of the AOP

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Considerations for Potential Applications of the AOP (optional)


  1. Okey, A. B. (2007). An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. Toxicol.Sci. 98, 5-38.
  2. Kawajiri K., Fujii-Kuriyama Y. (2007). Cytochrome P450 gene regula- tion and physiological functions mediated by the aryl hydrocar- bon receptor. Arch. Biochem. Biophy. 464, 207-212.
  3. Nebert D.W., Roe A.L., Dieter M.Z., Solis W.A., Yang Y., Dalton T.P. (2000). Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem. Pharmacol. 59, 65-85.
  4. Di Bello D., Vaccaro E., Longo V., Regoli F., Nigro M., Benedetti M., Giovanni P., Pretti C. (2007). Presence and inducibility by beta-naphthoflavone of CYP1A1, CYP1B1 and phase II enzymes in Trematomus bernacchii, an Antarctic fish. Aquat. Toxicol. 84, 19-26.
  5. Jonsson, M.E., Berg, C., Goldstone, J.V., Stegeman, J.J. (1998). New CYP1 genes in the frog Xenopus (Silurana) tropicalis: induction patterns and effects of AHR agonists during development. Toxicol. Appl. Pharmacol. 250, 170-183.
  6. Walker, M.K., Spitsbergen, J.M., Olson, J.R., Peterson, R.E. (1991). 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) toxicity during early life stage development of lake trout (Salvelinus namaycush). Can. J. Fish. Aquat. Sci. 48, 875-883.
  7. Van den Berg, M., Birnbaum, L., Bosveld, A.T.C., Brunstrom, B., Cook, P., Feeley, M., 712 Giesy, J.P., Hanberg, A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C., 713 van Leeuwen, R.X.R., Liem, A.K.D., Nolt, C., Peterson, R.E., Poellinger, L., Safe, S., 714 Schrenk, D., Tillitt, D., Tysklind, M., Younes, M., Waern, F., Zacharewski, T. (1998). Toxic equivalency factors (TEFs) for PCBs, PCDDs PCDFs for human and wildlife. Environ. Health Perspect. 106, 775-792.