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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) . 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 . 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) ,.
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 ,. Interestingly, compared to birds and mammals, most fishes are relatively insensitive to mono-ortho PCBs . 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|
|Event||Support for Essentiality|
|CYP1A1, Up Regulation|
|AHR nuclear translocator (ARNT)-dependent pathways, Altered regulation|
|Oxidative Stress, Increase|
|CYP1B1, Up Regulation|
|Pericardial edema, Increase|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
|Atlantic killifish||Fundulus heteroclitus||Strong||NCBI|
|rainbow trout||Oncorhynchus mykiss||Very Strong||NCBI|
|fathead minnow||Pimephales promelas||Strong||NCBI|
|channel catfish||Ictalurus punctatus||Moderate||NCBI|
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
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
Applicability of the AOP
Life Stage Applicability,
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
Considerations for Potential Applications of the AOP (optional)
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.