Aop:21
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Abstract
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 |
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AHR, Activation |
Key Events
Event | Support for Essentiality |
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CYP1A1, Up Regulation | |
AHR nuclear translocator (ARNT)-dependent pathways, Altered regulation | |
Oxidative Stress, Increase | |
CYP1B1, Up Regulation |
Adverse Outcome
Adverse Outcome |
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Embryotoxicity, N/A |
Pericardial edema, Increase |
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
Life Stage | Evidence | Links |
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Embryo | Very Strong | |
Juvenile | Moderate |
Taxonomic Applicability
Name | Scientific Name | Evidence | Links |
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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 |
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Overall Assessment of the AOP
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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)
References
- ↑ 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.