Key Event Title
Key Event Component
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Aryl hydrocarbon receptor activation leading to uroporphyria||AdverseOutcome|
Level of Biological Organization
|herring gull||Larus argentatus||Strong||NCBI|
|Japanese quail||Coturnix japonica||Strong||NCBI|
Life Stage Applicability
How This Key Event Works
Figure 1: The heme biosynthetic pathway. Deficiency in a particular gene along the pathway results in the indicated form of porphyria: 8 separate disorders that are characterized by hepatic accumulation and increased excretion of porphyrins. Source: Frank, J., and Poblete-Gutierrez, P. (2010) Porphyria cutanea tarda--when skin meets liver. Best. Pract. Res. Clin Gastroenterol. 24 (5), 735-745.
Porphyria is a disorder in which the disturbance of heme biosynthesis results in accumulation and excretion of porphyrins. A variety of porphyrias exist depending on which enzyme in the pathway is deficient (Figure 1). In the case of chemically induced urporphyria, uroporphyrinogen decarboxylase (UROD), which converts uroporphyrinogen to coproporphyrinogen, is inhibited. In humans, this disorder is known as porphyria cutanea tarda and may be caused by chemical exposure or a hereditary deficiency in UROD. The accumulation of porphyrins in the liver causes cirrhosis, mild fatty infiltration, patchy focal necrosis, and inflammation of portal tracts. When the activity of UROD is reduced to less than 30% of normal, the disorder manifests as an overt skin disease; the accumulation of porphyrins in the skin causes photosensitization that is characterized by fragile skin, superficial erosions, sub-epidermal bullae, hypertrichosis, patchy pigmentation and scarring.
How It Is Measured or Detected
Porphyria is easily confirmed through a urinary or fecal analysis to measure the levels and pattern of excreted porphyrins. Samples are quantified using a high-performance liquid chromatograph equipped with a fluorescence detector. Frank and Poblete-Gutiérrez illustrate how the types of porphyria can be differentiated by the relative abundance of different porphyrins (Figure 2). Uroporphyria is the animal model equivalent to human porphyria cutanea tard 
Evidence Supporting Taxonomic Applicability
Chemical-induced uroporphyria has only been detected in birds and mammals , including an accidental outbreak in humans due to hexachlorobenzen-contaminated grain in the 1950s. Fish are less susceptible to chemical-induced uroporphyria, but elevated levels of HCP have been documented in highly contaminated environments.
Regulatory Examples Using This Adverse Outcome
Uroporphyria is a disorder affecting multiple organs and can significantly decrease the quality of life in humans. The outbreak of porphyria in Turkish populations in the 1950's due to contaminated grain has significant, long-term health effects.
Uroporphyria has been detected in one wild animal population (Herring gulls in contaminated Great Lakes colonies); although the disorder is characterized by hepatotoxicity, it has not been shown to lead to death, and therefore is not expected to cause population decline. Elevated porphyrins however are apparent long before overt signs of toxicity are manifested, making it a sensitive biomarker of chemical exposure; monitoring porphyrin levels in at-risk wild populations would identify the need for remediation of contaminated sights before the occurrence of overt adverse effects.
- ↑ 1.0 1.1 Kennedy, S. W., and Fox, G. A. (1990). Highly carboxylated porphyrins as a biomarker of polyhalogenated aromatic hydrocarbon exposure in wildlife: Confirmation of their presence in Great Lakes herring gull chicks in the early 1970s and important methodological details. Chemosphere 21, 407-415.
- ↑ Rifkind, A. B. (2006). CYP1A in TCDD toxicity and in physiology - With particular reference to CYP dependent arachidonic acid metabolism and other endogenous substrates. Drug Metabolism Reviews 38, 291-335.
- ↑ Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001). Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol.Appl.Pharmacol. 173, 89-98.
- ↑ 4.0 4.1 Frank, J., and Poblete-Gutierrez, P. (2010) Porphyria cutanea tarda--when skin meets liver. Best. Pract. Res. Clin Gastroenterol. 24(5), 735-745.
- ↑ 5.0 5.1 5.2 Smith, A. G., and Elder, G. H. (2010) Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. Chem. Res. Toxicol. 23 (4), 712-723.
- ↑ Kennedy, S. W., Wigfield, D. C., and Fox, G. A. (1986). Tissue porphyrin pattern determination by high-speed high-performance liquid chromatography. Anal. Biochem. 157 (1), 1-7.
- ↑ Fox, G. A., Norstrom, R. J., Wigfield, D. C., and Kennedy, S. W. (1988) Porphyria in herring gulls: A biochemical response to chemical contamination of great lakes food chains. ‘’Environmental Toxicology and Chemistry’’ ‘’’7’’’ (10), 831-839
- ↑ Kennedy, S. W., Fox, G. A., Trudeau, S. F., Bastien, L. J., and Jones, S. P. (1998) Highly carboxylated porphyrin concentration: A biochemical marker of PCB exposure in herring gulls. Marine Environmental Research 46 (1-5), 65-69.
- ↑ Cripps, D. J., Peters, H. A., Gocmen, A., and Dogramici, I. (1984) Porphyria turcica due to hexachlorobenzene: a 20 to 30 year follow-up study on 204 patients. Br. J Dermatol. 111 (4), 413-422.
- ↑ Wainwright, J. S., Hopkins, K. M., Bums Jr., T.A., and Di Giulio, R. T. (1995) Investigation of potential biomarkers of exposure to bleached kraft mill effluent in North Carolina rivers. Durham, NC.
- ↑ Lorenzen, A., Shutt, J. L., and Kennedy, S. W. (1997b). Sensitivity of common tern (Sterna hirundo) embryo hepatocyte cultures to CYP1A induction and porphyrin accumulation by halogenated aromatic hydrocarbons and common tern egg extracts. Archives of Environmental Contamination and Toxicology 32, 126-134.
- ↑ Lorenzen, A., and Kennedy, S. W. (1995). Sensitivities of Chicken and Pheasant Embryos and Cultured Embryonic Hepatocytes to Cytochrome P4501A Induction and Porphyrin Accumulation by TCDD, TCDF and PCBs. Organohalogen Compounds 25, 65-68.
- ↑ Farmahin, R., Manning, G. E., Crump, D., Wu, D., Mundy, L. J., Jones, S. P., Hahn, M. E., Karchner, S. I., Giesy, J. P., Bursian, S. J., Zwiernik, M. J., Fredricks, T. B., and Kennedy, S. W. (2013b). Amino acid sequence of the ligand binding domain of the aryl hydrocarbon receptor 1 (AHR1) predicts sensitivity of wild birds to effects of dioxin-like compounds. Toxicol.Sci. 131, 139-152.
- ↑ Head, J. A., Hahn, M. E., and Kennedy, S. W. (2008). Key amino acids in the aryl hydrocarbon receptor predict dioxin sensitivity in avian species. Environ.Sci.Technol. 42, 7535-7541.
- ↑ Manning, G. E., Farmahin, R., Crump, D., Jones, S. P., Klein, J., Konstantinov, A., Potter, D., and Kennedy, S. W. (2012). A luciferase reporter gene assay and aryl hydrocarbon receptor 1 genotype predict the embryolethality of polychlorinated biphenyls in avian species. Toxicol.Appl.Pharmacol. 263, 390-399.