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Event: 369

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Uroporphyria

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Uroporphyria

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
porphyria increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
AHR activation-uroporphyria AdverseOutcome Amani Farhat (send email) Open for citation & comment WPHA/WNT Endorsed

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rats Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
human Homo sapiens High NCBI
herring gull Larus argentatus High NCBI
chicken Gallus gallus High NCBI
Japanese quail Coturnix japonica High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Juvenile High
Adult High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Unspecific Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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[1]. 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[4]. 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[5].

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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[6]. Frank and Poblete-Gutiérrez[4] 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 tarda [5]

Figure 2: Biochemical characteristics of the porphyrias in urine, stool, and blood (plasma and erythrocytes). Source: http://www.mayomedicallaboratories.com/articles/communique/2015/03-porphyria-testing/; Accessed December 9, 2015

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Chemical-induced uroporphyria has only been detected in birds[7][1][8] and mammals[5] , including an accidental outbreak in humans due to hexachlorobenzen-contaminated grain in the 1950s[9]. Fish are less susceptible to chemical-induced uroporphyria, but elevated levels of highly carboxylated porphyrins (HCP) have been documented in highly contaminated environments[10].

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

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 had significant, long-term health effects[9]

Uroporphyria has been detected in one wild animal population (Herring gulls in contaminated Great Lakes colonies[8]); 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.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help
  1. 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.
  2. 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.
  3. 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. 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. 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.
  6. 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.
  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
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.