Aop:105

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/105


AOP Title

Alpha2u-microglobulin cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)
Short name: α2u-globulin- renal adenomas/carcinomas

Authors

Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

Status

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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

Background (optional)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Binding of chemicals to 2u (serum), Increased

Key Events

Event Support for Essentiality
Accumulation of alpha2u microglobulin (proximal tubular epithelium), Increased
Cytotoxicity (renal tubular cell), Increase
Regenerative cell proliferation (tubular epithelial cells), Increase
Hyperplasia (renal tubular cells), Increase

Adverse Outcome

Adverse Outcome
Adenomas/carcinomas (renal tubular), Increase

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Binding of chemicals to 2u (serum), Increased Directly Leads to Accumulation of alpha2u microglobulin (proximal tubular epithelium), Increased
Accumulation of alpha2u microglobulin (proximal tubular epithelium), Increased Directly Leads to Cytotoxicity (renal tubular cell), Increase
Cytotoxicity (renal tubular cell), Increase Directly Leads to Regenerative cell proliferation (tubular epithelial cells), Increase
Regenerative cell proliferation (tubular epithelial cells), Increase Directly Leads to Hyperplasia (renal tubular cells), Increase
Hyperplasia (renal tubular cells), Increase Directly Leads to Adenomas/carcinomas (renal tubular), Increase

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus norvegicus Rattus norvegicus NCBI

Sex Applicability

Sex Evidence Links
Male

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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  • Sex: This AOP applies to males only (Swenberg, 1993).
  • Life stages: The relevant life stages for this AOP are reproductively mature adults. Alpha2u-microglobulin is found in the urine of female and sexually immature rats at concentrations that are less than 1/100 that found in young adult males (Vandoren et al 1983, Ekstrom et al 1984, as cited in Swenberg 1993). Hepatic synthesis accounts for most of the o2u in male rats, with synthesis beginning at the onset of sexual maturity and increasing to 20 weeks of age, after which it plateaus and then begins to decline with increasing age (Roy et al 1983, as cited in Swenberg 1993).
  • Taxonomic: The taxonomic applicability domain of this AOP is rats, Rattus norvegicus (Swenberg, 1993).

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References

Swenberg, J. A. (1993). Alpha 2u-globulin nephropathy: review of the cellular and molecular mechanisms involved and their implications for human risk assessment. Environ Health Perspect, 101 Suppl 6, 39-44.