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Aop: 105

AOP Title

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Alpha2u-microglobulin cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)

Short name:

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α2u-globulin- renal adenomas/carcinomas

Graphical Representation

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Click to download graphical representation template

Authors

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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)

Point of Contact

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Charles Wood   (email point of contact)

Contributors

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  • Charles Wood

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite 1.29 Under Development


This AOP was last modified on January 27, 2018 15:34

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Revision dates for related pages

Page Revision Date/Time
Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium) September 16, 2017 10:16
Increase, Cytotoxicity (renal tubular cell) September 16, 2017 10:16
Increase, Regenerative cell proliferation (tubular epithelial cells) September 16, 2017 10:16
Increase, Adenomas/carcinomas (renal tubular) September 16, 2017 10:16
Increase, Hyperplasia (renal tubular cells) September 16, 2017 10:16
Increased, Binding of chemicals to 2u (serum) September 16, 2017 10:16
Increased, Binding of chemicals to 2u (serum) leads to Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium) December 03, 2016 16:37
Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium) leads to Increase, Cytotoxicity (renal tubular cell) December 03, 2016 16:37
Increase, Cytotoxicity (renal tubular cell) leads to Increase, Regenerative cell proliferation (tubular epithelial cells) December 03, 2016 16:37
Increase, Regenerative cell proliferation (tubular epithelial cells) leads to Increase, Hyperplasia (renal tubular cells) December 03, 2016 16:38
Increase, Hyperplasia (renal tubular cells) leads to Increase, Adenomas/carcinomas (renal tubular) December 03, 2016 16:38

Abstract

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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)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 714 Increased, Binding of chemicals to 2u (serum) Increased, Binding of chemicals to 2u (serum)
2 KE 708 Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium) Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium)
3 KE 709 Increase, Cytotoxicity (renal tubular cell) Increase, Cytotoxicity (renal tubular cell)
4 KE 710 Increase, Regenerative cell proliferation (tubular epithelial cells) Increase, Regenerative cell proliferation (tubular epithelial cells)
5 KE 767 Increase, Hyperplasia (renal tubular cells) Increase, Hyperplasia (renal tubular cells)
6 AO 713 Increase, Adenomas/carcinomas (renal tubular) Increase, Adenomas/carcinomas (renal tubular)

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Increased, Binding of chemicals to 2u (serum) leads to Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium) adjacent
Increased, Accumulation of alpha2u microglobulin (proximal tubular epithelium) leads to Increase, Cytotoxicity (renal tubular cell) adjacent
Increase, Cytotoxicity (renal tubular cell) leads to Increase, Regenerative cell proliferation (tubular epithelial cells) adjacent
Increase, Regenerative cell proliferation (tubular epithelial cells) leads to Increase, Hyperplasia (renal tubular cells) adjacent
Increase, Hyperplasia (renal tubular cells) leads to Increase, Adenomas/carcinomas (renal tubular) adjacent

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Rattus norvegicus Rattus norvegicus NCBI

Sex Applicability

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Sex Evidence
Male

Overall Assessment of the AOP

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Domain of Applicability

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Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.

  • 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

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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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.