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Event: 239

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Activation, Pregnane-X receptor, NR1l2

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. More help
Activation, Pregnane-X receptor, NR1l2
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
signaling nuclear receptor subfamily 1 group I member 2 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
Nuclear receptor induced TH Catabolism and Developmental Hearing Loss MolecularInitiatingEvent Katie Paul Friedman (send email) Open for adoption Under Development
PXR activation leads to liver steatosis MolecularInitiatingEvent John Frisch (send email) Under development: Not open for comment. Do not cite
Activation, Pregnane-X receptor leads to increased plasma LDL cholesterol via synthesis MolecularInitiatingEvent John Frisch (send email) Under development: Not open for comment. Do not cite
Activation, Pregnane-X receptor leads to increased plasma LDL cholesterol via PCSK9 MolecularInitiatingEvent John Frisch (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI
Homo sapiens Homo sapiens Moderate NCBI
mammals mammals High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

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. More help

Pregnane X receptor (PXR), also known as steroid NR subfamily 1, group I, member 2 (NR1I2), is a nuclear receptor that can be activated by pregnenolone and progesterone and many chemicals due to low specificity; once activated it binds to Retinoid X receptor (RXR) and increases upregulation of target genes (Mellor et al. 2016).  PXR has an important role in lipid homeostasis by regulating the rate of lipid intake particularly through activation of cluster of differentiation 36, also known as platelet glycoprotein 4 [(CD36) (Zhou et al. 2006; Gwag et al. 2019)].

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

Effects of Pregnane X receptor (PXR) activation on expression of downstream genes can be investigating using transcriptomics and/or RT-qPCR approaches.  The following ToxCast assays measure PXR activation: ATG_PXRE_CIS; ATG_PXR_TRANS; TOX21_PXR_agonist; ATG_mPXR_XSP2; NVS_NR_hPXR (U.S. EPA 2024).  Indigo Biosciences sells a commercial assay for human PXR activation (INDIGO Biosciences 2024).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Life Stage: All life stages.

Sex: Applies to both males and females.

Taxonomic: Appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats). According to the evaluation of the plausible taxonomic domain of applicability (tDOA) by Haigis et al., 2023, PXR was found only to be conserved across mammalian species compared to the human (Homo sapiens) protein target using the U.S. Environmental Protection Agency's Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS v6.0; seqapass.epa.gov/seqapass/) tool, while acknowledging the potential existence of interspecies differences in conservation. No structural protein conservation of amphibian, fish, reptilian or avian PXR was found.

References

List of the literature that was cited for this KE description. More help

Gwag, T., Meng, Z., Sui, Y., Helsley, R.N., Park, S.-H., Wang, S., Greenberg, R.N., and Zhou, C.  2019.  Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis. Journal of Hepatology 70: 930–940.

Haigis A-C., Vergauwen L., Lalone C.A., Villeneuve D.L., O'Brien J.M., Knapen D. (2023). Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption. Toxicol Sci. 195, 1-27.

INDIGO Biosciences. 2024.  Retrieved from https://indigobiosciences.com/product/human-pxr-reporter-assay-kit/.

LaLone, C.A., Villeneuve, D.L., Doering, J.A., Blackwell, B.R., Transue, T.R., Simmons, C.W., Swintek, J., Degitz, S.J., Williams, A.J., and Ankley, G.T.  2018.  Evidence for Cross Species Extrapolation of Mammalian-Based High-Throughput Screening Assay Results.  Environmental Science and Technology 52: 13960−13971.

Mellor, C.L., Steinmetz, F.P., and Cronin, T.D.  2016. The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways. Critical Reviews in Toxicology  46(2): 138-152. DOI:10.3109/10408444.2015.1089471.

U.S. EPA. 2024. ToxCast & Tox21 Summary Files from invitrodb_v4. Retrieved from https://www.epa.gov/chemical-research/toxicity-forecaster-toxcasttm-data. 

Zhou, J., Zhai, Y., Mu, Y., Gong, H., Uppal, H., Toma, D., Ren, S., Evans, R.M., and Xie, W.   2006.  A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent lipogenic pathway.  The Journal of Biological Chemistry 281(21): 15013–15020.

NOTE: Italics indicate edits from John Frisch June 2024