
This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Aop: 401
Title
G protein-coupled estrogen receptor 1 (GPER) signal pathway in the endocrine disrupting effect
Short name
Graphical Representation
Point of Contact
Contributors
- Fei Li
- Agnes Aggy
Status
Author status | OECD status | OECD project | SAAOP status |
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Under development: Not open for comment. Do not cite |
This AOP was last modified on July 16, 2022 18:37
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Abstract
Endocrine-disrupting chemicals can interfere with hormone action via various pathways, thereby increasing the risk of adverse health outcomes. Organophosphorus ester (OPEs) retardants, a group of new emerging endocrine disruption chemicals, have been referred to as metabolism disruptors and reported to induce chronic health problems. However, the toxicity pathways were mainly focused on nuclear receptor signaling pathways. Significantly, the membrane receptor pathway (such as G protein-coupled estrogen receptor 1 (GPER) signaling pathway) had been gradually realized as the important role in respond more effective to lipid metabolism disorder than traditional nuclear receptors, whereas the detailed mechanism was unclear yet. Therefore, this study develop toxicity pathways for the mechanism interpretation. Results verified that TPP could damage the structures of cell membranes and exert an agonistic effect of GPER as the molecular initiating event. Then, the activated GPER could trigger the PI3K-Akt/NCOR1 and mTOR/S6K2/PPARα transduction pathways as key event 1 (KE1) and affect the process of lipid metabolism and synthesis (CPT1A, CPT2, SREBF2 and SCD) as KE2. As a result, these alterations led to lipid accumulation as adverse effect at cellular-levels. Furthermore, the potential outcomes (such as immunity damage, weight change and steatohepatitis) at high biological levels were expanded. These findings improved knowledge to deeply understand toxicity pathways of phosphorus flame retardants and then provided a theoretical basis for risk assessments.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Relationships Between Two Key Events (Including MIEs and AOs)
Network View
Prototypical Stressors
Life Stage Applicability
Taxonomic Applicability
Sex Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
The GPER activation was identified as a staple MIE in lipid metabolism abnormality induced by TPP through GPER signaling pathway. TPP could exert an agonistic effect of GPER by affecting TM6 to induce the subsequent signaling pathways including PI3K-Akt/NCOR1 and mTOR/S6K2/PPARα as KE1 (Fig. 6). The alterations affected a multitude of cellular process that down-regulate the expression of genes (CPT1A and CPT2) related to fatty acid oxidation metabolism and up-regulate the expression of genes (SREBF2 and SCD) related to lipid and fatty acid synthesis (KE2). These KEs ultimately resulted in excessive accumulation of lipids through molecular cause-effect relationships to lipid metabolism abnormality