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AOP: 401
Title
G protein-coupled estrogen receptor 1 (GPER) signal pathway in the lipid metabolism disrupting effects
Short name
Graphical Representation
Point of Contact
Contributors
- Fei Li
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on May 26, 2023 03:09
Revision dates for related pages
Page | Revision Date/Time |
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protein-coupled estrogen receptor 1 (GPER) activation | July 18, 2022 05:03 |
Activation, PI3K | April 13, 2017 10:41 |
Activation, AKT | April 12, 2017 14:27 |
Activation, mTORC1 | April 12, 2017 14:28 |
Activation, PPARα | December 28, 2020 12:48 |
Abnormal lipid metabolism | April 07, 2022 09:21 |
Down Regulation, CPT1A | September 16, 2017 10:15 |
Up Regulation, SREBF2 | September 16, 2017 10:17 |
Up Regulation, SCD-1 | September 16, 2017 10:15 |
N/A, Steatohepatisis | November 27, 2017 13:41 |
Triphenyl phosphate | March 30, 2020 16:54 |
Abstract
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.
AOP Development Strategy
Context
Triphenyl phosphate (TPP) was appeared as an important candidate metabolism disruptors. TPP was one of the high production volume flame retardants, which has been used in various commercial mixtures, thus causing the frequent detection and high-dose exposure in both environmental media and biota. Toxicity studies had revealed that TPP could interact with essential regulators of lipids to induce lipid abnormalities and metabolic disorders. TPP could affect peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptors (LXRs) to induce lipid abnormalities . It also could modulate saturation of phospholipids (Hu et al., 2020) and increase the cholesterol or triglyceride concentrations in bloods. Under this circumstance, it is extraordinarily exigent to assess the health risk of TPP.
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 2029 | protein-coupled estrogen receptor 1 (GPER) activation | GPER activation |
KE | 1310 | Activation, PI3K | Activation, PI3K |
KE | 1299 | Activation, AKT | Activation, AKT |
KE | 1300 | Activation, mTORC1 | Activation, mTORC1 |
KE | 227 | Activation, PPARα | Activation, PPARα |
KE | 1995 | Abnormal lipid metabolism | Abnormal lipid metabolism |
KE | 472 | Down Regulation, CPT1A | Down Regulation, CPT1A |
KE | 1284 | Up Regulation, SREBF2 | Up Regulation, SREBF2 |
KE | 462 | Up Regulation, SCD-1 | Up Regulation, SCD-1 |
AO | 1489 | N/A, Steatohepatisis | steatohepatitis |
Relationships Between Two Key Events (Including MIEs and AOs)
Network View
Prototypical Stressors
Name |
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Triphenyl phosphate |
Life Stage Applicability
Taxonomic Applicability
Sex Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
GPER活化被鉴定为TPP通过GPER信号通路诱导的脂质代谢异常中的主要MIE。TPP可以通过 影响TM6来诱导随后的信号通路,包括PI3K-Akt / NCOR1和mTOR / S6K2 / PPARα作为KE1(图6)来发挥GPER的激动作用。CPT1A和CPT2)与脂肪酸氧化代谢有关,并上调与脂质和脂肪酸合成(KE2)相关的基因(SREBF2和SCD)的表达。这些KLE最终通过与脂质代谢异常的分子因果关系导致脂质过度积累
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
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