The adverse outcome pathway (AOP) of estrogen interference effect induced by triphenyl phosphate (TPP): Integrated multi-omics and molecular dynamics approaches.
Ecotoxicol Environ Saf
; 234: 113387, 2022 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-35272188
ABSTRACT
Triphenyl phosphate (TPP) has been detected with increasing frequency in various biota and environmental media, and it has been confirmed that G protein-coupled estrogen receptor (GPER) was involved in the estrogenic activity of TPP. Therefore, it is necessary to link the estrogen-interfering effects and possible mechanisms of action of TPP with the molecular initiation event (MIE) to improve its adverse outcome pathway framework. In this study, transcriptomic and proteomic methods were used to analyze the estrogen interference effect of TPP mediated by GPER, and the causal relationship was supplemented by molecular dynamics simulation and fluorescence analysis. The omics results showed that TPP could regulate the response of key GPER signaling factors and the activation of downstream pathways including PI3K-Akt signaling pathway, MAPK signaling pathway, and estrogen signaling pathway. The similar activation effect of TPP and agonist G1 change of GPER was proved by molecular dynamics simulation. After TPP binding, the conformation of GPER will change from the inactive to active state. Therefore, TPP may affect cell proliferation, metastasis, and apoptosis and regulate gene transcription and kinase activity, leading to abnormal immune function and other estrogen-dependent cell processes and cancer through GPER, ultimately causing the estrogen interference effect.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article