Use of Tox21 screening data to profile PFAS bioactivities on nuclear receptors, cellular stress pathways, and cytochrome p450 enzymes.
J Hazard Mater
; 473: 134642, 2024 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-38776814
ABSTRACT
Per- and poly-fluoroalkyl substances (PFAS) are synthetic chemicals widely used in commercial products. PFAS are a global concern due to their persistence in the environment and extensive associations with adverse health outcomes. While legacy PFAS have been extensively studied, many non-legacy PFAS lack sufficient toxicity information. In this study, we first analyzed the bioactivity of PFAS using Tox21 screening data surveying more than 75 assay endpoints (e.g., nuclear receptors, stress response, and metabolism) to understand the toxicity of non-legacy PFAS and investigate potential new targets of PFAS. From the Tox21 screening data analysis, we confirmed several known PFAS targets/pathways and identified several potential novel targets/pathways of PFAS. To confirm the effect of PFAS on these novel targets/pathways, we conducted several cell- and enzyme-based assays in the follow-up studies. We found PFAS inhibited cytochromes P450s (CYPs), especially CYP2C9 with IC50 values of < 1 µM. Considering PFAS affected other targets/pathways at > 10 µM, PFAS have a higher affinity to CYP2C9. This PFAS-CYP2C9 interaction was further investigated using molecular docking analysis. The result suggested that PFAS directly bind to the active sites of CYP2C9. These findings have important implications to understand the mechanism of PFAS action and toxicity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Cytoplasmic and Nuclear
/
Cytochrome P-450 Enzyme System
/
Fluorocarbons
Limits:
Humans
Language:
En
Journal:
J Hazard Mater
Year:
2024
Document type:
Article