Estrogenic Activity of Structurally Distinct PFASs Through Estrogen Receptor Pathway

Area of Science:

• Environmental Chemistry
• Toxicology
• Endocrinology

Background:

• The Stockholm Convention mandates phasing out certain per- and polyfluoroalkyl substances (PFASs) like PFOA, PFOS, and PFHxS.
• Rising environmental presence of other PFASs necessitates understanding their toxicological profiles.
• The estrogenic effects and mechanisms of diverse PFASs remain largely uncharacterized.

Purpose of the Study:

• To investigate and compare the estrogenic activities of eight typical PFASs.
• To elucidate the underlying molecular mechanisms of PFAS-induced estrogenicity.
• To assess the role of the estrogen receptor (ER) in mediating PFAS effects.

Main Methods:

• MCF-7 cell proliferation assays to evaluate estrogenic effects.
• Estrogen receptor (ER) antagonist treatment to confirm ER involvement.
• Luciferase reporter gene assays and fluorescence competitive binding assays to assess ER activation and binding.
• Molecular docking simulations to predict binding affinities with ER.

Main Results:

• Four PFASs (PFOA, PFOS, PFHxS, and PFOSA) promoted MCF-7 cell proliferation, indicating estrogenic activity.
• Perfluorooctane sulfonamide (PFOSA) demonstrated the most potent estrogenic effect among the tested compounds.
• PFOSA, PFOS, and PFOA showed decreasing estrogenic activity, correlating with their functional groups (sulfonamide > sulfonic acid > carboxylic acid).
• PFASs directly bind to and activate the estrogen receptor (ER), confirmed by multiple assays and molecular docking.

Conclusions:

• Various PFASs exert estrogenic effects through ER-mediated pathways.
• Receptor binding affinity is a critical factor influencing the estrogenic potency of PFASs.
• PFOS precursors and other structurally diverse PFASs warrant increased attention for environmental risk assessment due to their estrogenic potential.