6PPD and 6PPD Quinone Induce Endometrial Cell Dysfunction via Activating ERα and GPER at Human-Relevant Levels

Area of Science:

• Environmental Science
• Toxicology
• Endocrinology

Background:

• Widespread environmental presence of 6PPD and 6PPD-Q from tires raises health concerns.
• Endometrial cell dysfunction is a potential risk associated with these environmental contaminants.

Purpose of the Study:

• Investigate the effects of 6PPD and 6PPD-Q on endometrial cells.
• Elucidate the roles of estrogen receptor (ER) and G-protein-coupled estrogen receptor (GPER) signaling pathways in 6PPD/6PPD-Q-induced endometrial dysfunction.

Main Methods:

• Fluorescence competitive binding and reporter gene assays to assess ER binding and transcriptional activity.
• Calcium mobilization assays to evaluate GPER activation.
• Molecular dynamics simulations to understand differential activation potency.
• Analysis of cell proliferation, migration, and inflammatory markers.

Main Results:

• 6PPD and 6PPD-Q selectively bind and activate ERα (LOEC 500 nM and 10 nM, respectively).
• Both compounds activate GPER signaling (LOEC 1 nM) and 6PPD-Q shows higher potency.
• Endometrial cell proliferation, migration, and inflammation are stimulated via ERα/GPER pathways at nanomolar concentrations.

Conclusions:

• 6PPD and 6PPD-Q induce endometrial cell dysfunction through ERα and GPER activation.
• These effects, including proliferation and migration, occur at environmentally relevant nanomolar concentrations.
• The findings highlight potential reproductive health risks associated with tire-derived contaminants.