Environmental Health Risk Assessment of Dynamic Lipid Metabolism in PCB-118-Induced Insulin Resistance Models Using a Polarity-Ultrasensitive Fluorescent Probe

As environmental hazardous persistent organic pollutants (POPs), polychlorinated biphenyls (PCBs) disrupt lipid metabolism and promote insulin resistance (IR). However, tools for dynamically monitoring their metabolic effects are limited. Herein, we developed a lipid droplet (LD)-targeted fluorescent probe <b>LD-DCDSB</b>, featuring a rationally designed donor-acceptor-donor (D-A-D) structure with an electron transfer (ET) effect. The probe exhibits a large Stokes shift (158 nm), good photostability, and high sensitivity to polarity parameter Δ<i>f</i> (0.0206 to 0.265), enabling precise tracking of LDs across various cell types. The polarity-sensitive emission characteristics allow determination of the LDs polarity. Systematic studies demonstrated that adipocytes (3T3-L1) exhibit lower LD polarity compared with cancer cells (4T1, A549, and HepG2) and normal cells (HK-2, HTERT, and HUVEC). In PCB-118-induced IR, <b>LD-DCDSB</b> revealed pathological LD hypertrophy, increased LD numbers, and reduced cellular polarity, which were reversible with metformin or Fsp27 siRNA. Mechanistic studies linked PCB-118 to ROS-mediated apoptosis, contributing to PCB-118-induced metabolic dysfunction. Additionally, the probe visualized IR progression <i>in vivo</i>, showing specific fluorescence increases that were rescued by metformin. This work bridges environmental toxicology and metabolic diagnostics, elucidating PCB-118's role in LD dysfunction and providing a platform for assessing pollutant risks and therapeutic interventions.