PCBs exposure and renal injury: comprehensive assessment strategy based upon TRAEC strategy.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants characterized by their significant bioaccumulation and presence in various organ tissues. However, there remains a lack of systematic assessment regarding the link between PCB exposure and renal injury, leading to limited public understanding of their overall environmental risks. To address this, we used the Targeted Risk Assessment of Environmental Chemicals (TRAEC) framework. While existing studies mainly focus on acute renal injury caused by high-dose PCB exposure, we modeled an environmentally relevant scenario by chronically treating C57BL/6J mice with PCB138 (100 μg/kg every other day for 48 weeks). Environmentally relevant PCB138 exposure caused severe pathological renal injury. Mechanistically, we confirmed that PCB138 exerts its nephrotoxic effects by activating aryl hydrocarbon receptor (AhR) nuclear translocation, which further transcriptionally upregulates its canonical target gene Cyp1a1 and triggers downstream signaling cascades. Upon PCB138 exposure, renal cells initially undergo intrinsic apoptosis via a Bax/Bcl-2 imbalance, which then activates the NF-κB pathway to provoke inflammation and ultimately drives renal fibrosis through the TGF-β/Smad signaling pathway. By systematically integrating published research and our primary data, the TRAEC-based assessment for PCBs yielded a composite evidence score of 6.79, indicating a moderate to high risk of renal injury. Additionally, following PCB exposure, mice received daily administration of 225 mg/kg theabrownin (TB), a black tea-derived bioactive compound, over an 8-week treatment course. TB treatment significantly reduced PCB138-induced renal apoptosis, inflammation, and fibrosis. Overall, our study establishes an environmentally relevant framework for evaluating PCB renal toxicity, clarifies how PCBs activate AhR and the sequence of downstream pathway activation, and provides a solid rationale for TB as a promising therapeutic candidate.