Single-cell transcriptomics showed that maternal polychlorinated biphenyl exposure dysregulated cell type-specific...

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that bioaccumulate in the food chain and readily cross the placenta, raising concerns for developmental toxicity. Although PCB exposure has been associated with metabolic and neurodevelopmental disorders, its cell type-specific effects on liver development remain poorly understood. This study aimed to investigate how maternal exposure to an environmentally relevant Fox River PCB mixture affects liver development in female offspring at single-cell resolution. We hypothesized that developmental PCB exposure disrupts hepatic metabolic and immune function in a cell-type-specific manner. Using single-cell RNA sequencing on liver tissue from postnatal day 28 female mice exposed to PCBs throughout gestation and lactation, we identified major hepatic and immune cell populations and assessed cell-specific transcriptional responses. PCB exposure significantly altered the proportions of endothelial cells and Kupffer cells and reduced neutrophil abundance in the liver. Transcriptomic analysis revealed that PCBs dysregulated key functional pathways in hepatocytes and nonparenchymal cells, including endoplasmic reticulum stress responses, drug metabolism, and glucose/insulin signaling. Notably, hepatocytes exhibited upregulation of phase I drug-metabolizing enzymes and uptake transporters, but downregulation of phase II enzymes and efflux transporters. Kupffer cells and endothelial cells exhibited altered immune and metabolic gene expression, and intercellular communication analysis predicted that PCB exposure disrupted fibronectin, collagen, and chemokine signaling. Reverse transcription-quantitative polymerase chain reaction validation confirmed increased expression of hepatic endoplasmic reticulum stress markers. Together, these findings demonstrate that developmental PCB exposure induces persistent, cell-type-specific transcriptomic reprogramming in the liver, impairing metabolic and immune functions. This study highlights the utility of single-cell transcriptomics for revealing toxicant effects with cellular precision during critical windows of development. SIGNIFICANCE STATEMENT: Our findings showed that developmental exposure to a persistent organic pollutant led to transcriptomic changes that differed across cell types that form the liver. Our study highlights the use of single cell technology to investigate toxic effects for mechanistic insights with greater precision.