Lim, J. J.; Suh, Y.; Li, X.; Wilson, R.; Lehmler, H.-J.; Lein, P. J.; Cui, J. Y.

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that bioaccumulate in the food chain and readily cross the placenta, raising concerns for developmental toxicity. While 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 early-life PCB exposure disrupts hepatic metabolic and immune function in a cell type-specific manner. Using single-cell RNA sequencing (scRNA-seq) on liver tissue from postnatal day 28 female mice perinatally exposed to PCBs, 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. Transcriptomic analysis revealed that PCBs dysregulated key pathways in hepatocytes and non-parenchymal cells, including ER 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 had altered immune and metabolic gene expression, and intercellular communication analysis predicted disrupted fibronectin, collagen, and chemokine signaling due to PCB exposure. RT-qPCR validation confirmed increased hepatic ER stress marker expression. Together these findings demonstrate that perinatal 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.