Pulmonary Proteomic Responses to Subacute 2,2′,5,5′-Tetrachlorobiphenyl-4-ol Exposure via a Subcutaneous Implant in Adolescent Female Rats

Hydroxylated polychlorinated biphenyls (OH-PCBs) are biologically active metabolites that may contribute to adverse respiratory outcomes, yet their effects on the developing lung remain poorly characterized. This study investigated the impact of 2,2′,5,5′-tetrachlorobiphenyl-4-ol (4-OH-PCB52), a human-relevant metabolite, on the pulmonary molecular pathways in postnatal day 28 female adolescent rats using a multi-omics approach. Animals were exposed to 4-OH-PCB52 (sham; low 1%; medium 5%; high 10%; (w/w)) via a subcutaneous implant release system for 28 days. Targeted analysis by gas chromatography–tandem mass spectrometry (GC-MS/MS) detected 4-OH-PCB52 in the medium 5% and high 10% exposure dose groups. At both higher doses, proteomic profiling revealed significant alterations in protein markers related to pulmonary post-transcriptional regulation, metabolism and chemical biotransformation, immunity and inflammation, oxidative stress and programmed cell death, and surfactant production and mucociliary clearance. In contrast, RNA sequencing did not identify differentially expressed genes. Collectively, these findings demonstrate that adolescent exposure to 4-OH-PCB52 perturbs key molecular markers associated with lung homeostasis, with potential implications for altered lung development and increased susceptibility to respiratory disorders during adulthood.