Subacute exposure of male adolescent rats to 2,2′,5,5′-tetrachlorobiphenyl-4-ol via a polymeric implant causes gene expression changes in the brain and metabolomic disruption in serum

Polychlorinated biphenyls (PCBs) remain an environmental health concern due to their persistence and ongoing release from legacy and emerging sources. 2,2′,5,5′-Tetrachlorobiphenyl (PCB52), a PCB congener frequently detected in the environment and human blood, is oxidized to 2,2′,5,5′-tetrachlorobiphenyl-4-ol (4−52). The neurotoxicity of this hydroxylated (OH-PCB) metabolite remains poorly characterized. In this study, we exposed 4-week-old male Sprague Dawley rats to 4–52 via a polymeric implant drug delivery system grafted in the subcutaneous cavity at 4–52 concentrations of 0 %, 1 %, 5 %, and 10 % in the implant (w/w) for 28 days. Metabolomic analyses were performed in the serum. RNA sequencing, immunofluorescence, and dopamine (DA) measurement with electrochemical detection were used to characterize the effects of 4–52 on the striatum and cerebellum, brain regions implicated in PCB neurotoxicity. Serum metabolomic analysis revealed disruptions in the "arginine biosynthesis" pathway following 4–52 exposure. Exposure to 4–52 caused moderate transcriptomic changes in pathways related to "oxidative phosphorylation" and "neuroactive ligand-receptor interactions." Immunofluorescence showed no significant alterations in microglial, astrocytic, or apoptotic biomarkers. In the medium dose group, the levels of the DA metabolite DOPAL (3,4-dihydroxyphenylacetaldehyde) were significantly reduced in the striatum. Subsequent multi-omics network analysis identified interactions among OH-PCBs, endogenous metabolites, and the transcriptome. For example, levels of glutamic acid, aspartic acid, choline, and glycerophosphocholine negatively correlated with 4–52 in the striatum. Expression levels of heat shock protein (HSP) family genes, Hsp90b1, Hspa8, and Hspa5, positively correlated with serum metabolites, including proline, 1-methylguanidine, and methionine sulfoxide. These findings identify novel biomarkers and targets of 4–52-induced neurotoxicity.