Journal article
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
Toxicology (Amsterdam), Vol.514, 154120
06/2025
DOI: 10.1016/j.tox.2025.154120
PMCID: PMC11994288
PMID: 40097135
Abstract
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.
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•2,2′,5,5′-Tetrachlorobiphenyl-4-ol (4−52) affected the brain transcriptome•4-52 disrupted the serum metabolome, including arginine biosynthesis•4-52 altered dopamine metabolism in the striatum in a dose-dependent manner•Network analysis identified novel targets and biomarkers of 4-52 exposure
Details
- Title: Subtitle
- 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
- Creators
- Hui Wang - University of IowaAmanda J. Bullert - University of IowaMorgan J. Linahon - University of IowaMichael E. Dailey - University of IowaJonathan A. Doorn - University of IowaAloysius J. Klingelhutz - University of IowaJames A. Ankrum - University of IowaHans-Joachim Lehmler - Department of Occupational and Environmental Health, the University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Toxicology (Amsterdam), Vol.514, 154120
- DOI
- 10.1016/j.tox.2025.154120
- PMID
- 40097135
- PMCID
- PMC11994288
- NLM abbreviation
- Toxicology
- ISSN
- 0300-483X
- eISSN
- 1879-3185
- Publisher
- Elsevier B.V
- Grant note
- Iowa Superfund Research Program: NIH P42 ES013661 Environmental Health Sciences Research Center: NIH P30 ES005605
This research was funded by the Iowa Superfund Research Program (grant NIH P42 ES013661) and conducted in laboratory facilities supported by the Environmental Health Sciences Research Center (grant NIH P30 ES005605). The content is solely the responsibility of the au-thors and does not necessarily represent the official views of the Na-tional Institute of Environmental Health Sciences or the National Institutes of Health.
- Language
- English
- Electronic publication date
- 03/15/2025
- Date published
- 06/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Public Health Administration; Microbiology and Immunology; Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Biology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Iowa Superfund Research Program; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984801890302771
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