Journal article
Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice
Chemical research in toxicology, Vol.36(8), pp.1386-1397
07/19/2023
DOI: 10.1021/acs.chemrestox.3c00128
PMCID: PMC10445290
PMID: 37467352
Appears in UI Libraries Support Open Access
Abstract
Polychlorinated biphenyls (PCBs) are environmental contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. Adipose tissue levels were significantly higher in wild-type (WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice. We also observed genotype-dependent differences in the enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were significantly lower in KI than in WT mice in blood and the liver, while the opposite trend was observed in female mice. In conclusion, the study highlights the differences in the atropselective disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.
Details
- Title: Subtitle
- Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice
- Creators
- Xueshu Li - University of IowaAmanda J Bullert - University of IowaWeiguo Han - University of ArizonaWeizhu Yang - University of ArizonaQing-Yu Zhang - University of ArizonaXinxin Ding - University of ArizonaHans-Joachim Lehmler - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.36(8), pp.1386-1397
- DOI
- 10.1021/acs.chemrestox.3c00128
- PMID
- 37467352
- PMCID
- PMC10445290
- NLM abbreviation
- Chem Res Toxicol
- eISSN
- 1520-5010
- Publisher
- American Chemical Society
- Grant note
- DOI: 10.13039/100000066, name: National Institute of Environmental Health Sciences, award: P30 ES005605, P30 ES006694, P42 ES013661, R01 ES014901, R01 ES020867, R01 ES031098, R21 ES027169
- Language
- English
- Date published
- 07/19/2023
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984445526502771
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