Journal article
Elucidating the Metabolism of Chiral PCB95 in Wildtype and Transgenic Mouse Models with Altered Cytochrome P450 Enzymes Using Intestinal Content Screening
Chemical research in toxicology, Vol.37(12), pp.1989-2002
12/16/2024
DOI: 10.1021/acs.chemrestox.4c00350
PMCID: PMC11653397
PMID: 39561283
Appears in UI Libraries Support Open Access
Abstract
Polychlorinated biphenyls (PCBs), such as 2,2′,3,5′,6-pentachlorobiphenyl (PCB95), are persistent organic pollutants associated with adverse health outcomes, including developmental neurotoxicity. PCB95 is a chiral neurotoxic PCB congener atropselectively metabolized to potentially neurotoxic metabolites in vivo. However, the metabolic pathways of most PCB congeners, including PCB95, remain unknown. To address this knowledge gap, we analyzed the intestinal contents of mice exposed to PCB95 to elucidate the PCB95 metabolism pathway and assess if genetic manipulation of hepatic drug-metabolizing enzymes affects PCB95 metabolism. Our study exposed male and female wildtype (WT), Cyp2abfgs-null (KO), and CYP2A6-transgenic/Cyp2abfgs-null (KI) mice orally to 1.0 mg/kg body weight of PCB95. Intestinal content was collected 24 h after PCB administration. aS-PCB95 was enriched in all intestinal content samples, irrespective of sex and genotype. Gas chromatography–tandem mass spectrometry (GC–MS/MS) analyses identified 5 mono- (OH-PCB95) and 4 dihydroxylated PCB (diOH-PCB95) metabolites. Liquid chromatography–high-resolution mass spectrometry (LC–HRMS) identified 15 polar hydroxylated, methoxylated, and sulfated PCB95 metabolites, including 3 dechlorinated metabolites. A sex difference in the relative OH-PCB95 levels was observed only for KO in the LC–HRMS analysis. Genotype-dependent differences were observed for female, but not male, mice, with OH-PCB95 levels in female KO (FKO) mice tending to be lower than those in female WT (FWT) and KI (FKI) mice. Based on the GC–MS/MS analysis, these differences are due to the unknown PCB95 metabolites, X1-95 and Y1-95. These findings demonstrate that combining GC–MS/MS analyses and LC–HRMS subject screening of the intestinal content of PCB95-exposed mice can significantly advance our understanding of PCB95 metabolism in vivo.
Details
- Title: Subtitle
- Elucidating the Metabolism of Chiral PCB95 in Wildtype and Transgenic Mouse Models with Altered Cytochrome P450 Enzymes Using Intestinal Content Screening
- Creators
- Xueshu Li - University of IowaAmanda J. Bullert - University of IowaBinita Gautam - University of IowaWeiguo Han - University of ArizonaWeizhu Yang - University of ArizonaQing-Yu Zhang - University of ArizonaXinxin Ding - University of ArizonaHans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242, United States, Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242, United States
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.37(12), pp.1989-2002
- DOI
- 10.1021/acs.chemrestox.4c00350
- PMID
- 39561283
- PMCID
- PMC11653397
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Publisher
- American Chemical Society
- Grant note
- National Institute of Environmental Health Sciences, National Institutes of Health: R01 ES014901, R21 ES027169, R01 ES031098 Environmental Health Sciences Research Center: P30 ES005605 Iowa Superfund Research Program: P43 ES013661 Southwest Environmental Health Sciences Research Center: P30 ES006694
This work was supported by grants R01 ES014901, R21 ES027169, and R01 ES031098 from the National Institute of Environmental Health Sciences, National Institutes of Health. In addition, the Environmental Health Sciences Research Center (P30 ES005605) and the Iowa Superfund Research Program (P43 ES013661) supported the authentication of the test compounds and the analytical work. Dr. Weiguo Han was supported in part by the Southwest Environmental Health Sciences Research Center (P30 ES006694). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health.
- Language
- English
- Electronic publication date
- 11/19/2024
- Date published
- 12/16/2024
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984749835002771
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