Journal article
Toxicokinetics of Chiral PCB 136 and Its Hydroxylated Metabolites in Mice with a Liver-Specific Deletion of Cytochrome P450 Reductase
Chemical research in toxicology, Vol.32(4), pp.727-736
04/15/2019
DOI: 10.1021/acs.chemrestox.8b00389
PMCID: PMC6465157
PMID: 30729780
Abstract
Exposure to polychlorinated biphenyls (PCBs) has been implicated in adverse human health effects, including developmental neurotoxicity. Several neurotoxic PCBs are chiral and undergo atropisomeric enrichment in vivo due to atropselective metabolism by cytochrome P450 enzymes. Here we study how the liver-specific deletion of the cytochrome P450 reductase ( cpr) gene alters the toxicokinetics of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice. Male and female mice with a liver-specific deletion of cpr (KO) and congenic wild-type (WT) mice were exposed to a single oral dose of racemic PCB 136 (6.63 mg/kg). Levels and chiral signatures of PCB 136 and its hydroxylated metabolites were determined 1-48 h after PCB exposure in whole blood. Blood levels of PCB 136 were typically higher in M-WT compared to F-WT mice. At the later time points, F-KO mice had significantly higher PCB 136 levels than F-WT mice. 2,2',3',4,6,6'-Hexachlorobiphenyl-3-ol (3-150), 2,2',3,3',6,6'-hexachlorobiphenyl-4-ol (4-136), 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol (5-136), and 4,5-dihydroxy-2,2',3,3',6,6'-hexachlorobiphenyl (4,5-136) were detected in blood, with 5-136 and 4-136 being major metabolites. At later time points, the sum of HO-PCB (∑HO-PCB) levels exceeded PCB 136 levels in the blood; however, higher ∑HO-PCB than PCB 136 levels were observed later in KO than WT mice. PCB 136 and its major metabolites displayed atropisomeric enrichment in a manner that depended on the time point, sex, and genotype. Toxicokinetic analysis revealed sex and genotype-dependent differences in toxicokinetic parameters for PCB 136 atropisomers and its metabolites. The results suggest that mice with a liver-specific deletion of the cpr gene can potentially be used to assess how an altered metabolism of neurotoxic PCB congeners affects neurotoxic outcomes following exposure of the offspring to PCBs via the maternal diet.
Details
- Title: Subtitle
- Toxicokinetics of Chiral PCB 136 and Its Hydroxylated Metabolites in Mice with a Liver-Specific Deletion of Cytochrome P450 Reductase
- Creators
- Xueshu Li - Department of Occupational and Environmental Health, College of Public Health , University of Iowa , Iowa City , Iowa 52242 , United StatesXianai Wu - Department of Occupational and Environmental Health, College of Public Health , University of Iowa , Iowa City , Iowa 52242 , United StatesKevin M Kelly - Department of Occupational and Environmental Health, College of Public Health , University of Iowa , Iowa City , Iowa 52242 , United StatesPeter Veng-Pedersen - College of Pharmacy , University of Iowa , Iowa City , Iowa 52242 , United StatesHans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health , University of Iowa , Iowa City , Iowa 52242 , United States
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.32(4), pp.727-736
- DOI
- 10.1021/acs.chemrestox.8b00389
- PMID
- 30729780
- PMCID
- PMC6465157
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS P30 ES006694 / NIEHS NIH HHS P42 ES013661 / NIEHS NIH HHS R21 ES027169 / NIEHS NIH HHS
- Language
- English
- Date published
- 04/15/2019
- Academic Unit
- Anthropology; Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program
- Record Identifier
- 9984001080502771
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