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      Disposition and Metabolomic Effects of 2,2’,5,5’-Tetrachlorobiphenyl in Female Rats Following Intraperitoneal Exposure

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          Abstract

          The disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100 mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100 mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies.

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis

            Abstract We present a new update to MetaboAnalyst (version 4.0) for comprehensive metabolomic data analysis, interpretation, and integration with other omics data. Since the last major update in 2015, MetaboAnalyst has continued to evolve based on user feedback and technological advancements in the field. For this year's update, four new key features have been added to MetaboAnalyst 4.0, including: (1) real-time R command tracking and display coupled with the release of a companion MetaboAnalystR package; (2) a MS Peaks to Pathways module for prediction of pathway activity from untargeted mass spectral data using the mummichog algorithm; (3) a Biomarker Meta-analysis module for robust biomarker identification through the combination of multiple metabolomic datasets and (4) a Network Explorer module for integrative analysis of metabolomics, metagenomics, and/or transcriptomics data. The user interface of MetaboAnalyst 4.0 has been reengineered to provide a more modern look and feel, as well as to give more space and flexibility to introduce new functions. The underlying knowledgebases (compound libraries, metabolite sets, and metabolic pathways) have also been updated based on the latest data from the Human Metabolome Database (HMDB). A Docker image of MetaboAnalyst is also available to facilitate download and local installation of MetaboAnalyst. MetaboAnalyst 4.0 is freely available at http://metaboanalyst.ca.
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              Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies?

              Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to master, quick, suitable for chronic treatments and with low impact of stress on laboratory rodents, there is a common concern that it may not be an acceptable route for drug administration in experimental studies. The latter is likely due to sparsity of information regarding pharmacokinetics of pharmacological agents and the mechanisms through which agents get systemic exposure after IP administration. In this review, we summarize the main mechanisms involved in bioavailability of IP administered drugs and provide examples of pharmacokinetic profiles for small and large molecules in comparison to other routes of administration. We conclude with a notion that IP administration of drugs in experimental studies involving rodents is a justifiable route for pharmacological and proof-of-concept studies where the goal is to evaluate the effect(s) of target engagement rather than properties of a drug formulation and/or its pharmacokinetics for clinical translation.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Roles/Writing - original draftRole: Writing - review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing - review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Roles/Writing - original draftRole: Writing - review & editing
                Journal
                bioRxiv
                BIORXIV
                bioRxiv
                Cold Spring Harbor Laboratory
                09 August 2023
                : 2023.06.19.544952
                Affiliations
                [a ]Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
                [b ]Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA
                [c ]Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
                [d ]Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, IA 52242, USA
                [e ]Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
                Author notes
                Corresponding Author: Dr. Hans-Joachim Lehmler, The University of Iowa, Department of Occupational and Environmental Health, University of Iowa Research Park, #221 IREH, Iowa City, IA 52242-5000, Phone: (319) 335-4981, Fax: (319) 335-4290, hans-joachim-lehmler@ 123456uiowa.edu
                Article
                10.1101/2023.06.19.544952
                10441371
                37609242
                db29c14e-eed8-47fa-b103-e07ef8936a73

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.

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                Funding
                Funded by: National Institute of Environmental Health Sciences/National Institutes of Health
                Award ID: R01ES014901
                Award ID: R01ES031098
                Award ID: P30ES005605
                Award ID: P42ES013661
                Categories
                Article

                disposition,dose-response,hydroxylated metabolites,polychlorinated biphenyls,pcb 52

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