Summary of Study ST003529

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001717. The data can be accessed directly via it's Project DOI: 10.21228/M8RX4J This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Perform statistical analysis  |  Show all samples  |  Show named metabolites  |  Download named metabolite data  
Download mwTab file (text)   |  Download mwTab file(JSON)   |  Download data files (Contains raw data)
Study IDST003529
Study TitleMeasurement of itaconic acid in liver of male mice treated with TCDD
Study Typechromatograms
Study SummaryIn this study, we tested the hypothesis that the dose-dependent disruption of propionyl-CoA metabolism produces toxic intermediates that contribute to TCDD hepatotoxicity and progression of steatosis to steatohepatitis with fibrosis. Our results suggest TCDD dose-dependently reduced cobalamin (Cbl aka vitamin B12) levels compromising methylmalonyl-CoA mutase (MUT) activity and limiting the metabolism of propionyl-CoA to succinyl-CoA using the canonical Cbl-dependent carboxylation pathway. More recently, lower Cbl levels have been linked to itaconate, a cis-aconitate metabolite produced in large quantities by activated macrophages. In the current study, targeted metabolomics analysis of hepatic extracts detected a dose-dependent increase in itaconic acid. Itaconate can be activated to itaconyl-CoA which can then interact with the 5-deoxyadenosyl moiety of AdoCbl to form an uncharacterized adduct that disrupts auxiliary repair protein interactions, inactivates AdoCbl, and reduces Cbl levels that inhibit MUT activity.
Institute
Michigan State University
DepartmentBiochemistry and Molecular Biology
Last NameZacharewski
First NameTimothy
Address48824:East Lansing
Emailtzachare@msu.edu
Phone517-884-2054
Submit Date2023-07-27
Num Groups5
Total Subjects20
Num Males20
Raw Data AvailableYes
Raw Data File Type(s)mzML, raw(Waters)
Analysis Type DetailLC-MS
Release Date2024-11-04
Release Version1
Timothy Zacharewski Timothy Zacharewski
https://dx.doi.org/10.21228/M8RX4J
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001717
Project DOI:doi: 10.21228/M8RX4J
Project Title:Prj171_Mm_TCDD_RDDR-28D_Male
Project Type:targeted metabolomics
Project Summary:The aryl hydrocarbon receptor (AhR) is a transcription factor activated by structurally diverse chemicals, endogenous metabolites, and natural products. AhR activation causes the dissociation of chaperone proteins, followed by translocation to the nucleus and dimerization with the AhR nuclear translocator (ARNT). The complex binds dioxin response elements (DREs; 5’-GCGTG-3’) eliciting changes in gene expression. AhR activation by its most potent ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promotes the development and progression of non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of pathologies that spans simple, reversible, and benign lipid accumulation (hepatic steatosis), to steatosis with inflammation (steatohepatitis) and collagen deposition (fibrosis/cirrhosis) in the absence of excessive alcohol consumption. NAFLD prevalence is projected to increase from ~83 million in 2015 to ~101 million by 2030 in the US alone, while increasing the risk for more complex disorders including Metabolic Syndrome, cardiovascular disease, diabetes, cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). The role of AhR-mediated metabolic dysregulation in hepatotoxicity and the etiology of more complex metabolic diseases warrants further investigation. Therofore, in this project on PND28 mice were orally gavaged at the start of the light cycle (zeitgeber [ZT] 0-1) with 0.1 ml sesame oil vehicle or 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 30 ug/kg body weight TCDD every 4 days for 28 days for a total of 7 treatments. The first gavage was administered on day 0, with the last gavage administered on day 24 of the 28-day study. On day 28, tissue samples were harvested (ZT 0-3), immediately flash frozen in liquid nitrogen and stored at -80°C until analysis.
Institute:Michigan State University
Department:Biochemistry and Molecular Biology
Last Name:Zacharewski
First Name:Timothy
Address:48824:East Lansing
Email:tzachare@msu.edu
Phone:517-884-2054
Funding Source:NIEHS; Superfund Basic Research Program R01ES029541:P42ES004911

Subject:

Subject ID:SU003658
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Age Or Age Range:56
Gender:male
Animal Animal Supplier:Charles Rivers Laboratories
Animal Housing:cage_type: Innovive Innocage; bedding_type: ALPHA-dri
Animal Light Cycle:12:12
Animal Feed:Harlan Teklad 8940
Animal Water:Innovive
Species Group:Mammal

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source dose_group
SA387294XS_082721_012Liver 0.0 microgram per kilogram
SA387295XS_082721_011Liver 0.0 microgram per kilogram
SA387296XS_082721_013Liver 0.0 microgram per kilogram
SA387297XS_082721_010Liver 0.0 microgram per kilogram
SA387302XS_082721_023Liver 10.0 microgram per kilogram
SA387303XS_082721_025Liver 10.0 microgram per kilogram
SA387304XS_082721_024Liver 10.0 microgram per kilogram
SA387305XS_082721_022Liver 10.0 microgram per kilogram
SA387298XS_082721_015Liver 1.0 microgram per kilogram
SA387299XS_082721_016Liver 1.0 microgram per kilogram
SA387300XS_082721_017Liver 1.0 microgram per kilogram
SA387301XS_082721_014Liver 1.0 microgram per kilogram
SA387310XS_082721_027Liver 30.0 microgram per kilogram
SA387311XS_082721_028Liver 30.0 microgram per kilogram
SA387312XS_082721_029Liver 30.0 microgram per kilogram
SA387313XS_082721_026Liver 30.0 microgram per kilogram
SA387306XS_082721_019Liver 3.0 microgram per kilogram
SA387307XS_082721_020Liver 3.0 microgram per kilogram
SA387308XS_082721_018Liver 3.0 microgram per kilogram
SA387309XS_082721_021Liver 3.0 microgram per kilogram
Showing results 1 to 20 of 20

Collection:

Collection ID:CO003651
Collection Summary:Tissue was carefully excised and immediately frozen in liquid nitrogen.
Sample Type:Liver
Storage Conditions:Snap Frozen
Storage Vials:2 mL screwcap tube

Treatment:

Treatment ID:TR003667
Treatment Summary:Mice were orally gavaged with 0.1 mL of the test article in vehicle to achieve the expected dosage every 4 days for 28 days for a total of 7 administrations.
Treatment Compound:DTXSID2021315: TCDD
Treatment Route:Oral Gavage Route of Administration
Treatment Dose:['0.0', '0.01', '0.03', '0.1', '0.3', '1.0', '10.0', '3.0', '30.0']
Treatment Dosevolume:0.1 mL
Treatment Vehicle:DTXSID9033971: Sesame Oil
Animal Fasting:ad libitum
Animal Endp Euthanasia:Carbon dioxide asphyxiation
Animal Endp Tissue Coll List:Liver

Sample Preparation:

Sampleprep ID:SP003665
Sampleprep Summary:Frozen liver samples (40 mg) were homogenized (Polytron PT2100, Kinematica) in acetonitrile:water ratio 8:2, vortexed, shaken for 5 min at 4 C, and centrifuged at maximum speed (3000 x g). Supernatant was dried under nitrogen and dried extracts were reconstituted in 200 microliters of a 1:9 methanol:water solution containing 2% formic acid.
Processing Storage Conditions:-80C

Combined analysis:

Analysis ID AN005797
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column Waters ACQUITY UPLC HSS T3 (100 x 2.1mm,1.8um)
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name Waters Xevo-TQ-S
Ion Mode NEGATIVE
Units normalized peak area

Chromatography:

Chromatography ID:CH004402
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC HSS T3 (100 x 2.1mm,1.8um)
Column Temperature:-
Flow Gradient:0 min - 100% A, 1.0 min - 100% A, 2.0 min - 80% A, 4.0 min - 1% A, 5.0 min - 1% A, 5.01 min - 100% A, 7.0 min - 100% A
Flow Rate:0.3 ml/minute
Solvent A:100% water; 0.1% formic acid
Solvent B:100% acetonitrile; 0.1% formic acid
Chromatography Type:Reversed phase

MS:

MS ID:MS005517
Analysis ID:AN005797
Instrument Name:Waters Xevo-TQ-S
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:protocol
Ion Mode:NEGATIVE
  logo