Summary of Study ST003339

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 PR002076. The data can be accessed directly via it's Project DOI: 10.21228/M88G1K 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.

Study ID	ST003339
Study Title	DINCH and MINCH reach adipose and liver tissues and levels are partially retained during recovery period
Study Summary	This study focused on determining the concentrations of DINCH, MINCH, and secondary metabolites in adipose tissue depots following treatment and recovery, using targeted metabolomics. Additionally, these concentrations were measured in the liver, the primary organ for biotransformation. Analysis of DINCH, MINCH, and secondary metabolite concentrations revealed significant variability both between and within individual tissues in males and females. Post-treatment, DINCH was present in all examined tissues, with the highest concentrations found compared to its metabolites. Among the metabolites, MINCH and OH-MINCH were predominant in the liver, while MINCH was the sole metabolite detected in adipose tissue. Following the recovery period, all DINCH metabolites were reduced to trace levels. Notably, there was a significant reduction of DINCH concentrations in the liver and brown adipose tissue (BAT), but no reduction in visceral adipose tissue (VIS AT) and subcutaneous adipose tissue (SC AT).
Institute	Helmholtz Centre for Environmental Research
Last Name	Engelmann
First Name	Beatrice
Address	Permoserstr. 15, 04299 Leipzig
Email	beatrice.engelmann@ufz.de
Phone	004934160251099
Submit Date	2024-07-17
Raw Data Available	Yes
Raw Data File Type(s)	wiff
Analysis Type Detail	LC-MS
Release Date	2024-08-12
Release Version	1

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Project:

Project ID:	PR002076
Project DOI:	doi: 10.21228/M88G1K
Project Title:	Characterization of Metabolic and Molecular Effects Following Dietary Exposure to the Plasticizer DINCH in vivo
Project Summary:	With the phthalate plasticizer di-(2-ethylhexyl) phthalate (DEHP) being restricted because of its harmful health impacts, it has been replaced by alternatives such as diisononylcyclohexane-1,2-dicarboxylate (DINCH). Although recent research suggests that the main metabolite of DINCH, monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH), promotes adipocyte differentiation in vitro, in vivo studies have not shown changes in body weight, lipid metabolism, or adipogenic effects. However, these studies followed OECD guidelines, which are not specifically designed to detect potential metabolic disruptions in adipose tissue. Therefore, we conducted an in-depth in vivo study using the C57BL/6N mouse model to comprehensively evaluate the physiological and functional impacts of DINCH exposure on adipose tissue, including molecular-level effects.
Institute:	Helmholtz Centre for Environmental Research
Last Name:	Engelmann
First Name:	Beatrice
Address:	Permoserstr. 15, 04299 Leipzig
Email:	beatrice.engelmann@ufz.de
Phone:	004934160251099

Subject:

Subject ID:	SU003460
Subject Type:	Mammal
Subject Species:	Mus musculus
Taxonomy ID:	10090
Genotype Strain:	C57BL/6N
Gender:	Male and female

Factors:

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

mb_sample_id	local_sample_id	Sample source	Treatment	Sex
SA364363	BAT_F_HFD highDINCH_A77	brown adipose tissue	High DINCH Recovery Group	Female
SA364364	BAT_F_HFD highDINCH_A46	brown adipose tissue	High DINCH Recovery Group	Female
SA364365	BAT_F_HFD highDINCH_A45	brown adipose tissue	High DINCH Recovery Group	Female
SA364366	BAT_F_HFD highDINCH_A14	brown adipose tissue	High DINCH Recovery Group	Female
SA364367	BAT_F_HFD highDINCH_A13	brown adipose tissue	High DINCH Recovery Group	Female
SA364368	BAT_F_HFD highDINCH_A78	brown adipose tissue	High DINCH Recovery Group	Female
SA364369	BAT_M_HFD highDINCH_A6	brown adipose tissue	High DINCH Recovery Group	Male
SA364370	BAT_M_HFD highDINCH_A37	brown adipose tissue	High DINCH Recovery Group	Male
SA364371	BAT_M_HFD highDINCH_A8	brown adipose tissue	High DINCH Recovery Group	Male
SA364372	BAT_M_HFD highDINCH_A70	brown adipose tissue	High DINCH Recovery Group	Male
SA364373	BAT_M_HFD highDINCH_A7	brown adipose tissue	High DINCH Recovery Group	Male
SA364374	BAT_M_HFD highDINCH_A69	brown adipose tissue	High DINCH Recovery Group	Male
SA364375	BAT_M_HFD highDINCH_A5	brown adipose tissue	High DINCH Recovery Group	Male
SA364376	BAT_F_HFD_highDINCH_N29	brown adipose tissue	High DINCH Treatment Group	Female
SA364377	BAT_F_HFD_highDINCH_N30	brown adipose tissue	High DINCH Treatment Group	Female
SA364378	BAT_F_HFD_highDINCH_N31	brown adipose tissue	High DINCH Treatment Group	Female
SA364379	BAT_F_HFD_highDINCH_N61	brown adipose tissue	High DINCH Treatment Group	Female
SA364380	BAT_F_HFD_highDINCH_N62	brown adipose tissue	High DINCH Treatment Group	Female
SA364381	BAT_M_HFD_highDINCH_N22	brown adipose tissue	High DINCH Treatment Group	Male
SA364382	BAT_M_HFD_highDINCH_N23	brown adipose tissue	High DINCH Treatment Group	Male
SA364383	BAT_M_HFD_highDINCH_N21	brown adipose tissue	High DINCH Treatment Group	Male
SA364384	BAT_M_HFD_highDINCH_N56	brown adipose tissue	High DINCH Treatment Group	Male
SA364385	BAT_M_HFD_highDINCH_N54	brown adipose tissue	High DINCH Treatment Group	Male
SA364386	BAT_F_HFD Ctrl_A62	brown adipose tissue	High Fat Diet Control Recovery Group	Female
SA364387	BAT_F_HFD Ctrl_A63	brown adipose tissue	High Fat Diet Control Recovery Group	Female
SA364388	BAT_F_HFD Ctrl_A61	brown adipose tissue	High Fat Diet Control Recovery Group	Female
SA364389	BAT_F_HFD Ctrl_A29	brown adipose tissue	High Fat Diet Control Recovery Group	Female
SA364390	BAT_M_HFD Ctrl_A53	brown adipose tissue	High Fat Diet Control Recovery Group	Male
SA364391	BAT_M_HFD Ctrl_A21	brown adipose tissue	High Fat Diet Control Recovery Group	Male
SA364392	BAT_M_HFD Ctrl_A22	brown adipose tissue	High Fat Diet Control Recovery Group	Male
SA364393	BAT_M_HFD Ctrl_A54	brown adipose tissue	High Fat Diet Control Recovery Group	Male
SA364394	BAT_M_HFD Ctrl_A23	brown adipose tissue	High Fat Diet Control Recovery Group	Male
SA364395	BAT_F_HFD_Ctrl_N45	brown adipose tissue	High Fat Diet Control Treatment Group	Female
SA364396	BAT_F_HFD_Ctrl_N46	brown adipose tissue	High Fat Diet Control Treatment Group	Female
SA364397	BAT_F_HFD_Ctrl_N47	brown adipose tissue	High Fat Diet Control Treatment Group	Female
SA364398	BAT_F_HFD_Ctrl_N13	brown adipose tissue	High Fat Diet Control Treatment Group	Female
SA364399	BAT_F_HFD_Ctrl_N14	brown adipose tissue	High Fat Diet Control Treatment Group	Female
SA364400	BAT_M_HFD_Ctrl_N8	brown adipose tissue	High Fat Diet Control Treatment Group	Male
SA364401	BAT_M_HFD_Ctrl_N37	brown adipose tissue	High Fat Diet Control Treatment Group	Male
SA364402	BAT_M_HFD_Ctrl_N6	brown adipose tissue	High Fat Diet Control Treatment Group	Male
SA364403	BAT_M_HFD_Ctrl_N39	brown adipose tissue	High Fat Diet Control Treatment Group	Male
SA364404	BAT_M_HFD_Ctrl_N38	brown adipose tissue	High Fat Diet Control Treatment Group	Male
SA364405	BAT_F_HFD lowDINCH_A75	brown adipose tissue	Low DINCH Recovery Group	Female
SA364406	BAT_F_HFD lowDINCH_A74	brown adipose tissue	Low DINCH Recovery Group	Female
SA364407	BAT_F_HFD lowDINCH_A73	brown adipose tissue	Low DINCH Recovery Group	Female
SA364408	BAT_F_HFD lowDINCH_A42	brown adipose tissue	Low DINCH Recovery Group	Female
SA364409	BAT_F_HFD lowDINCH_A41	brown adipose tissue	Low DINCH Recovery Group	Female
SA364410	BAT_F_HFD lowDINCH_A11	brown adipose tissue	Low DINCH Recovery Group	Female
SA364411	BAT_F_HFD lowDINCH_A10	brown adipose tissue	Low DINCH Recovery Group	Female
SA364412	BAT_M_HFD lowDINCH_A2	brown adipose tissue	Low DINCH Recovery Group	Male
SA364413	BAT_M_HFD lowDINCH_A1	brown adipose tissue	Low DINCH Recovery Group	Male
SA364414	BAT_M_HFD lowDINCH_A33	brown adipose tissue	Low DINCH Recovery Group	Male
SA364415	BAT_M_HFD lowDINCH_A35	brown adipose tissue	Low DINCH Recovery Group	Male
SA364416	BAT_M_HFD lowDINCH_A3	brown adipose tissue	Low DINCH Recovery Group	Male
SA364417	BAT_M_HFD lowDINCH_A65	brown adipose tissue	Low DINCH Recovery Group	Male
SA364418	BAT_M_HFD lowDINCH_A66	brown adipose tissue	Low DINCH Recovery Group	Male
SA364419	BAT_M_HFD lowDINCH_A67	brown adipose tissue	Low DINCH Recovery Group	Male
SA364420	BAT_F_HFD_lowDINCH_N28	brown adipose tissue	Low DINCH Treatment Group	Female
SA364421	BAT_F_HFD_lowDINCH_N57	brown adipose tissue	Low DINCH Treatment Group	Female
SA364422	BAT_F_HFD_lowDINCH_N58	brown adipose tissue	Low DINCH Treatment Group	Female
SA364423	BAT_F_HFD_lowDINCH_N25	brown adipose tissue	Low DINCH Treatment Group	Female
SA364424	BAT_F_HFD_lowDINCH_N26	brown adipose tissue	Low DINCH Treatment Group	Female
SA364425	BAT_M_HFD_lowDINCH_N51	brown adipose tissue	Low DINCH Treatment Group	Male
SA364426	BAT_M_HFD_lowDINCH_N49	brown adipose tissue	Low DINCH Treatment Group	Male
SA364427	BAT_M_HFD_lowDINCH_N52	brown adipose tissue	Low DINCH Treatment Group	Male
SA364428	BAT_M_HFD_lowDINCH_N17	brown adipose tissue	Low DINCH Treatment Group	Male
SA364429	BAT_M_HFD_lowDINCH_N18	brown adipose tissue	Low DINCH Treatment Group	Male
SA364143	L_F_HFD highDINCH_A48_neg	Liver	High DINCH Recovery Group	Female
SA364144	L_F_HFD highDINCH_A80_neg	Liver	High DINCH Recovery Group	Female
SA364145	L_F_HFD highDINCH_A79_neg	Liver	High DINCH Recovery Group	Female
SA364146	L_F_HFD highDINCH_A78_neg	Liver	High DINCH Recovery Group	Female
SA364147	L_F_HFD highDINCH_A77_neg	Liver	High DINCH Recovery Group	Female
SA364148	L_F_HFD highDINCH_A15_neg	Liver	High DINCH Recovery Group	Female
SA364149	L_F_HFD highDINCH_A47_neg	Liver	High DINCH Recovery Group	Female
SA364150	L_F_HFD highDINCH_A46_neg	Liver	High DINCH Recovery Group	Female
SA364151	L_F_HFD highDINCH_A45_neg	Liver	High DINCH Recovery Group	Female
SA364152	L_F_HFD highDINCH_A16_neg	Liver	High DINCH Recovery Group	Female
SA364153	L_F_HFD highDINCH_A15_pos	Liver	High DINCH Recovery Group	Female
SA364154	L_F_HFD highDINCH_A14_neg	Liver	High DINCH Recovery Group	Female
SA364155	L_F_HFD highDINCH_A13_neg	Liver	High DINCH Recovery Group	Female
SA364156	L_F_HFD highDINCH_A14_pos	Liver	High DINCH Recovery Group	Female
SA364157	L_F_HFD highDINCH_A13_pos	Liver	High DINCH Recovery Group	Female
SA364158	L_F_HFD highDINCH_A47_pos	Liver	High DINCH Recovery Group	Female
SA364159	L_F_HFD highDINCH_A80_pos	Liver	High DINCH Recovery Group	Female
SA364160	L_F_HFD highDINCH_A79_pos	Liver	High DINCH Recovery Group	Female
SA364161	L_F_HFD highDINCH_A78_pos	Liver	High DINCH Recovery Group	Female
SA364162	L_F_HFD highDINCH_A77_pos	Liver	High DINCH Recovery Group	Female
SA364163	L_F_HFD highDINCH_A48_pos	Liver	High DINCH Recovery Group	Female
SA364164	L_F_HFD highDINCH_A46_pos	Liver	High DINCH Recovery Group	Female
SA364165	L_F_HFD highDINCH_A45_pos	Liver	High DINCH Recovery Group	Female
SA364166	L_F_HFD highDINCH_A16_pos	Liver	High DINCH Recovery Group	Female
SA364167	L_M_HFD highDINCH_A71_neg	Liver	High DINCH Recovery Group	Male
SA364168	L_M_HFD highDINCH_A7_neg	Liver	High DINCH Recovery Group	Male
SA364169	L_M_HFD highDINCH_A70_neg	Liver	High DINCH Recovery Group	Male
SA364170	L_M_HFD highDINCH_A39_neg	Liver	High DINCH Recovery Group	Male
SA364171	L_M_HFD highDINCH_A72_neg	Liver	High DINCH Recovery Group	Male
SA364172	L_M_HFD highDINCH_A6_neg	Liver	High DINCH Recovery Group	Male
SA364173	L_M_HFD highDINCH_A8_neg	Liver	High DINCH Recovery Group	Male
SA364174	L_M_HFD highDINCH_A69_neg	Liver	High DINCH Recovery Group	Male
SA364175	L_M_HFD highDINCH_A8_pos	Liver	High DINCH Recovery Group	Male

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Collection:

Collection ID:	CO003453
Collection Summary:	For euthanasia, a lethal dose of isoflurane (Baxter Deutschland GmbH, Germany) was administered. The organs were dissected and promptly cryopreserved using liquid nitrogen. The specimens were stored at -80°C for long-term preservation.
Sample Type:	Adipose Tissue, Liver
Storage Conditions:	-80℃

Treatment:

Treatment ID:	TR003469
Treatment Summary:	The C57BL/6N mice were bred and kept under pathogen-free conditions, with 3-4 mice per cage, maintained at a constant ambient temperature of 23°C with a 12-hour light/dark cycle and had unlimited access to water and food throughout the study.The experimental groups included mice fed either a standard chow diet or a high-fat diet with two concentrations of 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH): (1) 4500 ppm (LD) and (2) 15000 ppm (HD). The dietary intervention began at four weeks of age and continued for 16 weeks. Following this period, the mice were divided into two groups: one for endpoint analysis (Treatment) and the other for a recovery period on a standard chow diet for an additional 10 weeks (Recovery). Mice were randomly assigned to experimental groups at three weeks of age, ensuring no significant differences in initial body weights among the groups.

Treatment ID:

TR003469

Treatment Summary:

The C57BL/6N mice were bred and kept under pathogen-free conditions, with 3-4 mice per cage, maintained at a constant ambient temperature of 23°C with a 12-hour light/dark cycle and had unlimited access to water and food throughout the study.The experimental groups included mice fed either a standard chow diet or a high-fat diet with two concentrations of 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH): (1) 4500 ppm (LD) and (2) 15000 ppm (HD). The dietary intervention began at four weeks of age and continued for 16 weeks. Following this period, the mice were divided into two groups: one for endpoint analysis (Treatment) and the other for a recovery period on a standard chow diet for an additional 10 weeks (Recovery). Mice were randomly assigned to experimental groups at three weeks of age, ensuring no significant differences in initial body weights among the groups.

Sample Preparation:

Sampleprep ID:	SP003467
Sampleprep Summary:	Tissues were extracted using a methanol/chloroform/water (1:1:1) mixture. Each tissue sample was combined with methanol (-20 °C) and ice-cold water in a 1:1 ratio. The samples were then lysed using a tissue lyser (Qiagen, Germany) at a frequency of 30 Hz for 10 minutes. An equal volume of -20°C cold chloroform was added to the mixture, which was then shaken at 1,400 rpm and 4 °C for 20 minutes. The samples were centrifuged at 18,000 x g and 4°C for 5 minutes, and 300 µL of the non-polar fraction was collected and evaporated to dryness using a Concentrator plus (Eppendorf, Germany). After LC-MS analysis of the samples, absolute concentrations were approximated from raw AUC values (uploaded here) by comparison to an external calibration curve obtained from extracted tissues conditioned with DINCH, MINCH, and secondary metabolites. Specifically, 50 mg of each tissue type (subcutaneous, visceral, brown adipose, and liver tissue from HFD animals) was incubated for 2 hours with 50 µL of a standard mix at varying concentrations (100 µM, 50 µM, 25 µM, 10 µM, 5 µM, 1 µM, 500 nM, 100 nM, 10 nM, and 1 nM) and subsequently extracted using the aforementioned methanol/chloroform/water (1:1:1) extraction method.

Sampleprep ID:

SP003467

Sampleprep Summary:

Tissues were extracted using a methanol/chloroform/water (1:1:1) mixture. Each tissue sample was combined with methanol (-20 °C) and ice-cold water in a 1:1 ratio. The samples were then lysed using a tissue lyser (Qiagen, Germany) at a frequency of 30 Hz for 10 minutes. An equal volume of -20°C cold chloroform was added to the mixture, which was then shaken at 1,400 rpm and 4 °C for 20 minutes. The samples were centrifuged at 18,000 x g and 4°C for 5 minutes, and 300 µL of the non-polar fraction was collected and evaporated to dryness using a Concentrator plus (Eppendorf, Germany). After LC-MS analysis of the samples, absolute concentrations were approximated from raw AUC values (uploaded here) by comparison to an external calibration curve obtained from extracted tissues conditioned with DINCH, MINCH, and secondary metabolites. Specifically, 50 mg of each tissue type (subcutaneous, visceral, brown adipose, and liver tissue from HFD animals) was incubated for 2 hours with 50 µL of a standard mix at varying concentrations (100 µM, 50 µM, 25 µM, 10 µM, 5 µM, 1 µM, 500 nM, 100 nM, 10 nM, and 1 nM) and subsequently extracted using the aforementioned methanol/chloroform/water (1:1:1) extraction method.

Combined analysis:

Analysis ID	AN005472	AN005473
Analysis type	MS	MS
Chromatography type	Reversed phase	Reversed phase
Chromatography system	Agilent 1290 Infinity II	Agilent 1290 Infinity II
Column	Chromolith Performance RP-18e (100 x 2.0 mm, 1.5 µm)	Chromolith Performance RP-18e (100 x 2.0 mm, 1.5 µm)
MS Type	ESI	ESI
MS instrument type	Triple quadrupole	Triple quadrupole
MS instrument name	ABI Sciex 6500+ QTrap	ABI Sciex 6500+ QTrap
Ion Mode	POSITIVE	NEGATIVE
Units	nmol/g	nmol/g

Chromatography:

Chromatography ID:	CH004156
Chromatography Summary:	Measurement of DINCH
Instrument Name:	Agilent 1290 Infinity II
Column Name:	Chromolith Performance RP-18e (100 x 2.0 mm, 1.5 µm)
Column Temperature:	40℃
Flow Gradient:	0-1 min:20% B, 1-2.5 min: 20-50% B, 2.5-4.5 min: 50-95% B, 4.5-12 min: 95% B, 12-13 min: 95-20% B, 13-15 min: 20% B
Flow Rate:	0-4.5 min: 0.4mL/min, 4.5-12 min: 0.6mL/min, 12-15 min: 0.4mL/min
Solvent A:	100% Water; 0.05% formic acid
Solvent B:	100% Acetonitrile; 0.05% formic acid
Chromatography Type:	Reversed phase

Chromatography ID:	CH004157
Chromatography Summary:	Measurement of MINCH
Instrument Name:	Agilent 1290 Infinity II
Column Name:	Chromolith Performance RP-18e (100 x 2.0 mm, 1.5 µm)
Column Temperature:	40℃
Flow Gradient:	0-1 min:20% B, 1-2.5 min: 20-50% B, 2.5-6.5 min: 50-95% B, 6.5-10 min: 95% B, 10-11min: 95-20% B, 11-13 min: 20% B
Flow Rate:	0-6.5 min: 0.4mL/min, 6.5-10 min: 0.6mL/min, 10-13 min: 0.4mL/min
Solvent A:	100% Water; 0.05% formic acid
Solvent B:	100% Acetonitrile; 0.05% formic acid
Chromatography Type:	Reversed phase

MS:

MS ID:	MS005198
Analysis ID:	AN005472
Instrument Name:	ABI Sciex 6500+ QTrap
Instrument Type:	Triple quadrupole
MS Type:	ESI
MS Comments:	For identification and quantitation, a scheduled MRM method was used, with specific transitions for DINCH. Data acquisition and peak integration were performed in Analyst® software (Version 1.7.1). Calculation of concentration was done using external calibration curves as descripted in the preparation section.
Ion Mode:	POSITIVE

MS ID:	MS005199
Analysis ID:	AN005473
Instrument Name:	ABI Sciex 6500+ QTrap
Instrument Type:	Triple quadrupole
MS Type:	ESI
MS Comments:	For identification and quantitation, a scheduled MRM method was used, with specific transitions for MINCH. Data acquisition and peak integration were performed in Analyst® software (Version 1.7.1). Calculation of concentration was done using external calibration curves as descripted in the preparation section.
Ion Mode:	NEGATIVE