Summary of Study ST002937

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 PR001827. The data can be accessed directly via it's Project DOI: 10.21228/M8JQ6C 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	ST002937
Study Title	Deep Metabolic Phenotyping of Newborn Cord Blood Reveals Maternal-Fetal Interactions and Disease Risk
Study Type	Untargeted MS and Targeted MS
Study Summary	Metabolites are small molecules circulating in the mother, placental, and fetal blood that can have a profound effect on a developing fetus (1, 2). Many metabolites from pregnant mothers cross the placenta to provide energy, structural components, essential nutrients, and signals to the developing fetus (3, 4). Issues with proper transmission of metabolites to the fetus, whether through gestational diabetes, placental insufficiency, or other sources can permanently damage the fetus (5-7). However, quantification of many metabolites entering and exiting the fetus are unknown; associations between microbial metabolites in umbilical cords and disease have not been thoroughly investigated; and there remains a lack of quantifiable metabolic effects of some of the most common medications administered during pregnancy and parturition. Here we identified and quantified many metabolites with a gradient between arterial and venous cord blood; we demonstrated that exogenous metabolites in umbilical cords associate with many health outcomes; and we show that medications can profoundly alter the metabolic milieu of the fetus. We greatly expanded the number of metabolites that demonstrate a gradient between arterial and venous blood, indicating absorption by the fetus, including several essential fatty acids. The microbial metabolites 3-indolepropionic acid, hydroxyhippuric acid and others are associated with many newborn diseases. Lastly, we show that exogenous medications like bupivacaine and betamethasone can have a profound impact on newborn metabolic profile. This study is the most comprehensive study of umbilical cord metabolic and disease associations to date. It reveals important aspects of fetal biology, like the reliance on specific essential fatty acid and taurine. It suggests several interventions in pregnant mothers that may help newborn health, including new fatty acids. This study serves as a valuable reference for investigators wishing to better understand the impact of medications on the developing fetus and neonate.
Institute	Stanford University
Department	Department of Genetics
Laboratory	Snyder Lab
Last Name	Lancaster
First Name	Samuel
Address	240 Pasteur Dr, BMI bldg 4400, Stanford California, 94305
Email	slancast@stanford.edu
Phone	(612)-600-4033
Submit Date	2023-08-31
Raw Data Available	Yes
Raw Data File Type(s)	wiff, raw(Thermo)
Analysis Type Detail	LC-MS
Release Date	2023-11-10
Release Version	1

Select appropriate tab below to view additional metadata details:

Project:

Project ID:	PR001827
Project DOI:	doi: 10.21228/M8JQ6C
Project Title:	Deep Metabolic Phenotyping of Newborn Cord Blood Reveals Maternal-Fetal Interactions and Disease Risk
Project Summary:	Metabolites are small molecules circulating in the mother, placental, and fetal blood that can have a profound effect on a developing fetus (1, 2). Many metabolites from pregnant mothers cross the placenta to provide energy, structural components, essential nutrients, and signals to the developing fetus (3, 4). Issues with proper transmission of metabolites to the fetus, whether through gestational diabetes, placental insufficiency, or other sources can permanently damage the fetus (5-7). However, quantification of many metabolites entering and exiting the fetus are unknown; associations between microbial metabolites in umbilical cords and disease have not been thoroughly investigated; and there remains a lack of quantifiable metabolic effects of some of the most common medications administered during pregnancy and parturition. Here we identified and quantified many metabolites with a gradient between arterial and venous cord blood; we demonstrated that exogenous metabolites in umbilical cords associate with many health outcomes; and we show that medications can profoundly alter the metabolic milieu of the fetus. We greatly expanded the number of metabolites that demonstrate a gradient between arterial and venous blood, indicating absorption by the fetus, including several essential fatty acids. The microbial metabolites 3-indolepropionic acid, hydroxyhippuric acid and others are associated with many newborn diseases. Lastly, we show that exogenous medications like bupivacaine and betamethasone can have a profound impact on newborn metabolic profile. This study is the most comprehensive study of umbilical cord metabolic and disease associations to date. It reveals important aspects of fetal biology, like the reliance on specific essential fatty acid and taurine. It suggests several interventions in pregnant mothers that may help newborn health, including new fatty acids. This study serves as a valuable reference for investigators wishing to better understand the impact of medications on the developing fetus and neonate.
Institute:	Stanford University
Department:	Department of Genetics
Laboratory:	Snyder Lab
Last Name:	Lancaster
First Name:	Samuel
Address:	240 Pasteur Dr, BMI bldg 4400, Stanford California, 94305
Email:	slancast@stanford.edu
Phone:	(612)-600-4033

Subject:

Subject ID:	SU003050
Subject Type:	Human
Subject Species:	Homo sapiens
Taxonomy ID:	9606

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id	local_sample_id	type
SA318433	51	A
SA318434	211A	A
SA318435	71A	A
SA318436	147A	A
SA318437	264A	A
SA318438	215A	A
SA318439	329	A
SA318440	134A	A
SA318441	108A	A
SA318442	57A	A
SA318443	228	A
SA318444	101A	A
SA318445	217	A
SA318446	139	AV
SA318447	253	AV
SA318448	465	AV
SA318449	471	AV
SA318450	467	AV
SA318451	469	AV
SA318452	141	AV
SA318453	145	AV
SA318454	143	AV
SA318455	463	AV
SA318456	461	AV
SA318457	459	AV
SA318458	159	AV
SA318459	249	AV
SA318460	155	AV
SA318461	251	AV
SA318462	395	AV
SA318463	151	AV
SA318464	256	AV
SA318465	153	AV
SA318466	149	AV
SA318467	475	AV
SA318468	386	AV
SA318469	116	AV
SA318470	118	AV
SA318471	267	AV
SA318472	121	AV
SA318473	114	AV
SA318474	112	AV
SA318475	108	AV
SA318476	272	AV
SA318477	110	AV
SA318478	224	AV
SA318479	265	AV
SA318480	123	AV
SA318481	457	AV
SA318482	134	AV
SA318483	392	AV
SA318484	136	AV
SA318485	132	AV
SA318486	258	AV
SA318487	263	AV
SA318488	389	AV
SA318489	261	AV
SA318490	477	AV
SA318491	473	AV
SA318492	453	AV
SA318493	203	AV
SA318494	201	AV
SA318495	205	AV
SA318496	428	AV
SA318497	407	AV
SA318498	431	AV
SA318499	236	AV
SA318500	435	AV
SA318501	193	AV
SA318502	195	AV
SA318503	197	AV
SA318504	433	AV
SA318505	426	AV
SA318506	424	AV
SA318507	411	AV
SA318508	417	AV
SA318509	226	AV
SA318510	222	AV
SA318511	414	AV
SA318512	419	AV
SA318513	229	AV
SA318514	409	AV
SA318515	211	AV
SA318516	422	AV
SA318517	213	AV
SA318518	403	AV
SA318519	191	AV
SA318520	398	AV
SA318521	170	AV
SA318522	172	AV
SA318523	449	AV
SA318524	174	AV
SA318525	451	AV
SA318526	247	AV
SA318527	455	AV
SA318528	340	AV
SA318529	381	AV
SA318530	167	AV
SA318531	245	AV
SA318532	176	AV

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Collection:

Collection ID:	CO003043
Collection Summary:	Plasma was collected from umbilical cords at the Lucile Packard Children’s Hospital Stanford with permission from the Institutional Review Board (IRB #46411). All umbilical cords were collected and sent for clinically-indicated testing to Pathology where blood gas analysis was performed following Stanford protocol. Leftover and discarded samples were obtained for research. Arterial and venous blood were extracted from umbilical cords by heparinized syringe and transferred to low binding tubes.
Sample Type:	Blood (plasma)

Treatment:

Treatment ID:	TR003059
Treatment Summary:	Samples were centrifuged at 1300g for 10 minutes. Plasma was aliquoted in cryovials and frozen at -80°C.

Sample Preparation:

Sampleprep ID:	SP003056
Sampleprep Summary:	Metabolites and lipids were extracted in 96-well high throughput fashion using a liquid-liquid biphasic separation with cold methyl tert-butyl ether (MTBE), methanol, and water. To begin, 1 mL MTBE was added to 40 μl of plasma and spiked with 40 μl of deuterated lipid internal standards (Sciex, cat# 5040156, lot# LPISTDKIT-103). The samples were agitated at 4°C for 30 minutes. After the addition of 250 μl cold water, samples were vortexed for 1 minute then centrifuged at 3,800 g for 5 minutes at 4°C. The upper organic phase contained the lipids while the lower aqueous phase contained metabolites with precipitated proteins at the bottom of the tube. For quality control, reference plasma samples (40 μl plasma), as well as controls lacking samples (blanks), were processed in parallel. 1) Metabolites: To further precipitate proteins, 500 μl 1:1:1 acetone: acetonitrile: methanol spiked with 16 labeled metabolite internal standards was added to 300 μl of the aqueous phase and 200 μl of the organic phase and incubated overnight at -20°C. After centrifugation at 3,800 g for 10 min at 4°C, the metabolic extracts were dried down under a stream of nitrogen gas and resuspended in 100 μl 50/50 methanol/water for LC-MS. 2) Complex lipids: 700 µl of the organic phase was dried down under a stream of nitrogen and resolubilized in 200 μl of methanol for storage at -20°C until analysis. The day of the analysis, samples were dried down, resuspended in 300 μl of 10 mM ammonium acetate in 90/10 methanol/toluene, and centrifuged at 3,800 g for 5 min at 4°C.

Sampleprep ID:

SP003056

Sampleprep Summary:

Metabolites and lipids were extracted in 96-well high throughput fashion using a liquid-liquid biphasic separation with cold methyl tert-butyl ether (MTBE), methanol, and water. To begin, 1 mL MTBE was added to 40 μl of plasma and spiked with 40 μl of deuterated lipid internal standards (Sciex, cat# 5040156, lot# LPISTDKIT-103). The samples were agitated at 4°C for 30 minutes. After the addition of 250 μl cold water, samples were vortexed for 1 minute then centrifuged at 3,800 g for 5 minutes at 4°C. The upper organic phase contained the lipids while the lower aqueous phase contained metabolites with precipitated proteins at the bottom of the tube. For quality control, reference plasma samples (40 μl plasma), as well as controls lacking samples (blanks), were processed in parallel. 1) Metabolites: To further precipitate proteins, 500 μl 1:1:1 acetone: acetonitrile: methanol spiked with 16 labeled metabolite internal standards was added to 300 μl of the aqueous phase and 200 μl of the organic phase and incubated overnight at -20°C. After centrifugation at 3,800 g for 10 min at 4°C, the metabolic extracts were dried down under a stream of nitrogen gas and resuspended in 100 μl 50/50 methanol/water for LC-MS. 2) Complex lipids: 700 µl of the organic phase was dried down under a stream of nitrogen and resolubilized in 200 μl of methanol for storage at -20°C until analysis. The day of the analysis, samples were dried down, resuspended in 300 μl of 10 mM ammonium acetate in 90/10 methanol/toluene, and centrifuged at 3,800 g for 5 min at 4°C.

Combined analysis:

Analysis ID	AN004817	AN004818	AN004819	AN004820	AN004821	AN004822
Analysis type	MS	MS	MS	MS	MS	MS
Chromatography type	Reversed phase	Reversed phase	HILIC	HILIC	None (Direct infusion)	None (Direct infusion)
Chromatography system	Thermo Dionex Ultimate 3000	Thermo Dionex Ultimate 3000	Thermo Vanquish	Thermo Vanquish	Shimazdu LC-30AD	Shimazdu LC-30AD
Column	Agilent Zorbax SBaq (50 x 2.1mm x 1.7 um)	Agilent Zorbax SBaq (50 x 2.1mm x 1.7 um)	Merck SeQuant ZIC-HILIC (100 x 2.1mm,3.5um)	Merck SeQuant ZIC-HILIC (100 x 2.1mm,3.5um)	None	None
MS Type	ESI	ESI	ESI	ESI	ESI	ESI
MS instrument type	Orbitrap	Orbitrap	Orbitrap	Orbitrap	Triple quadrupole	Triple quadrupole
MS instrument name	Thermo Q Exactive Plus Orbitrap	Thermo Q Exactive Plus Orbitrap	Thermo Q Exactive HF hybrid Orbitrap	Thermo Q Exactive HF hybrid Orbitrap	ABI Sciex 5500 QTrap	ABI Sciex 5500 QTrap
Ion Mode	POSITIVE	NEGATIVE	POSITIVE	NEGATIVE	POSITIVE	NEGATIVE
Units	Relative Abundance	Relative Abundance	Relative Abundance	Relative Abundance	Relative Abundance	Relative Abundance

Chromatography:

Chromatography ID:	CH003640
Instrument Name:	Thermo Dionex Ultimate 3000
Column Name:	Agilent Zorbax SBaq (50 x 2.1mm x 1.7 um)
Column Temperature:	60
Flow Gradient:	N/A
Flow Rate:	0.6 ml/min
Solvent A:	0.06% acetic acid in water
Solvent B:	0.06% acetic acid in methanol
Chromatography Type:	Reversed phase

Chromatography ID:	CH003641
Instrument Name:	Thermo Vanquish
Column Name:	Merck SeQuant ZIC-HILIC (100 x 2.1mm,3.5um)
Column Temperature:	40
Flow Gradient:	N/A
Flow Rate:	0.5 ml/min
Solvent A:	10 mM ammonium acetate in 50/50 acetonitrile/water
Solvent B:	10 mM ammonium acetate in 95/5 acetonitrile/water
Chromatography Type:	HILIC

Chromatography ID:	CH003642
Instrument Name:	Shimazdu LC-30AD
Column Name:	None
Column Temperature:	20
Flow Gradient:	N/A
Flow Rate:	0.15 ml/min
Solvent A:	9:1 Methanol Toluene with 10 mM ammonium acetate
Solvent B:	N/A
Chromatography Type:	None (Direct infusion)

MS:

MS ID:	MS004563
Analysis ID:	AN004817
Instrument Name:	Thermo Q Exactive Plus Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Data from each mode were independently analyzed using Progenesis QI software (v2.3) (Nonlinear Dynamics, Durham, NC). Metabolic features from blanks and those that did not show sufficient linearity upon dilution in QC samples (r<0.6) were discarded. Only metabolic features present in >2/3 of the samples were kept for further analysis. Missing values were imputed by drawing from a random distribution of low values in the corresponding sample. Intensity drift was corrected using SERRF. Data quality post-normalization was verified by ensuring clustering of pooled sample replicates on a principal component analysis (PCA) plot.
Ion Mode:	POSITIVE

MS ID:	MS004564
Analysis ID:	AN004818
Instrument Name:	Thermo Q Exactive Plus Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Data from each mode were independently analyzed using Progenesis QI software (v2.3) (Nonlinear Dynamics, Durham, NC). Metabolic features from blanks and those that did not show sufficient linearity upon dilution in QC samples (r<0.6) were discarded. Only metabolic features present in >2/3 of the samples were kept for further analysis. Missing values were imputed by drawing from a random distribution of low values in the corresponding sample. Intensity drift was corrected using SERRF. Data quality post-normalization was verified by ensuring clustering of pooled sample replicates on a principal component analysis (PCA) plot.
Ion Mode:	NEGATIVE

MS ID:	MS004565
Analysis ID:	AN004819
Instrument Name:	Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Data from each mode were independently analyzed using Progenesis QI software (v2.3) (Nonlinear Dynamics, Durham, NC). Metabolic features from blanks and those that did not show sufficient linearity upon dilution in QC samples (r<0.6) were discarded. Only metabolic features present in >2/3 of the samples were kept for further analysis. Missing values were imputed by drawing from a random distribution of low values in the corresponding sample. Intensity drift was corrected using SERRF. Data quality post-normalization was verified by ensuring clustering of pooled sample replicates on a principal component analysis (PCA) plot.
Ion Mode:	POSITIVE

MS ID:	MS004566
Analysis ID:	AN004820
Instrument Name:	Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Data from each mode were independently analyzed using Progenesis QI software (v2.3) (Nonlinear Dynamics, Durham, NC). Metabolic features from blanks and those that did not show sufficient linearity upon dilution in QC samples (r<0.6) were discarded. Only metabolic features present in >2/3 of the samples were kept for further analysis. Missing values were imputed by drawing from a random distribution of low values in the corresponding sample. Intensity drift was corrected using SERRF. Data quality post-normalization was verified by ensuring clustering of pooled sample replicates on a principal component analysis (PCA) plot.
Ion Mode:	NEGATIVE

MS ID:	MS004567
Analysis ID:	AN004821
Instrument Name:	ABI Sciex 5500 QTrap
Instrument Type:	Triple quadrupole
MS Type:	ESI
MS Comments:	Lipidyzer data were reported by the Lipidomics Workflow Manager (LWM, v1.0.5.0) software which calculates concentrations for each detected lipid as average intensity of the analyte MRM relative to the average intensity of the most structurally similar internal standard (IS) MRM multiplied by its concentration. Lipids detected in less than 2/3 of the samples were discarded and missing values were imputed by drawing from a random distribution of low values class-wise in the corresponding sample. Data quality was verified by ensuring clustering of the quality control replicates analyzed on a PCA plot. We detected lipid species belonging to 13 classes (e.g. CE, CER, DAG, FFA, HCER, LCER, DCER, LPE, LPC, PC, PE, SM, TAG) and their abundance were reported as concentrations in nmol/g. The Q1 and Q3 mass provided in the metadata were used to target specific lipid classes. Lipids with the designated Q1 mass, also known as the parent ion, are selected from the first quadrupole. The lipids are then fragmented and sent to the third quadrupole. In the third quadrupole, the desired lipid class is selected based on its Q3 mass.
Ion Mode:	POSITIVE

MS ID:	MS004568
Analysis ID:	AN004822
Instrument Name:	ABI Sciex 5500 QTrap
Instrument Type:	Triple quadrupole
MS Type:	ESI
MS Comments:	Lipidyzer data were reported by the Lipidomics Workflow Manager (LWM, v1.0.5.0) software which calculates concentrations for each detected lipid as average intensity of the analyte MRM relative to the average intensity of the most structurally similar internal standard (IS) MRM multiplied by its concentration. Lipids detected in less than 2/3 of the samples were discarded and missing values were imputed by drawing from a random distribution of low values class-wise in the corresponding sample. Data quality was verified by ensuring clustering of the quality control replicates analyzed on a PCA plot. We detected lipid species belonging to 13 classes (e.g. CE, CER, DAG, FFA, HCER, LCER, DCER, LPE, LPC, PC, PE, SM, TAG) and their abundance were reported as concentrations in nmol/g. The Q1 and Q3 mass provided in the metadata were used to target specific lipid classes. Lipids with the designated Q1 mass, also known as the parent ion, are selected from the first quadrupole. The lipids are then fragmented and sent to the third quadrupole. In the third quadrupole, the desired lipid class is selected based on its Q3 mass.
Ion Mode:	NEGATIVE