Human Milk Composition Is Associated with Maternal Body Mass Index in a Cross-Sectional, Untargeted Metabolomics Analysis of Human Milk from Guatemalan Mothers.

Background: Maternal overweight and obesity has been associated with poor lactation performance including delayed lactogenesis and reduced duration. However, the effect on human milk composition is less well understood. Objectives: We evaluated the relationship of maternal BMI on the human milk metabolome among Guatemalan mothers. Methods: We used data from 75 Guatemalan mothers who participated in the Household Air Pollution Intervention Network trial. Maternal BMI was measured between 9 and <20 weeks of gestation. Milk samples were collected at a single time point using aseptic collection from one breast at 6 mo postpartum and analyzed using high-resolution mass spectrometry. A cross-sectional untargeted high-resolution metabolomics analysis was performed by coupling hydrophilic interaction liquid chromatography (HILIC) and reverse phase C18 chromatography with mass spectrometry. Metabolic features associated with maternal BMI were determined by a metabolome-wide association study (MWAS), adjusting for baseline maternal age, education, and dietary diversity, and perturbations in metabolic pathways were identified by pathway enrichment analysis. Results: The mean age of participants at baseline was 23.62 ± 3.81 y, and mean BMI was 24.27 ± 4.22 kg/m2. Of the total metabolic features detected by HILIC column (19,199 features) and by C18 column (11,594 features), BMI was associated with 1026 HILIC and 500 C18 features. Enriched pathways represented amino acid metabolism, galactose metabolism, and xenobiotic metabolic metabolism. However, no significant features were identified after adjusting for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure (FDRBH < 0.2). Conclusions: Findings from this untargeted MWAS indicate that maternal BMI is associated with metabolic perturbations of galactose metabolism, xenobiotic metabolism, and xenobiotic metabolism by cytochrome p450 and biosynthesis of amino acid pathways. Significant metabolic pathway alterations detected in human milk were associated with energy metabolism-related pathways including carbohydrate and amino acid metabolism.This trial was registered at clinicaltrials.gov as NCT02944682.

High-Resolution Plasma Metabolomics and Thiamine Status in Critically Ill Adult Patients.

Background and Aim: Thiamine (Vitamin B1) is an essential micronutrient and a co-factor for metabolic functions related to energy metabolism. We determined the association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites using high resolution metabolomics in critically ill patients. Methods: Cross-sectional study performed in Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were ≥ 18 years of age, with an expected length of ICU stay longer than 48 hours, receiving furosemide therapy for at least 6 months before ICU admission. Results: Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP concentrations were measured using high-performance liquid chromatography (HPLC). Liquid chromatography/mass spectrometry was used for plasma high-resolution metabolomics. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies. We also compared metabolomic features from patients in the highest TPP concentration tertile to patients in the lowest TPP tertile as a secondary analysis. We enrolled 76 participants with a median age of 69 (range, 62.5-79.5) years. Specific metabolic pathways associated with whole blood TPP levels, using both regression and tertile analysis, included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways. Conclusions: Plasma high-resolution metabolomics analysis showed that whole blood TPP concentrations are significantly associated with metabolites and metabolic pathways linked to the metabolism of energy, amino acids, lipids, and the gut microbiome in adult critically ill patients.

Third Trimester Serum Amino Acid Metabolism is Associated with Maternal Breast Cancer Diagnosed within 15 years of Pregnancy.

A prospective metabolome-wide association study revealed widespread amino acid limitation in late pregnancy is associated with early onset breast cancer. Archival third trimester pregnancy serum samples from 172 women who subsequently were diagnosed with breast cancer within 38 years after pregnancy were compared to 351 women without breast cancer. No individual metabolite differed after false discovery rate adjustment, indicating that individual metabolites are unlikely to be useful for classification or prediction. Despite this, pathway enrichment analysis showed that amino acid pathways, including lysine, arginine, proline, aspartate, asparagine, alanine, tyrosine, tryptophan, histidine, branched-chain amino acid and urea cycle, were enriched among metabolites that differed at raw p < 0.05. Several of these pathways previously were linked to breast carcinogen exposures, including dichlorodiphenyltrichloroethane and perfluorinated alkyl substances. Network analyses showed that amino acids correlated with parity and the ratio of estriol to estrone and estradiol known risk factors for breast cancer in this cohort. Overall, amino acid associations were stronger for early onset breast cancer, defined here as occurring within the first 15 years following pregnancy. Although results must be interpreted cautiously, lower amino acid concentrations for histidine, threonine and proline, and stronger associations for tryptophan, histidine, and lysine pathways with breast cancer within 15 years, suggests that amino acid limitations during late pregnancy contribute to metabolic reprogramming that is causally related to early onset breast cancer. Environmental chemical effects on nutrient sensing could account for these effects through known oncogenic mechanisms linked to nutrient stress.

Exposome Epidemiology for Suspect Environmental Chemical Exposures during Pregnancy Linked to Subsequent Breast Cancer Diagnosis.

Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry (HRMS) of pregnancy cohort biospecimens in the Child Health and Development Studies (CHDS) to test for associations with breast cancer identified via the California Cancer Registry. Second (T2) and third (T3) trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database (T3DB) for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both T2 and T3 to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol (DNP), linked to variations in amino acid and nucleotide pathways in T2 and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in T3. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.

Exposome epidemiology for suspect environmental chemical exposures during pregnancy linked to subsequent breast cancer diagnosis.

Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry of pregnancy cohort biospecimens in the Child Health and Development Studies to test for associations with breast cancer identified via the California Cancer Registry. Second and third trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both second and third trimesters to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol, linked to variations in amino acid and nucleotide pathways in second trimester and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in third trimester. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.