PubMed

Metabolites. 2023 Apr 13;13(4):558. doi: 10.3390/metabo13040558.ABSTRACTHigh-throughput metabolomics has enabled the development of large-scale cohort studies. Long-term studies require multiple batch-based measurements, which require sophisticated quality control (QC) to eliminate unexpected bias to obtain biologically meaningful quantified metabolomic profiles. Liquid chromatography-mass spectrometry was used to analyze 10,833 samples in 279 batch measurements. The quantified profile included 147 lipids including acylcarnitine, fatty acids, glucosylceramide, lactosylceramide, lysophosphatidic acid, and progesterone. Each batch included 40 samples, and 5 QC samples were measured for 10 samples of each. The quantified data from the QC samples were used to normalize the quantified profiles of the sample data. The intra- and inter-batch median coefficients of variation (CV) among the 147 lipids were 44.3% and 20.8%, respectively. After normalization, the CV values decreased by 42.0% and 14.7%, respectively. The effect of this normalization on the subsequent analyses was also evaluated. The demonstrated analyses will contribute to obtaining unbiased, quantified data for large-scale metabolomics.PMID:37110217 | DOI:10.3390/metabo13040558

Metabolites. 2023 Apr 13;13(4):555. doi: 10.3390/metabo13040555.ABSTRACTTotal parenteral nutrition (TPN) is life-saving therapy for the pediatric patients with intestinal failure (IF) who cannot tolerate enteral nutrition (EN). However, TPN-induced metabolic alterations are also a critical issue for the maintenance of intestinal homeostasis, and thus the global metabolomic signatures need to be addressed. In this study, ileal mucosal biopsies were collected from 12 neonatal Bama piglets receiving either EN or TPN for 14 days, and changes in the intestinal metabolism were examined by multi-omics (HM350 Metabolomics + Tandem Mass Tag (TMT)-based proteomics). As a result, a total of 240 compounds were identified by metabolomics, including 56 down-regulated and 9 up-regulated metabolites. Notably, tissue levels of fatty acyl-carnitines (decreased by 35-85%) and succinate (decreased by 89%) dramatically decreased in the TPN group, suggestive of disrupted processes of fatty acid oxidation (FAO) and the citrate cycle, respectively. Interestingly, however, no differences were found in the production of adenosine 5'-triphosphate (ATP) between groups, suggesting that these dysregulated metabolites may have mainly led to the loss of bioactive compounds rather than energy deficit. Additionally, 4813 proteins were identified by proteomics in total, including 179 down-regulated and 329 up-regulated proteins. The analysis of protein-protein interactions (PPI) indicated that most of the differentially expressed proteins were clustered into "lipid metabolism" and "innate immune responses". In summary, this work provided new findings in TPN-induced intestinal metabolic alterations, which would be useful to the improvement of nutritional management for IF patients.PMID:37110213 | DOI:10.3390/metabo13040555

Metabolites. 2023 Apr 13;13(4):554. doi: 10.3390/metabo13040554.ABSTRACTDiet energy is a key component of pet food, but it is usually ignored during pet food development and pet owners also have limited knowledge of its importance. This study aimed to explore the effect of diet energy on the body condition, glucolipid metabolism, fecal microbiota and metabolites of adult beagles and analyze the relation between diet and host and gut microbiota. Eighteen healthy adult neutered male beagles were selected and randomly divided into three groups. Diets were formulated with three metabolizable energy (ME) levels: the low-energy (Le) group consumed a diet of 13.88 MJ/kg ME; the medium-energy (Me) group consumed a diet of 15.04 MJ/kg ME; and the high-energy (He) group consumed a diet of 17.05 MJ/kg ME. Moreover, the protein content of all these three diets was 29%. The experiment lasted 10 weeks, with a two-week acclimation period and an eight-week test phase. Body weight, body condition score (BCS), muscle condition score (MCS) and body fat index (BFI) decreased in the Le group, and the changes in these factors in the Le group were significantly higher than in the other groups (p < 0.05). The serum glucose and lipid levels of the Le and He groups changed over time (p < 0.05), but those of the Me group were stable (p > 0.05). The fecal pH of the Le and He groups decreased at the end of the trial (p < 0.05) and we found that the profiles of short-chain fatty acids (SCFAs) and bile acids (BAs) changed greatly, especially secondary BAs (p < 0.05). As SCFAs and secondary BAs are metabolites of the gut microbiota, the fecal microbiota was also measured. Fecal 16S rRNA gene sequencing found that the Me group had higher α-diversity indices (p < 0.05). The Me group had notably higher levels of gut probiotics, such as Faecalibacterium prausnitzii, Bacteroides plebeius and Blautia producta (p < 0.05). The diet-host-fecal microbiota interactions were determined by network analysis, and fecal metabolites may help to determine the best physical condition of dogs, assisting pet food development. Overall, feeding dogs low- or high-energy diets was harmful for glucostasis and promoted the relative abundance of pathogenic bacteria in the gut, while a medium-energy diet maintained an ideal body condition. We concluded that dogs that are fed a low-energy diet for an extended period may become lean and lose muscle mass, but diets with low energy levels and 29% protein may not supply enough protein for dogs losing weight.PMID:37110212 | DOI:10.3390/metabo13040554

Metabolites. 2023 Apr 13;13(4):553. doi: 10.3390/metabo13040553.ABSTRACTThis cross-sectional study aimed to investigate differences in skin surface lipids (SSL) and explore related metabolic pathways among females of different ages in Henan Province. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to determine the lipid composition of the skin surface of 58 female volunteers who were divided into three age groups. Statistical analysis was performed using Progenesis QI, Ezinfo, and MetaboAnalyst. Multivariate and enrichment analysis were used to identify the different SSL among the groups. A total of 530 lipid entities were identified and classified into eight classes. Among these, 63 lipids were significantly different between the groups. Lower levels of glycerolipids (GLs) and sphingolipids (SPs) were observed in the middle-aged group, while higher levels of GLs were found in the elder group. GLs belonged to the largest and statistically significant enrichment of lipid metabolic pathways, and the lipid individuals enriched to the sphingoid bases metabolism were the most and statistically significant. These findings suggest that there are differences in hand SSL among females of different ages, which may be related to GLs and sphingoid bases metabolism.PMID:37110211 | DOI:10.3390/metabo13040553

Metabolites. 2023 Apr 12;13(4):552. doi: 10.3390/metabo13040552.ABSTRACTZucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments.PMID:37110210 | DOI:10.3390/metabo13040552

Metabolites. 2023 Apr 11;13(4):546. doi: 10.3390/metabo13040546.ABSTRACTMenopause-associated asthma impacts a subset of women, tends to be more severe, and is less responsive to current treatments. We recently developed a model of menopause-associated asthma using 4-Vinylcyclohexene Diepoxide (VCD) and house dust mites (HDM). The goal of this study was to uncover potential biomarkers and drivers of menopause-onset asthma by assessing serum and bronchoalveolar lavage fluid (BALF) samples from mice with and without menopause and HDM challenge by large-scale targeted metabolomics. Female mice were treated with VCD/HDM to model menopause-associated asthma, and serum and BALF samples were processed for large-scale targeted metabolomic assessment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine metabolites of potential biological significance. We identified over 50 individual metabolites, impacting 46 metabolic pathways, in the serum and BALF that were significantly different across the four study groups. In particular, glutamate, GABA, phosphocreatine, and pyroglutamic acid, which are involved in glutamate/glutamine, glutathione, and arginine and proline metabolisms, were significantly impacted in the menopausal HDM-challenged mice. Additionally, several metabolites had significant correlations with total airway resistance including glutamic acid, histamine, uridine, cytosine, cytidine, and acetamide. Using metabolic profiling, we identified metabolites and metabolic pathways that may aid in discriminating potential biomarkers for and drivers of menopause-associated asthma.PMID:37110204 | DOI:10.3390/metabo13040546

Metabolites. 2023 Apr 10;13(4):542. doi: 10.3390/metabo13040542.ABSTRACTAn altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, n = 94), frail/pre-frail older adults with type 2 diabetes mellitus (F-T2DM, n = 66), and robust non-diabetic controls (n = 40). Partial least squares discriminant analysis (PLS-DA) models were built to define the amino acid signatures associated with the different frailty phenotypes. PLS-DA allowed correct classification of participants with 78.2 ± 1.9% accuracy. Older adults with F-T2DM showed an amino acid profile characterized by higher levels of 3-methylhistidine, alanine, arginine, ethanolamine, and glutamic acid. PF&S and control participants were discriminated based on serum concentrations of aminoadipic acid, aspartate, citrulline, cystine, taurine, and tryptophan. These findings suggest that different types of frailty may be characterized by distinct metabolic perturbations. Amino acid profiling may therefore serve as a valuable tool for frailty biomarker discovery.PMID:37110200 | DOI:10.3390/metabo13040542

Metabolites. 2023 Apr 10;13(4):538. doi: 10.3390/metabo13040538.ABSTRACTCognitive dysfunction is a frequent complication of type 2 diabetes mellitus (T2DM), usually accompanied by metabolic disorders. However, the metabolic changes in diabetic cognitive dysfunction (DCD) patients, especially compared to T2DM groups, are not fully understood. Due to the subtle differences in metabolic alterations between DCD groups and T2DM groups, the comprehensive detection of the untargeted metabolic profiles of hippocampus and urine samples of rats was conducted by LC-MS, considering the different ionization modes and polarities of the examined compounds, and feature-based molecular networking (FBMN) was performed to help identify differential metabolites from a comprehensive perspective in this study. In addition, an association analysis of the differential metabolites in hippocampus and urine was conducted by the O2PLS model. Finally, a total of 71 hippocampal tissue differential metabolites and 179 urine differential metabolites were identified. The pathway enrichment results showed that glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism, glycerol phospholipid metabolism, TCA cycle, and arginine biosynthesis in the hippocampus of DCD animals were changed. Seven metabolites (AUC > 0.9) in urine appeared as key differential metabolites that might reflect metabolic changes in the target tissue of DCD rats. This study showed that FBMN facilitated the comprehensive identification of differential metabolites in DCD rats. The differential metabolites may suggest an underlying DCD and be considered as potential biomarkers for DCD. Large samples and clinical experiments are needed for the subsequent elucidation of the possible mechanisms leading to these alterations and the verification of potential biomarkers.PMID:37110195 | DOI:10.3390/metabo13040538

Metabolites. 2023 Apr 9;13(4):534. doi: 10.3390/metabo13040534.ABSTRACTMetabolomics constitutes a promising approach to clinical diagnostics, but its practical implementation in clinical settings is hindered by the requirement for rapid and efficient analytical methods [...].PMID:37110192 | DOI:10.3390/metabo13040534

Metabolites. 2023 Apr 7;13(4):533. doi: 10.3390/metabo13040533.ABSTRACTThe intensive use of sunscreen products has raised concerns regarding their environmental toxicity and the adverse impacts of ultraviolet (UV) filters on ecologically important coral communities. Prior metabolomic analyses on symbiotic coral Pocillopora damicornis exposed to the UV filter butyl methoxydibenzoylmethane (BM, avobenzone) revealed unidentified ions in the holobiont metabolome. In the present study, follow-up differential metabolomic analyses in BM-exposed P. damicornis detected 57 ions with significantly different relative concentrations in exposed corals. The results showed an accumulation of 17 BM derivatives produced through BM reduction and esterification. The major derivative identified C16:0-dihydroBM, which was synthesized and used as a standard to quantify BM derivatives in coral extracts. The results indicated that relative amounts of BM derivatives made up to 95% of the total BM (w/w) absorbed in coral tissue after 7 days of exposure. Among the remaining metabolites annotated, seven compounds significantly affected by BM exposure could be attributed to the coral dinoflagellate symbiont, indicating that BM exposure might impair the photosynthetic capacity of the holobiont. The present results suggest that the potential role of BM in coral bleaching in anthropogenic areas should be investigated and that BM derivatives should be considered in future assessments on the fate and effects of BM in the environment.PMID:37110191 | DOI:10.3390/metabo13040533

Metabolites. 2023 Apr 7;13(4):530. doi: 10.3390/metabo13040530.ABSTRACTPerturbations of the gut microbiome are often intertwined with the onset and development of diverse metabolic diseases. It has been suggested that gut microbiome perturbation could be a potential mechanism through which environmental chemical exposure induces or exacerbates human diseases. Microplastic pollution, an emerging environmental issue, has received ever increasing attention in recent years. However, interactions between microplastic exposure and the gut microbiota remain elusive. This study aimed to decipher the responses of the gut microbiome upon microplastic polystyrene (MP) exposure by integrating 16S rRNA high-throughput sequencing with metabolomic profiling techniques using a C57BL/6 mouse model. The results indicated that MP exposure significantly perturbed aspects of the gut microbiota, including its composition, diversity, and functional pathways that are involved in xenobiotic metabolism. A distinct metabolite profile was observed in mice with MP exposure, which probably resulted from changes in gut bacterial composition. Specifically, untargeted metabolomics revealed that levels of metabolites associated with cholesterol metabolism, primary and secondary bile acid biosynthesis, and taurine and hypotaurine metabolism were changed significantly. Targeted approaches indicated significant perturbation with respect to the levels of short-chain fatty acids derived from the gut microbiota. This study can provide evidence for the missing link in understanding the mechanisms behind the toxic effects of microplastics.PMID:37110188 | DOI:10.3390/metabo13040530

Metabolites. 2023 Apr 6;13(4):525. doi: 10.3390/metabo13040525.ABSTRACTSurvivors of acute radiation exposure are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Non-invasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed to identify urinary metabolites indicative of radiation-induced cardiac damage by analyzing previously collected urine samples from a published study. The samples were collected from male and female wild-type (C57BL/6N) and transgenic mice constitutively expressing activated protein C (APCHi), a circulating protein with potential cardiac protective properties, who were exposed to 9.5 Gy of γ-rays. We utilized LC-MS-based metabolomics and lipidomics for the analysis of urine samples collected at 24 h, 1 week, 1 month, 3 months, and 6 months post-irradiation. Radiation caused perturbations in the TCA cycle, glycosphingolipid metabolism, fatty acid oxidation, purine catabolism, and amino acid metabolites, which were more prominent in the wild-type (WT) mice compared to the APCHi mice, suggesting a differential response between the two genotypes. After combining the genotypes and sexes, we identified a multi-analyte urinary panel at early post-irradiation time points that predicted heart dysfunction using a logistic regression model with a discovery validation study design. These studies demonstrate the utility of a molecular phenotyping approach to develop a urinary biomarker panel predictive of the delayed effects of ionizing radia-tion. It is important to note that no live mice were used or assessed in this study; instead, we focused solely on analyzing previously collected urine samples.PMID:37110184 | DOI:10.3390/metabo13040525

Metabolites. 2023 Apr 5;13(4):523. doi: 10.3390/metabo13040523.ABSTRACTInflammatory processes are common in intensive care (ICU) patients and can induce multiple changes in metabolism, leading to increased risks of morbidity and mortality. Metabolomics enables these modifications to be studied and identifies a patient's metabolic profile. The objective is to precise if the use of metabolomics at ICU admission can help in prognostication. This is a prospective ex-vivo study, realized in a university laboratory and a medico-surgical ICU. Metabolic profiles were analyzed by proton nuclear magnetic resonance. Using multivariable analysis, we compared metabolic profiles of volunteers and ICU patients divided into predefined subgroups: sepsis, septic shock, other shock and ICU controls. We also assessed possible correlations between metabolites and mortality. One hundred and eleven patients were included within 24 h of ICU admission, and 19 healthy volunteers. The ICU mortality rate was 15%. Metabolic profiles were different in ICU patients compared to healthy volunteers (p < 0.001). Among the ICU patients, only the subgroup of patients with septic shock had significant differences compared to the ICU control patients in several metabolites: pyruvate, lactate, carnitine, phenylalanine, urea, creatine, creatinine and myo-inositol. However, there was no correlation between these metabolite profiles and mortality. On the first day of ICU admission, we observed changes in some metabolic products in patients with septic shock, suggesting increased anaerobic glycolysis, proteolysis, lipolysis and gluconeogenesis. These changes were not correlated with prognosis.PMID:37110181 | DOI:10.3390/metabo13040523

Metabolites. 2023 Apr 5;13(4):522. doi: 10.3390/metabo13040522.ABSTRACTEpoxiconazole (EPX), a triazole fungicide, is widely used in agriculture to control pests and diseases. High residual and occupational exposure to EPX increases health risks, and evidence of potential harm to mammals remains to be added. In the present study, 6-week-old male mice were exposed to 10 and 50 mg/kg bw EPX for 28 days. The results showed that EPX significantly increased the liver weights. EPX also decreased the mucus secretion of the colon and altered intestinal barrier function in mice including a reduced expression of some genes (Muc2, meprinβ, tjp1). Moreover, EPX altered the composition and abundance of gut microbiota in the colon of mice. The alpha diversity indices (Shannon, Simpson) in the gut microbiota increased after exposure to EPX for 28 days. Interestingly, EPX increased the ratio of Firmicutes to Bacteroides and the abundance of other harmful bacteria including Helicobacter and Alistipes. Based on the untargeted metabolomic analysis, it was found that EPX altered the metabolic profiles of the liver in mice. KEGG analysis of differential metabolites revealed that EPX disrupted the pathway related to glycolipid metabolism, and the mRNA levels of related genes were also confirmed. In addition, the correlation analysis showed that the most altered harmful bacteria were associated with some significantly altered metabolites. The findings highlight that EPX exposure changed the micro-environment and lipid metabolism disturbance. These results also suggest that the potential toxicity of triazole fungicides to mammals cannot be ignored.PMID:37110180 | DOI:10.3390/metabo13040522

Metabolites. 2023 Apr 3;13(4):514. doi: 10.3390/metabo13040514.ABSTRACTDemographic and clinical factors influence the metabolome. The discovery and validation of disease biomarkers are often challenged by potential confounding effects from such factors. To address this challenge, we investigated the magnitude of the correlation between serum and urine metabolites and demographic and clinical parameters in a well-characterized observational cohort of 444 post-menopausal women participating in the Women's Health Initiative (WHI). Using LC-MS and lipidomics, we measured 157 aqueous metabolites and 756 lipid species across 13 lipid classes in serum, along with 195 metabolites detected by GC-MS and NMR in urine and evaluated their correlations with 29 potential disease risk factors, including demographic, dietary and lifestyle factors, and medication use. After controlling for multiple testing (FDR < 0.01), we found that log-transformed metabolites were mainly associated with age, BMI, alcohol intake, race, sample storage time (urine only), and dietary supplement use. Statistically significant correlations were in the absolute range of 0.2-0.6, with the majority falling below 0.4. Incorporation of important potential confounding factors in metabolite and disease association analyses may lead to improved statistical power as well as reduced false discovery rates in a variety of data analysis settings.PMID:37110172 | DOI:10.3390/metabo13040514

Metabolites. 2023 Mar 31;13(4):508. doi: 10.3390/metabo13040508.ABSTRACTColorectal cancer (CRC) is the second leading cause of cancer deaths. Despite recent advances, five-year survival rates remain largely unchanged. Desorption electrospray ionization mass spectrometry imaging (DESI) is an emerging nondestructive metabolomics-based method that retains the spatial orientation of small-molecule profiles on tissue sections, which may be validated by 'gold standard' histopathology. In this study, CRC samples were analyzed by DESI from 10 patients undergoing surgery at Kingston Health Sciences Center. The spatial correlation of the mass spectral profiles was compared with histopathological annotations and prognostic biomarkers. Fresh frozen sections of representative colorectal cross sections and simulated endoscopic biopsy samples containing tumour and non-neoplastic mucosa for each patient were generated and analyzed by DESI in a blinded fashion. Sections were then hematoxylin and eosin (H and E) stained, annotated by two independent pathologists, and analyzed. Using PCA/LDA-based models, DESI profiles of the cross sections and biopsies achieved 97% and 75% accuracies in identifying the presence of adenocarcinoma, using leave-one-patient-out cross validation. Among the m/z ratios exhibiting the greatest differential abundance in adenocarcinoma were a series of eight long-chain or very-long-chain fatty acids, consistent with molecular and targeted metabolomics indicators of de novo lipogenesis in CRC tissue. Sample stratification based on the presence of lympovascular invasion (LVI), a poor CRC prognostic indicator, revealed the abundance of oxidized phospholipids, suggestive of pro-apoptotic mechanisms, was increased in LVI-negative compared to LVI-positive patients. This study provides evidence of the potential clinical utility of spatially-resolved DESI profiles to enhance the information available to clinicians for CRC diagnosis and prognosis.PMID:37110166 | DOI:10.3390/metabo13040508

Metabolites. 2023 Mar 31;13(4):506. doi: 10.3390/metabo13040506.ABSTRACTThis prospective observational study aimed to evaluate the association of metabolomic alterations with weight loss outcomes following sleeve gastrectomy (SG). We evaluated the metabolomic profile of serum and feces prior to SG and three months post-SG, along with weight loss outcomes in 45 adults with obesity. The percent total weight loss for the highest versus the lowest weight loss tertiles (T3 vs. T1) was 17.0 ± 1.3% and 11.1 ± 0.8%, p < 0.001. Serum metabolite alterations specific to T3 at three months included a decrease in methionine sulfoxide concentration as well as alterations to tryptophan and methionine metabolism (p < 0.03). Fecal metabolite changes specific to T3 included a decrease in taurine concentration and perturbations to arachidonic acid metabolism, and taurine and hypotaurine metabolism (p < 0.002). Preoperative metabolites were found to be highly predictive of weight loss outcomes in machine learning algorithms, with an average area under the curve of 94.6% for serum and 93.4% for feces. This comprehensive metabolomics analysis of weight loss outcome differences post-SG highlights specific metabolic alterations as well as machine learning algorithms predictive of weight loss. These findings could contribute to the development of novel therapeutic targets to enhance weight loss outcomes after SG.PMID:37110164 | DOI:10.3390/metabo13040506

Metabolites. 2023 Mar 31;13(4):505. doi: 10.3390/metabo13040505.ABSTRACTThe in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother-newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24-32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity.PMID:37110162 | DOI:10.3390/metabo13040505

Metabolites. 2023 Mar 29;13(4):495. doi: 10.3390/metabo13040495.ABSTRACTOur current understanding of organophosphorus agent (pesticides and chemical warfare nerve agents) metabolism in humans is limited to the general transformation by cytochrome P450 enzymes and, to some extent, by esterases and paraoxonases. The role of compound concentrations on the rate of clearance is not well established and is further explored in the current study. We discuss the metabolism of 56 diverse organophosphorus compounds (both pesticides and chemical warfare nerve agent simulants), many of which were explored at two variable dose regimens (high and low), determining their clearance rates (Clint) in human liver microsomes. For compounds that were soluble at high concentrations, 1D-NMR, 31P, and MRM LC-MS/MS were used to calculate the Clint and the identity of certain metabolites. The determined Clint rates ranged from 0.001 to 2245.52 µL/min/mg of protein in the lower dose regimen and from 0.002 to 98.57 µL/min/mg of protein in the high dose regimen. Though direct equivalency between the two regimens was absent, we observed (1) both mono- and bi-phasic metabolism of the OPs and simulants in the microsomes. Compounds such as aspon and formothion exhibited biphasic decay at both high and low doses, suggesting either the involvement of multiple enzymes with different KM or substrate/metabolite effects on the metabolism. (2) A second observation was that while some compounds, such as dibrom and merphos, demonstrated a biphasic decay curve at the lower concentrations, they exhibited only monophasic metabolism at the higher concentration, likely indicative of saturation of some metabolic enzymes. (3) Isomeric differences in metabolism (between Z- and E- isomers) were also observed. (4) Lastly, structural comparisons using examples of the oxon group over the original phosphorothioate OP are also discussed, along with the identification of some metabolites. This study provides initial data for the development of in silico metabolism models for OPs with broad applications.PMID:37110155 | DOI:10.3390/metabo13040495

Metabolites. 2023 Mar 29;13(4):494. doi: 10.3390/metabo13040494.ABSTRACTHeat stress (HS) during late gestation implies unfavorable effects on dairy cows and their in-utero heat stressed offspring. The objective of the present study was to elucidate the effect of intrauterine (maternal) HS during the last week of gestation on blood metabolite concentrations of female dairy calves during their first week of life. We defined the mean temperature humidity index (mTHI) during the last gestation week of ≥60 as threshold for maternal HS. In this regard, we compared differences in metabolite concentrations of maternally heat stressed (MHSCALVES) (n = 14) and not heat stressed (NMHSCALVES) (n = 33) calves. We identified 15 metabolites from five different biochemical classes (phosphatidylcholines, cholesteryl esters, sphingomyelins, cresols and hexoses) as potential biomarkers for maternal HS in calves. The plasma concentrations of all significantly affected metabolites were lower in MHSCALVES when compared to NMHSCALVES. The effect of maternal HS during the last week of gestation on blood metabolite concentrations of the female offspring during the first week after birth might be due to HS induced intergenerational physiological alterations, impaired colostrum quality or epigenetic modifications of the calf genome. The results of this pilot study should be validated in ongoing fully standardized studies.PMID:37110153 | DOI:10.3390/metabo13040494