Multi-omics analysis of glucose-mediated signaling by a moonlighting Gß protein Asc1/RACK1.

Heterotrimeric G proteins were originally discovered through efforts to understand the effects of hormones, such as glucagon and epinephrine, on glucose metabolism. On the other hand, many cellular metabolites, including glucose, serve as ligands for G protein-coupled receptors. Here we investigate the consequences of glucose-mediated receptor signaling, and in particular the role of a Gα subunit Gpa2 and a non-canonical Gß subunit, known as Asc1 in yeast and RACK1 in animals. Asc1/RACK1 is of particular interest because it has multiple, seemingly unrelated, functions in the cell. The existence of such "moonlighting" operations has complicated the determination of phenotype from genotype. Through a comparative analysis of individual gene deletion mutants, and by integrating transcriptomics and metabolomics measurements, we have determined the relative contributions of the Gα and Gß protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating carbohydrate metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Of the two subunits, Gpa2 regulates a greater number of gene transcripts and was particularly important in determining the amplitude of response to glucose addition. We conclude that the two G protein subunits regulate distinct but complementary processes downstream of the glucose-sensing receptor, as well as processes that lead ultimately to changes in cell growth and metabolism.

Longitudinal associations of pre-pregnancy BMI and gestational weight gain with maternal urinary metabolites: an NYU CHES study.

BACKGROUND/OBJECTIVES: Excessive gestational weight gain (GWG) and pre-pregnancy obesity affect a significant portion of the US pregnant population and are linked with negative maternal and child health outcomes. The objective of this study was to explore associations of pre-pregnancy body mass index (pBMI) and GWG with longitudinally measured maternal urinary metabolites throughout pregnancy. SUBJECTS/METHODS: Among 652 participants in the New York University Children's Health and Environment Study, a longitudinal pregnancy cohort, targeted metabolomics were measured in serially collected urine samples throughout pregnancy. Metabolites were measured at median 10 (T1), 21 (T2), and 29 (T3) weeks gestation using the Biocrates AbsoluteIDQ® p180 Urine Extension kit. Acylcarnitine, amino acid, biogenic amine, phosphatidylcholine, lysophosphatidylcholine, sphingolipid, and sugar levels were quantified. Pregnant people 18 years or older, without type 1 or 2 diabetes and with singleton live births and valid pBMI and metabolomics data were included. GWG and pBMI were calculated using weight and height data obtained from electronic health records. Linear mixed effects models with interactions with time were fit to determine the gestational age-specific associations of categorical pBMI and continuous interval-specific GWG with urinary metabolites. All analyses were corrected for false discovery rate. RESULTS: Participants with obesity had lower long-chain acylcarnitine levels throughout pregnancy and lower phosphatidylcholine and glucogenic amino acids and higher phenylethylamine concentrations in T2 and T3 compared with participants with normal/underweight pBMI. GWG was associated with taurine in T2 and T3 and C5 acylcarnitine species, C5:1, C5-DC, and C5-M-DC, in T2. CONCLUSIONS: pBMI and GWG were associated with the metabolic environment of pregnant individuals, particularly in relation to mid-pregnancy. These results highlight the importance of both preconception and prenatal maternal health.

Oral administration of TiO2 nanoparticles during early life impacts cardiac and neurobehavioral performance and metabolite profile in an age- and sex-related manner.

BACKGROUND: Nanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague-Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2-5, PND 7-10, or PND 17-20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses. RESULTS: Heart rate was found to be significantly decreased in female pups when dosed between PND 7-10 and PND 17-20. Females dosed between PND 2-5 showed decrease acoustic startle response and when dosed between PND 7-10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17-20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism. CONCLUSION: Oral administration of TiO2 NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO2 NP.

Intravenous administration of three multiwalled carbon nanotubes to female rats and their effect on urinary biochemical profile.

This study was conducted to investigate the influence of outer diameter (OD) and length (L) of multiwalled carbon nanotubes (MWCNTs) on biodistribution and the perturbation of endogenous metabolite profiles. Three different-sized carboxylated MWCNTs (NIEHS-12-2: L 0.5-2 µm, OD 10-20 nm, NIEHS-13-2: L 0.5-2 µm, OD 30-50 nm, and NIEHS-14-2: L 10-30 µm, OD 10-20 nm) in water were administered to female Sprague-Dawley rats as a single intravenous dose of 1 mg/kg MWCNTs. Biodistribution in liver, lung, spleen, and lymph nodes was evaluated in tissue sections at 1 and 7 days' post-dosing using enhanced darkfield microscopy and hyperspectral imaging. Nuclear magnetic resonance (NMR) analysis was used for biochemical profiling and pathway mapping of endogenous metabolites in urine collected at 24-h intervals prior to dosing, at Day 1 and Day 7. At Day 1 and Day 7, all three MWCNTs were observed in liver. NIEHS-12-2 was observed in spleen, whereas NIEHS-13-2 and NIEHS-14-2 were not. All three MWCNTs were observed in lymph nodes and lung at Day 7. The urinary biochemical profile showed the highest positive fold change (FC) at Day 7 for the metabolites acetate, alanine, and lactate, whereas 1-methylnicotinamide, 2-oxoglutarate, and hippurate had some of the lowest FCs for all three MWCNTs. This study demonstrates that the observed tissue location of MWCNTs is size dependent. Overlaps in the perturbation of endogenous metabolite profiles were found regardless of their size, and the biochemical responses were more profound at Day 7 compared with Day 1, indicating a delayed biological response to MWCNTs.

Dietary Supplements for Athletic Performance in Women: Beta-Alanine, Caffeine, and Nitrate.

Beta-alanine, caffeine, and nitrate are dietary supplements generally recognized by the sport and exercise science community as evidence-based ergogenic performance aids. Evidence supporting the efficacy of these supplements, however, is greatly skewed due to research being conducted primarily in men. The physiological differences between men and women, most notably in sex hormones and menstrual cycle fluctuations, make generalizing male data to the female athlete inappropriate, and potentially harmful to women. This narrative review outlines the studies conducted in women regarding the efficacy of beta-alanine, caffeine, and nitrate supplementation for performance enhancement. Only nine studies on beta-alanine, 15 on caffeine, and 10 on nitrate in healthy women under the age of 40 years conducted in normoxia conditions were identified as relevant to this research question. Evidence suggests that beta-alanine may lower the rate of perceived exertion and extend training bouts in women, leading to greater functional adaptations. Studies of caffeine in women suggest the physiological responder status and caffeine habituation may contribute to caffeine's efficacy, with a potential plateau in the dose-response relationship of performance enhancement. Nitrate appears to vary in influence based on activity type and primary muscle group examined. However, the results summarized in the limited literature for each of these three supplements provide no consensus on dosage, timing, or efficacy for women. Furthermore, the literature lacks considerations for hormonal status and its role in metabolism. This gap in sex-based knowledge necessitates further research on these ergogenic supplements in women with greater considerations for the effects of hormonal status.

Associations between the gut microbiome and metabolome in early life.

BACKGROUND: The infant intestinal microbiome plays an important role in metabolism and immune development with impacts on lifelong health. The linkage between the taxonomic composition of the microbiome and its metabolic phenotype is undefined and complicated by redundancies in the taxon-function relationship within microbial communities. To inform a more mechanistic understanding of the relationship between the microbiome and health, we performed an integrative statistical and machine learning-based analysis of microbe taxonomic structure and metabolic function in order to characterize the taxa-function relationship in early life. RESULTS: Stool samples collected from infants enrolled in the New Hampshire Birth Cohort Study (NHBCS) at approximately 6-weeks (n = 158) and 12-months (n = 282) of age were profiled using targeted and untargeted nuclear magnetic resonance (NMR) spectroscopy as well as DNA sequencing of the V4-V5 hypervariable region from the bacterial 16S rRNA gene. There was significant inter-omic concordance based on Procrustes analysis (6 weeks: p = 0.056; 12 months: p = 0.001), however this association was no longer significant when accounting for phylogenetic relationships using generalized UniFrac distance metric (6 weeks: p = 0.376; 12 months: p = 0.069). Sparse canonical correlation analysis showed significant correlation, as well as identifying sets of microbe/metabolites driving microbiome-metabolome relatedness. Performance of machine learning models varied across different metabolites, with support vector machines (radial basis function kernel) being the consistently top ranked model. However, predictive R2 values demonstrated poor predictive performance across all models assessed (avg: - 5.06% -- 6 weeks; - 3.7% -- 12 months). Conversely, the Spearman correlation metric was higher (avg: 0.344-6 weeks; 0.265-12 months). This demonstrated that taxonomic relative abundance was not predictive of metabolite concentrations. CONCLUSIONS: Our results suggest a degree of overall association between taxonomic profiles and metabolite concentrations. However, lack of predictive capacity for stool metabolic signatures reflects, in part, the possible role of functional redundancy in defining the taxa-function relationship in early life as well as the bidirectional nature of the microbiome-metabolome association. Our results provide evidence in favor of a multi-omic approach for microbiome studies, especially those focused on health outcomes.

Biodistribution, cardiac and neurobehavioral assessments, and neurotransmitter quantification in juvenile rats following oral administration of aluminum oxide nanoparticles.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10 mg/kg Al2 O3 NP (diameter: 24 nm [transmission electron microscope], hydrodynamic diameter: 148 nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

One Step Forward for Reducing False Positive and False Negative Compound Identifications from Mass Spectrometry Metabolomics Data: New Algorithms for Constructing Extracted Ion Chromatograms and Detecting Chromatographic Peaks.

False positive and false negative peaks detected from extracted ion chromatograms (EIC) are an urgent problem with existing software packages that preprocess untargeted liquid or gas chromatography-mass spectrometry metabolomics data because they can translate downstream into spurious or missing compound identifications. We have developed new algorithms that carry out the sequential construction of EICs and detection of EIC peaks. We compare the new algorithms to two popular software packages XCMS and MZmine 2 and present evidence that these new algorithms detect significantly fewer false positives. Regarding the detection of compounds known to be present in the data, the new algorithms perform at least as well as XCMS and MZmine 2. Furthermore, we present evidence that mass tolerance in m/z should be favored rather than mass tolerance in ppm in the process of constructing EICs. The mass tolerance parameter plays a critical role in the EIC construction process and can have immense impact on the detection of EIC peaks.

Detailed Investigation and Comparison of the XCMS and MZmine 2 Chromatogram Construction and Chromatographic Peak Detection Methods for Preprocessing Mass Spectrometry Metabolomics Data.

XCMS and MZmine 2 are two widely used software packages for preprocessing untargeted LC/MS metabolomics data. Both construct extracted ion chromatograms (EICs) and detect peaks from the EICs, the first two steps in the data preprocessing workflow. While both packages have performed admirably in peak picking, they also detect a problematic number of false positive EIC peaks and can also fail to detect real EIC peaks. The former and latter translate downstream into spurious and missing compounds and present significant limitations with most existing software packages that preprocess untargeted mass spectrometry metabolomics data. We seek to understand the specific reasons why XCMS and MZmine 2 find the false positive EIC peaks that they do and in what ways they fail to detect real compounds. We investigate differences of EIC construction methods in XCMS and MZmine 2 and find several problems in the XCMS centWave peak detection algorithm which we show are partly responsible for the false positive and false negative compound identifications. In addition, we find a problem with MZmine 2's use of centWave. We hope that a detailed understanding of the XCMS and MZmine 2 algorithms will allow users to work with them more effectively and will also help with future algorithmic development.

Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure.

Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in Gómez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure.

Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences.

To date, no targeted therapies are available to treat triple negative breast cancer (TNBC), while other breast cancer subtypes are responsive to current therapeutic treatment. Metabolomics was conducted to reveal differences in two hormone receptor-negative TNBC cell lines and two hormone receptor-positive Luminal A cell lines. Studies were conducted in the presence and absence of paclitaxel (Taxol). TNBC cell lines had higher levels of amino acids, branched-chain amino acids, nucleotides, and nucleotide sugars and lower levels of proliferation-related metabolites like choline compared with Luminal A cell lines. In the presence of paclitaxel, each cell line showed unique metabolic responses, with some similarities by type. For example, in the Luminal A cell lines, levels of lactate and creatine decreased while certain choline metabolites and myo-inositol increased with paclitaxel. In the TNBC cell lines levels of glutamine, glutamate, and glutathione increased, whereas lysine, proline, and valine decreased in the presence of drug. Profiling secreted inflammatory cytokines in the conditioned media demonstrated a greater response to paclitaxel in the hormone-positive Luminal cells compared with a secretion profile that suggested greater drug resistance in the TNBC cells. The most significant differences distinguishing the cell types based on pathway enrichment analyses were related to amino acid, lipid and carbohydrate metabolism pathways, whereas several biological pathways were differentiated between the cell lines following treatment.

Microfluidics meets metabolomics to reveal the impact of Campylobacter jejuni infection on biochemical pathways.

Microfluidic devices that are currently being used in pharmaceutical research also have a significant potential for utilization in investigating exposure to infectious agents. We have established a microfluidic device cultured with Caco-2 cells, and utilized metabolomics to investigate the biochemical responses to the bacterial pathogen Campylobacter jejuni. In the microfluidic devices, Caco-2 cells polarize at day 5, are uniform, have defined brush borders and tight junctions, and form a mucus layer. Metabolomics analysis of cell culture media collected from both Caco-2 cell culture systems demonstrated a more metabolic homogenous biochemical profile in the media collected from microfluidic devices, compared with media collected from transwells. GeneGo pathway mapping indicated that aminoacyl-tRNA biosynthesis was perturbed by fluid flow, suggesting that fluid dynamics and shear stress impacts the cells translational quality control. Both microfluidic device and transwell culturing systems were used to investigate the impact of Campylobacter jejuni infection on biochemical processes. Caco-2 cells cultured in either system were infected at day 5 with C. jejuni 81-176 for 48 h. Metabolomics analysis clearly differentiated C. jejuni 81-176 infected and non-infected medias collected from the microfluidic devices, and demonstrated that C. jejuni 81-176 infection in microfluidic devices impacts branched-chain amino acid metabolism, glycolysis, and gluconeogenesis. In contrast, no distinction was seen in the biochemical profiles of infected versus non-infected media collected from cells cultured in transwells. Microfluidic culturing conditions demonstrated a more metabolically homogenous cell population, and present the opportunity for studying host-pathogen interactions for extended periods of time.

Potential serum biomarkers from a metabolomics study of autism.

BACKGROUND: Early detection and diagnosis are very important for autism. Current diagnosis of autism relies mainly on some observational questionnaires and interview tools that may involve a great variability. We performed a metabolomics analysis of serum to identify potential biomarkers for the early diagnosis and clinical evaluation of autism. METHODS: We analyzed a discovery cohort of patients with autism and participants without autism in the Chinese Han population using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS/MS) to detect metabolic changes in serum associated with autism. The potential metabolite candidates for biomarkers were individually validated in an additional independent cohort of cases and controls. We built a multiple logistic regression model to evaluate the validated biomarkers. RESULTS: We included 73 patients and 63 controls in the discovery cohort and 100 cases and 100 controls in the validation cohort. Metabolomic analysis of serum in the discovery stage identified 17 metabolites, 11 of which were validated in an independent cohort. A multiple logistic regression model built on the 11 validated metabolites fit well in both cohorts. The model consistently showed that autism was associated with 2 particular metabolites: sphingosine 1-phosphate and docosahexaenoic acid. LIMITATIONS: While autism is diagnosed predominantly in boys, we were unable to perform the analysis by sex owing to difficulty recruiting enough female patients. Other limitations include the need to perform test-retest assessment within the same individual and the relatively small sample size. CONCLUSION: Two metabolites have potential as biomarkers for the clinical diagnosis and evaluation of autism.

Macronutrient-differential dietary pattern impacts on body weight, hepatic inflammation, and metabolism.

Introduction: Obesity is a multi-factorial disease frequently associated with poor nutritional habits and linked to many detrimental health outcomes. Individuals with obesity are more likely to have increased levels of persistent inflammatory and metabolic dysregulation. The goal of this study was to compare four dietary patterns differentiated by macronutrient content in a postmenopausal model. Dietary patterns were high carbohydrate (HC), high fat (HF), high carbohydrate plus high fat (HCHF), and high protein (HP) with higher fiber. Methods: Changes in body weight and glucose levels were measured in female, ovariectomized C57BL/6 mice after 15 weeks of feeding. One group of five mice fed the HCHF diet was crossed over to the HP diet on day 84, modeling a 21-day intervention. In a follow-up study comparing the HCHF versus HP dietary patterns, systemic changes in inflammation, using an 80-cytokine array and metabolism, by untargeted liquid chromatography-mass spectrometry (LCMS)-based metabolomics were evaluated. Results: Only the HF and HCHF diets resulted in obesity, shown by significant differences in body weights compared to the HP diet. Body weight gains during the two-diet follow-up study were consistent with the four-diet study. On Day 105 of the 4-diet study, glucose levels were significantly lower for mice fed the HP diet than for those fed the HC and HF diets. Mice switched from the HCHF to the HP diet lost an average of 3.7 grams by the end of the 21-day intervention, but this corresponded with decreased food consumption. The HCHF pattern resulted in dramatic inflammatory dysregulation, as all 80 cytokines were elevated significantly in the livers of these mice after 15 weeks of HCHF diet exposure. Comparatively, only 32 markers changed significantly on the HP diet (24 up, 8 down). Metabolic perturbations in several endogenous biological pathways were also observed based on macronutrient differences and revealed dysfunction in several nutritionally relevant biosynthetic pathways. Conclusion: Overall, the HCHF diet promoted detrimental impacts and changes linked to several diseases, including arthritis or breast neoplasms. Identification of dietary pattern-specific impacts in this model provides a means to monitor the effects of disease risk and test interventions to prevent poor health outcomes through nutritional modification.

Untargeted metabolomics reveal signatures of a healthy lifestyle.

This cross-sectional study investigated differences in the plasma metabolome in two groups of adults that were of similar age but varied markedly in body composition and dietary and physical activity patterns. Study participants included 52 adults in the lifestyle group (LIFE) (28 males, 24 females) and 52 in the control group (CON) (27 males, 25 females). The results using an extensive untargeted ultra high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) metabolomics analysis with 10,535 metabolite peaks identified 486 important metabolites (variable influence on projections scores of VIP ≥ 1) and 16 significantly enriched metabolic pathways that differentiated LIFE and CON groups. A novel metabolite signature of positive lifestyle habits emerged from this analysis highlighted by lower plasma levels of numerous bile acids, an amino acid profile characterized by higher histidine and lower glutamic acid, glutamine, ß-alanine, phenylalanine, tyrosine, and proline, an elevated vitamin D status, higher levels of beneficial fatty acids and gut microbiome catabolism metabolites from plant substrates, and reduced levels of N-glycan degradation metabolites and environmental contaminants. This study established that the plasma metabolome is strongly associated with body composition and lifestyle habits. The robust lifestyle metabolite signature identified in this study is consistent with an improved life expectancy and a reduced risk for chronic disease.

Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification.

Introduction: Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed. Methods: Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences. Results: We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2). Conclusions: These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility.

Community-level exposomics: a population-centered approach to address public health concerns.

Environmental factors affecting health and vulnerability far outweigh genetics in accounting for disparities in health status and longevity in US communities. The concept of the exposome, the totality of exposure from conception onwards, provides a paradigm for researchers to investigate the complex role of the environment on the health of individuals. We propose a complementary framework, community-level exposomics, for population-level exposome assessment. The goal is to bring the exposome paradigm to research and practice on the health of populations, defined by various axes including geographic, social, and occupational. This framework includes the integration of community-level measures of the built, natural and social environments, environmental pollution-derived from conventional and community science approaches, internal markers of exposure that can be measured at the population-level and early responses associated with health status that can be tracked using population-based monitoring. Primary challenges to the implementation of the proposed framework include needed advancements in population-level measurement, lack of existing models with the capability to produce interpretable and actionable evidence and the ethical considerations of labeling geographically-bound populations by exposomic profiles. To address these challenges, we propose a set of recommendations that begin with greater engagement with and empowerment of affected communities and targeted investment in community-based solutions. Applications to urban settings and disaster epidemiology are discussed as examples for implementation.

A Review of Metabolic Targets of Anticancer Nutrients and Nutraceuticals in Pre-Clinical Models of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is notoriously aggressive and has poorer outcomes as compared with other breast cancer subtypes. Due to a lack of targeted therapies, TNBC is often treated with chemotherapeutics as opposed to hormone therapy or other targeted therapies available to individuals with estrogen receptor positive (ER+) breast cancers. Because of the lack of treatment options for TNBC, other therapeutic avenues are being explored. Metabolic reprogramming, a hallmark of cancer, provides potential opportunities to target cancer cells more specifically, increasing efficacy and reducing side effects. Nutrients serve a significant role in metabolic processes involved in DNA transcription, protein folding, and function as co-factors in enzyme activity, and may provide novel strategies to target cancer cell metabolism in TNBC. This article reviews studies that have investigated how nutrients/nutraceuticals target metabolic processes in TNBC cells alone or in combination with existing drugs to exert anticancer effects. These agents have been shown to cause perturbations in many metabolic processes related to glucose metabolism, fatty acid metabolism, as well as autophagy and oxidative stress-related metabolism. With this information, we present the potential of nutrients as metabolism-directed anticancer agents and the potential for using these agents alone or in cocktails as a new direction for TNBC therapy.

Investigation of eight cellulose nanomaterials' impact on Differentiated Caco-2 monolayer integrity and cytotoxicity.

The potential applications of cellulose nanomaterials (CNMs) as food additives or in food packaging, present a possible source of human ingestion. While micron- and macro-scale cellulose products are classified as Generally Regarded As Safe, the safety of ingested nano-scale cellulose is largely unknown. Using fully differentiated Caco-2 cells, the perturbation of intestinal barrier function and cytotoxicity was investigated for four nanocellulose crystals (CNCs) and four nanocellulose fibrils (CNFs) following 24 h of exposure at 50 µg/mL. Scanning electron microscope showed some aggregation of both CNCs and CNFs. X-ray photoelectron spectroscopy analyses showed that carbon and oxygen were the main elements. The zeta-potential for CNMs formulated in cell culture medium showed a negative surface charge. Two CNMs increased cell membrane permeability and three CNMs decreased the cell metabolic activity. While three CNMs lead to cytotoxic responses, no changes in apparent permeability coefficient (Papp) for dextran or tight junction integrity were found. Our results show that three CNMs induce cytotoxicity in differentiated Caco-2 cells, demonstrating the need to understand the role of size and shape. The interaction between CNMs and the intestinal epithelium needs to be evaluated to understand potential intestinal barrier dysfunction and resulting health implications following CNM ingestion.