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1.
J Endocr Soc ; 3(10): 1825-1836, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31555753

ABSTRACT

PURPOSE: To report age-specific serum estradiol concentration in nonsmoking, lean US men without comorbidities. We provide concentrations from 30 and 15 to 20 years ago given previously described declines in serum estradiol in US men over time. METHODS: We used data from the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1991) and continuous NHANES (1999 to 2004). Serum estradiol and SHBG were previously measured by competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, SHBG, and albumin. By age, we calculated median concentrations overall and for nonsmoking, lean (body mass index <25 kg/m2 and waist <102 cm) men without diabetes, cardiovascular disease, or cancer. RESULTS: Overall, respective total estradiol medians for men ages 20 to 39, 40 to 59, and ≥60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective total estradiol medians were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in continuous NHANES. Overall, respective free estradiol medians were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective free estradiol medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL continuous NHANES. CONCLUSION: We report US nationally representative serum estradiol concentrations in healthy men, which could be used for targeting estradiol during testosterone supplementation and for general good health.

2.
Toxicol Appl Pharmacol ; 367: 12-22, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30684530

ABSTRACT

Catechol-O-methyltransferase (COMT) acts as a 'gate-keeper' to prevent DNA damage during estrogen metabolism. Both experimental and epidemiological studies suggest the role of COMT in pathogenesis of human breast cancer (BCa). It was previously reported that inhibition of COMT enzyme activity in estradiol-treated human breast epithelial carcinoma-derived MCF-7 cells caused increased oxidative DNA damage and formation of mutagenic depurinating adducts. To improve our understanding of factors influencing estrogen metabolism in BCa, it requires a mechanistic study illustrating the regulation of this 'gate-keeper'. We investigated the epigenetic mechanisms underlying decreased COMT transcription in MCF-7 cells exposed to 17ß-estradiol (E2) and the phytoestrogen, genistein (GEN). CpG site-specific methylation at promoters for both soluble (S) and membrane-bound (MB) COMT transcripts were assessed. Both E2 and GEN induced CpG site-specific methylation within the distal promoter of MB-COMT. In addition, ChIP analysis showed that there was increased binding of DNMT3B, MBD2 and HDAC1 within this promoter. These epigenetic changes were associated with decreased COMT transcript levels. Interestingly, sulforaphane, an antioxidant commonly found in cruciferous vegetables, was able to reverse the estrogen-induced epigenetic changes and gene silencing of COMT. Our data provide a new insight in epigenetically targeting COMT transcription. Since reactive estrogen metabolites may contribute to breast cancer, our findings may help in developing prevention and/or intervention strategies for human BCa.


Subject(s)
Breast Neoplasms/genetics , Catechol O-Methyltransferase/genetics , DNA Methylation/drug effects , Epigenesis, Genetic/drug effects , Estradiol/toxicity , Genistein/toxicity , Promoter Regions, Genetic , Transcription, Genetic/drug effects , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Catechol O-Methyltransferase/metabolism , CpG Islands , Down-Regulation , Female , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells
3.
Cancer Epidemiol Biomarkers Prev ; 28(3): 578-583, 2019 03.
Article in English | MEDLINE | ID: mdl-30482876

ABSTRACT

BACKGROUND: Given the recent findings from pooled studies about a potential inverse association between selenium levels and prostate cancer risk, this cross-sectional study aimed to investigate the association between serum selenium and serum concentrations of sex steroid hormones including estradiol in a nationally representative sample of U.S. men to investigate one mechanism by which selenium may influence prostate cancer risk. METHODS: The study included 1,420 men ages 20 years or older who participated in the Third National Health and Nutrition Examination Survey between 1988 and 1994. We calculated age/race-ethnicity-adjusted and multivariable-adjusted geometric mean serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide, and sex hormone binding globulin, and compared them across quartiles of serum selenium. RESULTS: Adjusting for age, race/ethnicity, smoking status, serum cotinine, household income, physical activity, alcohol consumption, and percent body fat, mean total estradiol [e.g., Q1, 38.00 pg/mL (95% confidence interval (CI), 36.03-40.08) vs. Q4, 35.29 pg/mL (95% CI, 33.53-37.14); P trend = 0.050] and free estradiol [e.g., Q1, 0.96 pg/mL (95% CI, 0.92-1.01) vs. Q4, 0.90 (95% CI, 0.85-0.95); P trend = 0.065] concentrations decreased over quartiles of selenium. Stratification by smoking and alcohol consumption, showed that the latter observation was stronger for never smokers (P interaction = 0.073) and those with limited alcohol intake (P interaction = 0.017). No associations were observed for the other sex steroid hormones studied. CONCLUSIONS: Our findings suggests that a possible mechanism by which selenium may be protective for prostate cancer is related to estrogen. IMPACT: Further studies of longitudinal measurements of serum and toenail selenium in relation to serum measurements of sex steroid hormones are needed.


Subject(s)
Carcinogenesis/metabolism , Estradiol/blood , Estrogens/blood , Gonadal Steroid Hormones/blood , Prostatic Neoplasms/blood , Selenium/blood , Adult , Alcohol Drinking/adverse effects , Carcinogenesis/pathology , Cross-Sectional Studies , Follow-Up Studies , Humans , Male , Prognosis , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/prevention & control , Smoking/adverse effects , United States/epidemiology , Young Adult
4.
J Lipid Res ; 60(1): 149-160, 2019 01.
Article in English | MEDLINE | ID: mdl-30473544

ABSTRACT

Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL, and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL-cholesterol (HDL-C) concentrations were common, especially in children with subclinical inflammation. Among 982 proteins analyzed, the relative abundance of 11, 12, and 52 plasma proteins was correlated with LDL-cholesterol (r = -0.43∼0.70), triglycerides (r = -0.39∼0.53), and HDL-C (r = -0.49∼0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4∼40%, and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis, and tissue repair lower by 3∼20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease.


Subject(s)
Lipoproteins/blood , Lipoproteins/metabolism , Proteomics , Rural Population , Biomarkers/blood , Biomarkers/metabolism , Child , Female , Humans , Inflammation/blood , Inflammation/metabolism , Male , Nepal
5.
Sci Rep ; 8(1): 6390, 2018 04 23.
Article in English | MEDLINE | ID: mdl-29686285

ABSTRACT

Fetal growth restriction increases the risk of poor childhood growth and development and chronic disease in adulthood. Yet, little is known about biological pathways that mediate the long-lasting effects of suboptimal intrauterine growth. We explored the plasma proteome in a cohort of 500 Nepalese children 6-8 years of age to identify plasma proteins associated with multiple anthropometric size indicators at birth. Among 982 proteins analyzed, no proteins differed by birth weight, length, or weight-for-length indicators. However, 25 proteins were differentially abundant in children with a small vs normal head circumference at birth (<-2 vs. ≥-2 z-scores of the WHO growth standards). Angiopoietin-like 6 was 19.4% more abundant and the other 24 proteins were 7-21% less abundant in children with a small vs normal head circumference at birth, adjusted for potential confounders. The less abundant proteins included actins, actin filament organizing proteins (α-actinin, talin, filamin, cofilin, profilin, and vinculin), proteins involved in muscle contraction, and glycolytic enzymes, which were all positively correlated with each other. A novel cluster of childhood plasma proteins involved in angiogenesis and cytoskeleton dynamics was associated with a small head size at birth. The prognostic value of an altered proteomic phenotype remains to be investigated.


Subject(s)
Birth Weight , Blood Proteins/analysis , Fetal Growth Retardation/physiopathology , Head/anatomy & histology , Infant, Small for Gestational Age/metabolism , Anthropometry , Child , Cohort Studies , Female , Fetal Growth Retardation/epidemiology , Fetal Growth Retardation/metabolism , Head/physiology , Humans , Infant, Newborn , Infant, Small for Gestational Age/growth & development , Nepal/epidemiology , Prevalence , Proteomics
6.
Arch Biochem Biophys ; 646: 153-160, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29605494

ABSTRACT

Carotenoids are naturally occurring pigments that function as vitamin A precursors, antioxidants, anti-inflammatory agents or biomarkers of recent vegetable and fruit intake, and are thus important for population health and nutritional assessment. An assay approach that measures proteins could be more technologically feasible than chromatography, thus enabling more frequent carotenoid status assessment. We explored associations between proteomic biomarkers and concentrations of 6 common dietary carotenoids (α-carotene, ß-carotene, lutein/zeaxanthin, ß-cryptoxanthin, and lycopene) in plasma from 500 6-8 year old Nepalese children. Samples were depleted of 6 high-abundance proteins. Plasma proteins were quantified using tandem mass spectrometry and expressed as relative abundance. Linear mixed effects models were used to determine the carotenoid:protein associations, accepting a false discovery rate of q < 0.10. We quantified 982 plasma proteins in >10% of all child samples. Among these, relative abundance of 4 were associated with ß-carotene, 11 with lutein/zeaxanthin and 51 with ß-cryptoxanthin. Carotenoid-associated proteins are notably involved in lipid and vitamin A transport, antioxidant function and anti-inflammatory processes. No protein biomarkers met criteria for association with α-carotene or lycopene. Plasma proteomics may offer an approach to assess functional biomarkers of carotenoid status, intake and biological function for public health application. Original maternal micronutrient trial from which data were derived as a follow-up activity was registered at ClinicalTrials.gov: NCT00115271.


Subject(s)
Blood Proteins/metabolism , Carotenoids/metabolism , Biomarkers/blood , Biomarkers/metabolism , Blood Proteins/analysis , Carotenoids/blood , Child , Humans , Linear Models , Mass Spectrometry/methods , Nepal , Proteomics/methods
7.
Public Health Rep ; 132(4): 518-523, 2017.
Article in English | MEDLINE | ID: mdl-28640658

ABSTRACT

OBJECTIVES: In 2014, the National Board of Public Health Examiners performed a job task analysis (JTA) to revise the Certified in Public Health (CPH) examination. The objectives of this study were to describe the development, administration, and results of the JTA survey; to present an analysis of the survey results; and to review the implications of this first-ever public health JTA. METHODS: An advisory committee of public health professionals developed a list of 200 public health job tasks categorized into 10 work domains. The list of tasks was incorporated into a web-based survey, and a snowball sample of public health professionals provided 4850 usable responses. Respondents rated job tasks as essential (4), very important (3), important (2), not very important (1), and never performed (0). RESULTS: The mean task importance ratings ranged from 2.61 to 3.01 (important to very important). The highest mean ratings were for tasks in the ethics domain (mean rating, 3.01). Respondents ranked 10 of the 200 tasks as the most important, with mean task rankings ranging from 2.98 to 3.39. We found subtle differences between male and female respondents and between master of public health and doctor of public health respondents in their rankings. CONCLUSION: The JTA established a set of job tasks in 10 public health work domains, and the results provided a foundation for refining the CPH examination. Additional steps are needed to further modify the content outline of the examination. An empirical assessment of public health job tasks, using methods such as principal components analysis, may provide additional insight.


Subject(s)
Certification/standards , Educational Measurement/standards , Public Health , Task Performance and Analysis , Advisory Committees/standards , Female , Humans , Internet , Male , Surveys and Questionnaires
8.
J Nutr ; 147(3): 304-313, 2017 03.
Article in English | MEDLINE | ID: mdl-28148680

ABSTRACT

Background: Malnutrition affects body growth, size, and composition of children. Yet, few functional biomarkers are known to be associated with childhood morphology.Objective: This cross-sectional study examined associations of anthropometric indicators of height, musculature, and fat mass with plasma proteins by using proteomics in a population cohort of school-aged Nepalese children.Methods: Height, weight, midupper arm circumference (MUAC), triceps and subscapular skinfolds, upper arm muscle area (AMA), and arm fat area (AFA) were assessed in 500 children 6-8 y of age. Height-for-age z scores (HAZs), weight-for-age z scores (WAZs), and body mass index-for-age z scores (BAZs) were derived from the WHO growth reference. Relative protein abundance was quantified by using tandem mass spectrometry. Protein-anthropometry associations were evaluated by linear mixed-effects models and identified as having a false discovery rate (q) <5%.Results: Among 982 proteins, 1, 10, 14, and 17 proteins were associated with BAZ, HAZ, MUAC, and AMA, respectively (q < 0.05). Insulin-like growth factor (IGF)-I, 2 IGF-binding proteins, and carnosinase-1 were associated with both HAZ and AMA. Proteins involved in nutrient transport, activation of innate immunity, and bone mineralization were associated with HAZ. Several extracellular matrix proteins were positively associated with AMA alone. The proteomes of MUAC and AMA substantially overlapped, whereas no proteins were associated with AFA or triceps and subscapular skinfolds. Myosin light-chain kinase, possibly reflecting leakage from muscle, was inversely associated with BAZ. The proteome of WAZ was the largest (n = 33) and most comprehensive, including proteins involved in neural development and oxidative stress response, among others.Conclusions: Plasma proteomics confirmed known biomarkers of childhood growth and revealed novel proteins associated with lean mass in chronically undernourished children. Identified proteins may serve as candidates for assessing growth and nutritional status of children in similar undernourished settings. The antenatal micronutrient supplementation trial yielding the study cohort of children was registered at clinicaltrials.gov as NCT00115271.


Subject(s)
Anthropometry , Blood Proteins/chemistry , Child Nutrition Disorders/blood , Developmental Disabilities/epidemiology , Proteome/chemistry , Blood Proteins/metabolism , Child , Female , Humans , Male , Muscle, Skeletal , Nepal/epidemiology , Nutritional Status , Thinness
9.
Arch Toxicol ; 91(1): 217-230, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27039105

ABSTRACT

In the context of the Human Toxome project, mass spectroscopy-based metabolomics characterization of estrogen-stimulated MCF-7 cells was studied in order to support the untargeted deduction of pathways of toxicity. A targeted and untargeted approach using overrepresentation analysis (ORA), quantitative enrichment analysis (QEA) and pathway analysis (PA) and a metabolite network approach were compared. Any untargeted approach necessarily has some noise in the data owing to artifacts, outliers and misidentified metabolites. Depending on the chemical analytical choices (sample extraction, chromatography, instrument and settings, etc.), only a partial representation of all metabolites will be achieved, biased by both the analytical methods and the database used to identify the metabolites. Here, we show on the one hand that using a data analysis approach based exclusively on pathway annotations has the potential to miss much that is of interest and, in the case of misidentified metabolites, can produce perturbed pathways that are statistically significant yet uninformative for the biological sample at hand. On the other hand, a targeted approach, by narrowing its focus and minimizing (but not eliminating) misidentifications, renders the likelihood of a spurious pathway much smaller, but the limited number of metabolites also makes statistical significance harder to achieve. To avoid an analysis dependent on pathways, we built a de novo network using all metabolites that were different at 24 h with and without estrogen with a p value <0.01 (53) in the STITCH database, which links metabolites based on known reactions in the main metabolic network pathways but also based on experimental evidence and text mining. The resulting network contained a "connected component" of 43 metabolites and helped identify non-endogenous metabolites as well as pathways not visible by annotation-based approaches. Moreover, the most highly connected metabolites (energy metabolites such as pyruvate and alpha-ketoglutarate, as well as amino acids) showed only a modest change between proliferation with and without estrogen. Here, we demonstrate that estrogen has subtle but potentially phenotypically important alterations in the acyl-carnitine fatty acids, acetyl-putrescine and succinoadenosine, in addition to likely subtle changes in key energy metabolites that, however, could not be verified consistently given the technical limitations of this approach. Finally, we show that a network-based approach combined with text mining identifies pathways that would otherwise neither be considered statistically significant on their own nor be identified via ORA, QEA, or PA.


Subject(s)
Energy Metabolism/drug effects , Estradiol/pharmacology , Estrogens/pharmacology , Metabolome/drug effects , Metabolomics/methods , Models, Biological , Secondary Metabolism/drug effects , Toxicology/methods , Chromatography, High Pressure Liquid , Computational Biology , Data Mining , Databases, Factual , Endocrine Disruptors/pharmacology , Humans , MCF-7 Cells , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization
10.
Arch Toxicol ; 91(4): 1749-1762, 2017 Apr.
Article in English | MEDLINE | ID: mdl-27592001

ABSTRACT

The twenty-first century vision for toxicology involves a transition away from high-dose animal studies to in vitro and computational models (NRC in Toxicity testing in the 21st century: a vision and a strategy, The National Academies Press, Washington, DC, 2007). This transition requires mapping pathways of toxicity by understanding how in vitro systems respond to chemical perturbation. Uncovering transcription factors/signaling networks responsible for gene expression patterns is essential for defining pathways of toxicity, and ultimately, for determining the chemical modes of action through which a toxicant acts. Traditionally, transcription factor identification is achieved via chromatin immunoprecipitation studies and summarized by calculating which transcription factors are statistically associated with up- and downregulated genes. These lists are commonly determined via statistical or fold-change cutoffs, a procedure that is sensitive to statistical power and may not be as useful for determining transcription factor associations. To move away from an arbitrary statistical or fold-change-based cutoff, we developed, in the context of the Mapping the Human Toxome project, an enrichment paradigm called information-dependent enrichment analysis (IDEA) to guide identification of the transcription factor network. We used a test case of activation in MCF-7 cells by 17ß estradiol (E2). Using this new approach, we established a time course for transcriptional and functional responses to E2. ERα and ERß were associated with short-term transcriptional changes in response to E2. Sustained exposure led to recruitment of additional transcription factors and alteration of cell cycle machinery. TFAP2C and SOX2 were the transcription factors most highly correlated with dose. E2F7, E2F1, and Foxm1, which are involved in cell proliferation, were enriched only at 24 h. IDEA should be useful for identifying candidate pathways of toxicity. IDEA outperforms gene set enrichment analysis (GSEA) and provides similar results to weighted gene correlation network analysis, a platform that helps to identify genes not annotated to pathways.


Subject(s)
Estradiol/toxicity , Estrogen Receptor alpha/drug effects , Estrogen Receptor beta/drug effects , Toxicity Tests/methods , Animals , Cell Proliferation/drug effects , Estradiol/administration & dosage , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Gene Expression Regulation/drug effects , Humans , MCF-7 Cells , SOXB1 Transcription Factors/genetics , Signal Transduction/drug effects , Time Factors , Transcription Factor AP-2/genetics , Transcription Factors/genetics
11.
Int J Vitam Nutr Res ; 87(5-6): 1-10, 2017 Sep.
Article in English | MEDLINE | ID: mdl-27164173

ABSTRACT

Selenium deficiency or excess may have public health consequences, yet selenium status is infrequently characterized in populations, perhaps due to challenges in methodology. We are seeking to identify plasma proteins, using proteomics discovery and validation approaches, to serve as proxies for micronutrient status, including selenium, which may in the future be more readily assessed by robust, affordable field methods. In a sample of rural Nepalese children 6 - 8 years old (n = 500), the prevalence of selenium deficiency was 13.6 and 60.9 % at plasma selenium concentrations < 0.60 and < 0.89 µmol/L, respectively, assessed by atomic absorption spectroscopy. Relative abundance of selenoprotein P isoform 1 (SEPP1), glutathione reductase-3, and apolipoprotein A2 from discovery-based experiments was correlated with plasma selenium with a false discovery rate < 10 % (i. e., q < 0.10), all with p < 0.001. In linear mixed effects regression models to predict plasma selenium, only SEPP1 was significant (R2 = 0.63), estimating 8.2 % (95 % CI: 3.9 - 12.6) and 65.5(61.4 - 69.7)% of the in-sample population as deficient at each respective cut-off. Targeted quantification of SEPP1 in a preliminary series of specimens (n = 19) as a validation of the discovery approach revealed a high correlation with plasma selenium (r = 0.757, p = 0.0002). Plasma proteomics can identify valid plasma protein indicators of micronutrient status, as shown with selenium, comprising a step toward making population assessment of selenium status in vulnerable groups more accessible.

14.
Sci Rep ; 6: 28994, 2016 07 26.
Article in English | MEDLINE | ID: mdl-27456714

ABSTRACT

Common recommendations for cell line authentication, annotation and quality control fall short addressing genetic heterogeneity. Within the Human Toxome Project, we demonstrate that there can be marked cellular and phenotypic heterogeneity in a single batch of the human breast adenocarcinoma cell line MCF-7 obtained directly from a cell bank that are invisible with the usual cell authentication by short tandem repeat (STR) markers. STR profiling just fulfills the purpose of authentication testing, which is to detect significant cross-contamination and cell line misidentification. Heterogeneity needs to be examined using additional methods. This heterogeneity can have serious consequences for reproducibility of experiments as shown by morphology, estrogenic growth dose-response, whole genome gene expression and untargeted mass-spectroscopy metabolomics for MCF-7 cells. Using Comparative Genomic Hybridization (CGH), differences were traced back to genetic heterogeneity already in the cells from the original frozen vials from the same ATCC lot, however, STR markers did not differ from ATCC reference for any sample. These findings underscore the need for additional quality assurance in Good Cell Culture Practice and cell characterization, especially using other methods such as CGH to reveal possible genomic heterogeneity and genetic drifts within cell lines.


Subject(s)
Genetic Variation/genetics , Cell Line, Tumor , Comparative Genomic Hybridization/methods , Gene Expression Profiling/methods , Genetic Markers/genetics , Humans , MCF-7 Cells , Microsatellite Repeats/genetics , Reproducibility of Results
16.
Brain Behav Immun ; 56: 253-63, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27039242

ABSTRACT

Improving child cognition in impoverished countries is a public health priority. Yet, biological pathways and associated biomarkers of impaired cognition remain poorly understood and largely unknown, respectively. This study aimed to explore and quantify associations between functional plasma protein biomarkers and childhood intellectual test performance. We applied proteomics to quantify proteins in plasma samples of 249 rural Nepalese children, 6-8years of age who, 1year later at 7-9years of age, were administered the Universal Nonverbal Intelligence Test (UNIT). Among 751 plasma proteins quantified, 22 were associated with UNIT scores, passing a false discovery rate threshold of 5.0% (q<0.05). UNIT scores were higher by 2.3-9.2 points for every 50% increase in relative abundance of two insulin-like growth factor binding proteins (IGFBPs), six subclasses of apolipoprotein (Apo) and transthyretin, and lower by 4.0-15.3 points for each 50% increase in relative abundance of 13 proteins predominantly involved in inflammation. Among them, IGFBP-acid labile subunit, orosomucoid 1 (ORM1), Apo C-I, and pyruvate kinase isoenzymes M1/M2 jointly explained 37% of the variance in UNIT scores. After additional adjustment for height-for-age Z-score and household socio-economic status as indicators of long-term nutritional and social stress, associations with 6 proteins involved in inflammation, including ORM1, α-1-antichymotrypsin, reticulocalbin 1, and 3 components of the complement cascade, remained significant (q<0.05). Using untargeted proteomics, stable, constitutive facets of subclinical inflammation were associated with lower developmental test performance in this rural South Asian child population. Plasma proteomics may offer opportunities to identify functional, antecedent biomarkers of child cognitive development.


Subject(s)
Blood/metabolism , Child Nutritional Physiological Phenomena/physiology , Inflammation/blood , Intelligence/physiology , Nutritional Status/physiology , Proteomics , Child , Female , Humans , Inflammation/epidemiology , Male , Nepal/epidemiology
17.
OMICS ; 20(4): 214-23, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26913649

ABSTRACT

Vitamin K (VK) is a fat-soluble vitamin whose deficiency disrupts coagulation and may disturb bone and cardiovascular health. However, the scale and systems affected by VK deficiency in pediatric populations remains unclear. We conducted a study of the plasma proteome of 500 Nepalese children 6-8 years of age (male/female ratio = 0.99) to identify proteins associated with VK status. We measured the concentrations of plasma lipids and protein induced by VK absence-II (PIVKA-II) and correlated relative abundance of proteins quantified by mass spectrometry with PIVKA-II. VK deficiency (PIVKA-II>2 µg/L) was associated with a higher abundance of low-density lipoproteins, total cholesterol, and triglyceride concentrations (p<0.01). Among 978 proteins observed in >10% of the children, five proteins were associated with PIVKA-II and seven proteins were differentially abundant between VK deficient versus sufficient children, including coagulation factor-II, hemoglobin, and vascular endothelial cadherin, passing a false discovery rate (FDR) threshold of 10% (q<0.10). Among 27 proteins associated with PIVKA-II or VK deficiency at a less stringent FDR (q<0.20), a network comprised of hemoglobin subunits and erythrocyte anti-oxidative enzymes were highly and positively correlated each other (all r>0.7). Untargeted proteomics offers a novel systems approach to elucidating biological processes of coagulation, vascularization, and erythrocyte oxidative stress related to VK status. The results may help elucidate subclinical metabolic disturbances related to VK deficiency in populations.


Subject(s)
Vitamin K Deficiency/epidemiology , Child , Female , Humans , Male , Nepal/epidemiology
18.
PLoS One ; 10(12): e0144279, 2015.
Article in English | MEDLINE | ID: mdl-26636573

ABSTRACT

Inflammation is a condition stemming from complex host defense and tissue repair mechanisms, often simply characterized by plasma levels of a single acute reactant. We attempted to identify candidate biomarkers of systemic inflammation within the plasma proteome. We applied quantitative proteomics using isobaric mass tags (iTRAQ) tandem mass spectrometry to quantify proteins in plasma of 500 Nepalese children 6-8 years of age. We evaluated those that co-vary with inflammation, indexed by α-1-acid glycoprotein (AGP), a conventional biomarker of inflammation in population studies. Among 982 proteins quantified in >10% of samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Magnitude and significance of association varied more among proteins positively (n = 41) than negatively associated (n = 58) with AGP. The former included known positive acute phase proteins including C-reactive protein, serum amyloid A, complement components, protease inhibitors, transport proteins with anti-oxidative activity, and numerous unexpected intracellular signaling molecules. Negatively associated proteins exhibited distinct differences in abundance between secretory hepatic proteins involved in transporting or binding lipids, micronutrients (vitamin A and calcium), growth factors and sex hormones, and proteins of largely extra-hepatic origin involved in the formation and metabolic regulation of extracellular matrix. With the same analytical approach and the significance threshold, seventy-two out of the 99 proteins were commonly associated with CRP, an established biomarker of inflammation, suggesting the validity of the identified proteins. Our findings have revealed a vast plasma proteome within a free-living population of children that comprise functional biomarkers of homeostatic and induced host defense, nutrient metabolism and tissue repair, representing a set of plasma proteins that may be used to assess dynamics and extent of inflammation for future clinical and public health application.


Subject(s)
Blood Proteins/metabolism , Proteome/metabolism , Biomarkers/blood , Child , Female , Humans , Inflammation/blood , Male , Nepal
19.
J Nutr ; 145(12): 2646-56, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26446483

ABSTRACT

BACKGROUND: The term vitamin E describes a family of 8 vitamers, 1 of which is α-tocopherol, that is essential for human health. Vitamin E status remains largely unknown in low-income countries because of the complexity and cost of measurement. Quantitative proteomics may offer an approach for identifying plasma proteins for assessing vitamin E status in these populations. OBJECTIVE: To improve options for vitamin E status assessment, we sought to detect and quantify a set of plasma proteins associated with α- and γ-tocopherol concentrations in a cohort of 500 rural Nepalese children aged 6-8 y and, based on nutrient-protein associations, to predict the prevalence of vitamin E deficiency (α-tocopherol <12 µmol/L). METHODS: Study children were born to mothers enrolled in an earlier antenatal micronutrient trial in Sarlahi District, Nepal. Plasma α- and γ-tocopherol concentrations were measured by high-performance liquid chromatography. Plasma aliquots were depleted of 6 high-abundance proteins, digested with trypsin, labeled with isobaric mass tags, and assessed for relative protein abundance by tandem mass spectrometry. Linear mixed-effects models were used to evaluate the association between α-tocopherol status and relative protein abundance and to predict deficiency. RESULTS: We quantified 982 plasma proteins in >10% of all child samples, of which 119 correlated with α-tocopherol (false discovery rate, q < 0.10). Proteins were primarily involved in lipid transport, coagulation, repair, innate host defenses, neural function, and homeostasis. Six proteins [apolipoprotein (apo)C-III; apoB; pyruvate kinase, muscle; forkhead box 04; unc5 homolog C; and regulator of G-protein signaling 8] explained 71% of the variability in plasma α-tocopherol, predicting an in-sample population prevalence of vitamin E deficiency of 51.4% (95% CI: 46.4%, 56.3%) compared with a measured prevalence of 54.8%. Plasma γ-tocopherol was associated with 12 proteins (q < 0.10), 2 of which (apoC-III and Misato 1) explained 20% of its variability. CONCLUSIONS: In this undernourished population of children in South Asia, quantitative proteomics identified a large plasma α-tocopherome from which 6 proteins predicted the prevalence of vitamin E deficiency. The findings illustrate that protein biomarkers, once absolutely quantified, can potentially predict micronutrient deficiencies in populations. The maternal micronutrient supplementation trial from which data were derived as a follow-up activity was registered with clinicaltrials.gov as NCT00115271.


Subject(s)
Biomarkers/blood , Blood Proteins/analysis , Proteomics , Vitamin E Deficiency/blood , alpha-Tocopherol/blood , Child , Diet , Dietary Supplements , Humans , Malnutrition/blood , Micronutrients/deficiency , Nepal/epidemiology , Nutritional Status , Vitamin E Deficiency/epidemiology , gamma-Tocopherol/blood
20.
ALTEX ; 32(2): 112-24, 2015.
Article in English | MEDLINE | ID: mdl-25742299

ABSTRACT

The Human Toxome Project, funded as an NIH Transformative Research grant 2011-2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectroscopy-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies.


Subject(s)
Toxicology/methods , Animal Testing Alternatives , Animals , Databases, Factual , Endocrine Disruptors , Humans , Metabolomics , Mice , Toxicity Tests/methods , Transcriptome
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