National Institute of Environmental Health science

Antigua Guatemala, Guatemala

National Institute of Environmental Health science

Antigua Guatemala, Guatemala

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PubMed | National Institute of Environmental Health science, Hannover Medical School, NIEHS and Duke University
Type: | Journal: American journal of physiology. Lung cellular and molecular physiology | Year: 2017

Human genome-wide association studies (GWASs) have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms (SNPs) in serotonin receptor 4 (HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4


PubMed | National Institute of Environmental Health science, US Toxicology and Oak Ridge Institute for Science and Education
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2016

Microarray profiling of chemical-induced effects is being increasingly used in medium- and high-throughput formats. Computational methods are described here to identify molecular targets from whole-genome microarray data using as an example the estrogen receptor (ER), often modulated by potential endocrine disrupting chemicals. ER biomarker genes were identified by their consistent expression after exposure to 7 structurally diverse ER agonists and 3 ER antagonists in ER-positive MCF-7 cells. Most of the biomarker genes were shown to be directly regulated by ER as determined by ESR1 gene knockdown using siRNA as well as through chromatin immunoprecipitation coupled with DNA sequencing analysis of ER-DNA interactions. The biomarker was evaluated as a predictive tool using the fold-change rank-based Running Fisher algorithm by comparison to annotated gene expression datasets from experiments using MCF-7 cells, including those evaluating the transcriptional effects of hormones and chemicals. Using 141 comparisons from chemical- and hormone-treated cells, the biomarker gave a balanced accuracy for prediction of ER activation or suppression of 94% and 93%, respectively. The biomarker was able to correctly classify 18 out of 21 (86%) ER reference chemicals including very weak agonists. Importantly, the biomarker predictions accurately replicated predictions based on 18 in vitro high-throughput screening assays that queried different steps in ER signaling. For 114 chemicals, the balanced accuracies were 95% and 98% for activation or suppression, respectively. These results demonstrate that the ER gene expression biomarker can accurately identify ER modulators in large collections of microarray data derived from MCF-7 cells.


Leiss V.,University of Tübingen | Flockerzie K.,University of Tübingen | Novakovic A.,University of Tübingen | Rath M.,German Institute of Human Nutrition | And 5 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2014

Bordetella pertussis toxin (PTx), also known as islet-activating protein, induces insulin secretion by ADP-ribosylation of inhibitory G proteins. PTx-induced insulin secretion may result either from inactivation of Gαo proteins or from combined inactivation of Gαo, Gαi1, Gαi2, and Gαi3 isoforms. However, the specific role of Gαi2 in pancreatic β-cells still remains unknown. In global (Gαi2 −/−) and β-cell-specific (Gαi2 βcko) gene-targeted Gαi2 mouse models, we studied glucose homeostasis and islet functions. Insulin secretion experiments and intracellular Ca2+ measurements were used to characterize Gαi2 function in vitro. Gαi2 −/− and Gαi2 βcko mice showed an unexpected metabolic phenotype, i.e., significantly lower plasma insulin levels upon intraperitoneal glucose challenge in Gαi2 −/− and Gαi2 βcko mice, whereas plasma glucose concentrations were unchanged in Gαi2 −/− but significantly increased in Gαi2 βcko mice. These findings indicate a novel albeit unexpected role for Gαi2 in the expression, turnover, and/or release of insulin from islets. Detection of insulin secretion in isolated islets did not show differences in response to high (16 mM) glucose concentrations between control and β-cell-specific Gαi2-deficient mice. In contrast, the two- to threefold increase in insulin secretion evoked by L-arginine or L-ornithine (in the presence of 16 mM glucose) was significantly reduced in islets lacking Gαi2. In accord with a reduced level of insulin secretion, intracellular calcium concentrations induced by the agonistic amino acid L-arginine did not reach control levels in β-cells. The presented analysis of gene-targeted mice provides novel insights in the role of β-cell Gαi2 showing that amino acid-induced insulin-release depends on Gαi2. © 2014 the American Physiological Society.


PubMed | National Institute of Environmental Health science, Georgia Regents University and Augusta University
Type: | Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | Year: 2016

Prostaglandin E2 (PGE2) induces aromatase expression in adipose tissue leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE2 and estrogen in relation to postmenopausal breast cancer risk.Here we determined urinary estrogen metabolites (EMs) using mass spectrometry in a case-cohort study (295 incident breast cancer cases and 294 subcohort members), and using linear regression estimated the effect of urinary levels of a major PGE2 metabolite (PGE-M) on EMs. Hazard ratios (HRs) for the risk of developing breast cancer in relation to PGE-M and EMs were compared between Cox regression models with and without mutual adjustment.PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer (HRQ5vs.Q1 =1.54, 95% CI: 1.01-2.35), and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1 =1.52, 95% CI: 0.99-2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1 =2.01, 95% CI: 1.01-4.29), and this association was only nominally changed after consideration of E1 or E2 levels.Urinary levels of PGE-M and estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women.Increased breast cancer risk associated with PGE-M might not be fully explained by the estrogens-breast cancer association alone but also by additional effects related to inflammation.


Luo Y.-H.,National Institute of Environmental Health science | Wu Z.W.,National Health Research Institute | Tsai H.-T.,National Institute of Environmental Health science | Lin S.-Y.,National Health Research Institute | Lin P.,National Institute of Environmental Health science
Nano Letters | Year: 2015

In this study, we sought to control the assembly of an endotoxin known as the biologically supramolecular lipopolysaccharide (LPS, which consists of three portions: an O antigen, a core carbohydrate, and a lipid A molecule) in order to modulate immunological responses in a manner that has the potential for utilization in vaccine development. Changing the structures of LPS aggregates from lamellas to specific nonlamellas (i.e., cubosomes and hexosomes) can dramatically enhance the strength of LPS in causing inflammatory responses, leading to highly active responses. In order to control the formation of cubosome-free and hexosome-free nonlamellas, we designed a simple strategy based on the use of hydrophilic gold nanodots (AuNDs) to control LPS assembly to facilitate the formation of stable endotoxin nanovesicles, which are stable precursors of cubosomes and hexosomes with specific immunological effects. Structurally, the wall thicknesses of these nanovesicles are exactly twice the lengths of a single LPS molecule, indicating that the LPS molecules adopt a tail-to-tail arrangement (with the lipid A portions acting as the tail domain). The involvement of the hydrophilic AuNDs to laterally link polar domains of LPS can result in the progressive extension of an endotoxically active zone of lipid A assembly, leading to the eventual formation of large-size nanovesicles. Our results showed that endotoxin nanovesicles with such dense lipid A units can elicit the stronger inflammatory gene expressions, including interleukin 6 (IL-6), IL-1A, TNF-α, C-X-C chemokine ligand (CXCL) 1, 2, and 11, which have characteristics of T-helper 1 adjuvants. These findings provide evidence that the concept of manipulating the surface hydrophilicity of AuNDs to control LPS assembly in order to avoid the formation of highly active cubosomes and hexosomes, and thereby modulate immunological responses appropriately, could prove useful in vaccine development. © 2015 American Chemical Society.


Gonzalez N.L.,National Institute of Environmental Health science
Epidemiology | Year: 2016

BACKGROUND:: Douching was recently reported to be associated with elevated levels of urinary metabolites of endocrine disrupting phthalates, but there is no literature on douching in relation to ovarian cancer. Numerous case-control studies of genital talc use have reported an increased risk of ovarian cancer, but prospective cohort studies have not uniformly confirmed this association. Behavioral correlation between talc use and douching could produce confounding. METHODS:: The Sister Study (2003-2009) enrolled and followed 50,884 women in the US and Puerto Rico who had a sister diagnosed with breast cancer. At baseline participants were asked about douching and talc use during the previous 12 months. During follow-up (median of 6.6 years) 154 participants reported a diagnosis of ovarian cancer. We computed adjusted hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer risk using the Cox proportional hazards model. RESULTS:: There was little association between baseline perineal talc use and subsequent ovarian cancer (HR: 0.73 CI: 0.44, 1.2). Douching was more common among talc users (OR: 2.1 CI: 2.0, 2.3), and douching at baseline was associated with increased subsequent risk of ovarian cancer (HR: 1.8 CI: 1.2, 2.8). CONCLUSIONS:: Douching but not talc use was associated with increased risk of ovarian cancer in the Sister Study. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


PubMed | National Institute of Environmental Health science and West Virginia University
Type: | Journal: American journal of physiology. Heart and circulatory physiology | Year: 2016

Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The current study was designed to determine whether gestational nano-TiO


PubMed | National Institute of Environmental Health science and National Cancer Institute
Type: | Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | Year: 2016

Cigarettes are well known to cause cancer, but less is known about the risks of other tobacco products and use of more than one product.We examined cancer incidence in relation to exclusive use of six tobacco products (cigarettes, other combustibles (pipe, cigar, cigarillo), and smokeless tobacco (chewing tobacco, snuff)) in the Agricultural Health Study. We also examined the added cancer risks associated with use of cigarettes and other tobacco products.In our study population of 84,015, ever use of smokeless tobacco was higher than the general United States population, while cigarette use was lower and other combustible product use was about the same. The strongest associations for exclusive ever use were for lung cancer (cigarettes hazard ratio (HR)=15.48, 95% confidence interval (CI): 11.95, 20.06; other combustible tobacco HR=3.44, 95% CI: 1.53, 7.71; smokeless tobacco HR=2.21, 95% CI: 1.11, 4.42). Compared to exclusive cigarette smokers, cigarette smokers who additionally ever-used another combustible product had higher risks of smoking related cancers (HR=1.16, 95% CI: 1.04, 1.30), especially among those who smoked cigarettes for more than 15 years. Conclusion and Impact: Cigarette smokers who additionally ever used smokeless tobacco had cancer risks similar to exclusive cigarette smokers. Users of cigarettes and other combustible tobacco may have higher risks of certain cancers than exclusive cigarette users.


PubMed | National Institute of Environmental Health science, National Office Systems and Open Intelligence Inc.
Type: Journal Article | Journal: Scientometrics | Year: 2016

As federal programs are held more accountable for their research investments, The National Institute of Environmental Health Sciences (NIEHS) has developed a new method to quantify the impact of our funded research on the scientific and broader communities. In this article we review traditional bibliometric analyses, address challenges associated with them, and describe a new bibliometric analysis method, the Automated Research Impact Assessment (ARIA). ARIA taps into a resource that has only rarely been used for bibliometric analyses: references cited in important research artifacts, such as policies, regulations, clinical guidelines, and expert panel reports. The approach includes new statistics that science managers can use to benchmark contributions to research by funding source. This new method provides the ability to conduct automated impact analyses of federal research that can be incorporated in program evaluations. We apply this method to several case studies to examine the impact of NIEHS funded research.


PubMed | National Institute of Environmental Health science
Type: | Journal: Molecular pharmacology | Year: 2017

P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our lab has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries. C1P treatment induced P-glycoprotein transport activity in brain capillaries rapidly and reversibly. In contrast, C1P did not affect transport activity of two other major efflux transporters, MRP2 and BCRP. C1P induced P-glycoprotein transport activity without changing transporter protein expression. Inhibition of the key signaling components in the COX-2/PGE2 signaling cascade (phospholipase A2; COX-2, MRP4 and G-protein coupled EP 1 and EP2 receptors), abolished P-glycoprotein induction by C1P. We show that COX-2 and PGE2 are required for C1P-mediated increases in P-glycoprotein activity independent of transporter protein expression. This work describes how C1P activates a signaling cascade to dynamically regulate P-glycoprotein transport at the BBB, and offers potential clinical targets to modulate neuroprotection and drug delivery to the CNS.

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