28 results match your criteria: "Center for Ecogenetics and Environmental Health[Affiliation]"

During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study (SMWHS) experienced one of the three symptom severity clusters identified through latent class analysis: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); low-severity hot flashes with moderate levels of all other symptom groups (moderate severity); and low levels of all symptom groups (low severity). In an effort to determine whether gene polymorphisms were associated with these symptom severity classes, we tested associations between gene polymorphisms in the estrogen synthesis pathways (cytochrome P450 19 [CYP 19] and 17 beta hydroxysteroid dehydrogenase [ 17HSDB1]) and the three symptom severity clusters. SMWHS participants ( N = 137) recorded symptoms monthly in diaries and provided buccal smears for genotyping.

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The Werner syndrome (WS) is a prototypic adult Mendelian progeroid syndrome in which signs of premature aging are associated with genomic instability and an elevated risk of cancer. The WRN RECQ helicase protein binds and unwinds G-quadruplex (G4) DNA substrates in vitro, and we identified significant enrichment in G4 sequence motifs at the transcription start site and 5' ends of first introns (false discovery rate < 0.001) of genes down-regulated in WS patient fibroblasts.

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Using Domestic and Free-Ranging Arctic Canid Models for Environmental Molecular Toxicology Research.

Environ Sci Technol

February 2016

Department of Veterinary Medicine, University of Alaska, Fairbanks, 901 Koyukuk Dr, Fairbanks, Alaska 99775-7750, United States.

The use of sentinel species for population and ecosystem health assessments has been advocated as part of a One Health perspective. The Arctic is experiencing rapid change, including climate and environmental shifts, as well as increased resource development, which will alter exposure of biota to environmental agents of disease. Arctic canid species have wide geographic ranges and feeding ecologies and are often exposed to high concentrations of both terrestrial and marine-based contaminants.

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Comparison of toxicogenomic responses to phthalate ester exposure in an organotypic testis co-culture model and responses observed in vivo.

Reprod Toxicol

December 2015

Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA; Institute for Risk Analysis and Risk Communication, University of Washington, Seattle, WA 98105, USA; Center for Ecogenetics and Environmental Health and Institute for Risk Analysis and Risk Communication, University of Washington, Seattle, WA 98105, USA. Electronic address:

We have developed a three-dimensional testicular co-culture system (3D-TCS) which mimics in vivo testes. In this study, transcriptomic responses to phthalate esters (PE's) were compared in the 3D-TCS with responses in rat testes in vivo. Microarray data from the 3D-TCS and from in vivo testes were used to compare changes in gene expression patterns after exposure to developmentally toxic (DTPE) or developmentally non-toxic (DNTPE) phthalate esters.

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Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4).

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Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis.

Bone

July 2015

Seattle Children's Research Institute, Center for Developmental Biology and Regenerative Medicine, Seattle, WA, USA; Seattle Children's Craniofacial Center, Seattle, WA, USA. Electronic address:

Single suture craniosynostosis (SSC) is the premature fusion of one calvarial suture and occurs in 1-1700-2500 live births. Congenital fusion of either the sagittal, metopic, or coronal sutures represents 95% of all cases of SSC. Sagittal and metopic synostosis have a male preponderance (3:1) while premature fusion of the coronal suture has a female preponderance (2:1).

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Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured enzyme inhibition and fetal-brain gene expression in wild-type (PON1(+/+)), PON1-knockout (PON1(-/-)), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice.

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Bloom syndrome is a rare autosomal recessive disorder characterized by genetic instability and cancer predisposition, and caused by mutations in the gene encoding the Bloom syndrome, RecQ helicase-like (BLM) protein. To determine whether altered gene expression might be responsible for pathological features of Bloom syndrome, we analyzed mRNA and microRNA (miRNA) expression in fibroblasts from individuals with Bloom syndrome and in BLM-depleted control fibroblasts. We identified mRNA and miRNA expression differences in Bloom syndrome patient and BLM-depleted cells.

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Of mice, rats, and men: could Nrf2 activation protect against aflatoxin heptocarcinogenesis in humans?

Cancer Prev Res (Phila)

July 2014

Authors' Affiliations: Department of Environmental and Occupational Health Sciences; and.

In this issue, Johnson and colleagues provide a remarkable demonstration of the potential for "chemoprevention" of cancer from mutagenic chemicals. The authors demonstrated complete protection of rats from a carcinogenic treatment regimen with the potent dietary mutagen and hepatocarcinogen, aflatoxin B1 (AFB) by pretreatment with a synthetic oleanane triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). This study is notable for two reasons: (i) Activation of the Nrf2/Keap1/ARE "antioxidant response" pathway by CDDO-Im conferred complete protection against AFB-induced hepatocellular carcinomas in the Fisher F344 rat (a strain frequently used in life-time carcinogenicity bioassays), and (ii) extensive AFB-DNA adduct formation was seen in all animals at early time points, including those treated with CDDO-Im, albeit at lower levels (∼30% of the untreated animals), suggesting a strong divergence in the association between early DNA-damaging events, and tumor formation later in life.

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Genetic risk factors for major bleeding in patients treated with warfarin in a community setting.

Clin Pharmacol Ther

June 2014

1] Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle, Washington, USA [2] Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA.

The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long-term users and non-specialist care settings. We conducted a case-control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index.

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Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene.

PLoS One

April 2014

Department of Social and Preventive Medicine, the State University of New York, Buffalo, New York, United States of America ; Guangdong Medical Laboratory Animal Center, Foshan, Guangdong, China ; Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington, United States of America ; NIEHS Center for Ecogenetics and Environmental Health, and the Department of Environmental and Occupational Health, University of Washington, Seattle, Washington, United States of America.

Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of ∼8.

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Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response.

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Dietary modulation of the biotransformation and genotoxicity of aflatoxin B(1).

Toxicology

September 2012

Center for Ecogenetics and Environmental Health, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, United States.

Diet and its various components are consistently identified as among the most important 'risk factors' for cancer worldwide, yet great uncertainty remains regarding the relative contribution of nutritive (e.g., vitamins, calories) vs.

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Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice.

J Biol Chem

September 2006

Department of Environmental and Occupational Health Sciences, Comparative Medicine, and Pathology, and UW/NIEHS Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington 68105, USA.

Acetaminophen overdose is a leading cause of drug-related acute liver failure in the United States. Glutathione, a tripeptide antioxidant protects cells against oxidative damage from reactive oxygen species and plays a crucial role in the detoxification of xenobiotics, including acetaminophen. Glutathione is synthesized in a two-step enzymatic reaction.

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Numerous studies have suggested that the lifetime dose of unopposed estrogen is a significant risk factor for breast and uterine cancer. Estradiol (E2) plays a putative role as a tumor promoter through interaction with estrogen receptors but can also be metabolized to redox active and/or mutagenic semiquinones and quinones. Similarly, equine estrogens (components of certain hormone replacement therapy preparations) are converted to quinone metabolites.

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Biotransformation of methyl parathion by glutathione S-transferases.

Toxicol Sci

June 2004

Department of Environmental and Occupational Health Sciences and Center for Ecogenetics and Environmental Health, University of Washington, 4225 Roosevelt Way NE, #100, Seattle, Washington 98105, USA.

The organo(thio)phosphate esters are one of the most widely used classes of insecticides. Worldwide, organophosphate insecticides (OPs) result in numerous poisonings each year. In insects, glutathione S-transferases (GSTs) play an important role in OP resistance; limited data suggest that GST-mediated O-dealkylation occurs in humans as well.

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This paper describes and quantifies seafood consumption rates, and acquisition and preparation habits of 202 first- and second-generation Asian American and Pacific Islanders (AAPI) from 10 ethnic groups (Cambodian, Chinese, Filipino, Hmong, Japanese, Korean, Laotian, Mien, Samoan, and Vietnamese) in King County, Washington in 1997. Participants were all seafood consumers. Average and median seafood consumption rates were 117.

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Attenuation of nuclear factor kappa B (NF-kappaB) promotes apoptosis of kidney epithelial cells: a potential mechanism of mercury-induced nephrotoxicity.

Environ Health Perspect

October 2002

Center for Ecogenetics and Environmental Health, Department of Environmental Health, University of Washington, 4225 Roosevelt Way, Suite 100, Seattle, WA 98105, USA.

Nuclear factor kappa B (NF-kappaB), a pleiotropic transcriptional factor that promotes cell survival and protects cells from apoptosis, requires reduced thiols at critical steps in its activation pathway. Mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, impairs NF-kappaB activation and transcriptional activity in normal rat kidney epithelial (NRK52E) cells at concentrations as low as 0.5 microM by binding to specific reduced thiol moieties in the NF-kappaB activation pathway.

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It is now evident that most, if not all, of the remarkable species differences in susceptibility to AFB hepatocarcinogenesis is due in large part, if not exclusively, to differences in biotransformation. Certainly the relative rate of oxidative formation of the proximate carcinogen, AFB-8,9-exo-epoxide, is an important determinant of species and interindividual differences in susceptibility to AFB. However, mice produce relatively large amounts of exo-AFBO, yet are highly resistant to AFB-hepatocarcinogenesis because they express a particular form of GST with remarkably high catalytic activity toward the exo-epoxide of AFB.

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Expression of human microsomal epoxide hydrolase in Saccharomyces cerevisiae reveals a functional role in aflatoxin B1 detoxification.

Toxicol Sci

January 2002

Department of Environmental Health and Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington 98105, USA.

The metabolism and genotoxicity of the carcinogenic mycotoxin, aflatoxin B1 (AFB), was studied in the lower eukaryotic yeast Saccharomyces cerevisiae. Recombinant strains of yeast were engineered to express human cDNAs for CYP1A1, CYP1A2, and microsomal epoxide hydrolase (mEH). Coexpression of mEH with CYP1A1 or CYP1A2 resulted in significant decreases in measurements of AFB genotoxicity.

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DNA microarrays or chips can be used to simultaneously monitor the expression levels and/or genotypes of thousands of genes. The application of these techniques heralds a new era in toxicology research, where genotypes and toxicant-induced expression signatures may be used to monitor cellular responses to different doses, to classify toxins on the basis of their mechanisms of action, to monitor exposures, and to predict individual variability in toxicant sensitivity. This unit reviews the current state of microarray technologies and discusses potential applications in toxicology, with emphasis on the strengths and limitations of the technologies.

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Mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, mediates the toxicity associated with elemental, inorganic, and organic mercurial compounds. Studies of cellular events associated with Hg(2+) toxicity have focused largely on disruption of cell membranes and impairment of mitochondrial functions. In contrast, few studies have sought to define the specific molecular mechanisms through which Hg(2+) might affect toxicity via alteration of thiol-dependent signal transduction pathways that regulate cell proliferation and survival.

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This review presents a brief and non-comprehensive overview of a representative sampling of some of the broad array of toxicology-related learning, tutorial and information resources now becoming widely available to educators, health professionals, students and the general public in digital media and/or via the Internet. A broad variety of useful learning and reference resources in the general fields of toxicology and the environmental health sciences is provided to introduce the reader to the diverse types of information currently available. The sources and Internet links contained in this review will hopefully constitute a useful resource of basic toxicology information that should be readily accessible to most if not all readers.

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Cloning and characterization of the proximal promoter region of the mouse glutamate-L-cysteine ligase regulatory subunit gene.

Biochim Biophys Acta

July 2000

Department of Environmental Health and Center for Ecogenetics and Environmental Health, University of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle, WA 98105-6099, USA.

We describe upregulation of the mRNA for the mouse glutamate-cysteine ligase regulatory subunit gene (Glcl-r) in Hepa-1 cells treated with beta-napthoflavone (BNF) and tert-butylhydroquinone (tBHQ). A 2-kb fragment of the proximal promoter region of the gene was cloned and sequenced, and sequence analysis reveals a high degree of homology when compared to the human glutamate-cysteine ligase regulatory subunit gene promoter. Primer extension analysis indicates a major transcription start site 218 bp upstream of the translation start codon in a CpG-rich region, suggesting that transcription is Sp1 mediated.

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Biotransformation enzyme polymorphism and pesticide susceptibility.

Neurotoxicology

June 2000

Center for Ecogenetics and Environmental Health, Department of Environmental Health, University of Washington, Seattle 98105-6099, USA.

Numerous specific genetic polymorphisms (PM) in the multi-gene families of cytochromes P450 (CYPs) and glutathione S-transferases (GSTs) have been described in the human population in the past decade. For example, one or more PM have been identified in human CYP1A1, CYP1B1, CYP2C9, CYP2C18, CYP2D6, and CYP2E1. Recent studies using cDNA expressed human CYPs have suggested that CYP3A4 is the principal human CYP involved in the oxidation of parathion and probably other organo(thio)phosphate (OP) insecticides and thus PM in this CYP might influence susceptibility to OP.

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