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Record Count: 14
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DESCRIPTION (provided by applicant): Malignant melanoma is one of the fastest increasing cancers in the United States and no curative treatment is yet available. Solar ultraviolet (UV) radiation, especially childhood sun exposure is an important etiological risk factor of melanoma. Retinoid X Receptor a (RXRa), a member of the nuclear receptor (NR) superfamily, is a central coordinator for transducing diverse cellular signals. In the context of studying the role of RXRa in skin, we have discovered an unexpected and novel role for this NR in melanomagenesis: RXRa[ep-/-] mice, specifically lacking RXRa in epidermal keratinocytes, develop melanocytic growths (MGs) resembling melanoma at high frequency when subjected to a two-step chemical carcinogenesis protocol (DMBA+TPA). Our results suggest that RXRa may regulate a keratinocyte ? melanocyte signaling pathway(s) implicated in the control of melanocytic proliferation. Thus, we have generated a new mouse model for melanomagenesis. However, the molecular mechanisms that underlie these activities of RXR are not known. Given the importance of keratinocytes in regulating melanocyte mitogenesis, understanding how this regulation becomes aberrant in melanoma is significant, since it can possibly lead to the development of effective therapeutic strategies to counteract melanoma formation and progression. Our long-term goal is to identify the mechanisms of signal transduction between keratinocytes and melanocytes that contribute to the development of melanoma. Based on the above observations and from the preliminary data, we propose the following two specific aims. First, we propose to elucidate the cellular and molecular mechanisms by which keratinocytes control melanocyte mitogenesis and transformation leading to a malignant phenotype. Our working hypothesis is that RXRa, directly or indirectly, represses keratinocytic expression of endothelin 1 (ET-1), SCF, POMC and FGF2 which may serve to regulate melanocytic mitogenesis in a paracrine manner. Second, we propose to identify intracellular targets (melanocytic factors) that control melanocyte homeostasis and UV-induced melanomagenesis. Our working hypothesis is that melanocytic factors, such as cyclin dependent kinase-4 (Cdk4), may modulate the responsiveness of these cells to the mitogenic effects of keratinocyte-derived paracrine factors. We believe that our efforts in the context of the work described herein will lead to a detailed understanding of the mechanism(s) by which melanocyte mitogenesis and melanomagenesis are regulated by keratinocytic RXRa, and perhaps other paracrine factors. The proposed project is potentially innovative as our laboratory generated the RXRa [ep-/-] mouse that has been used for these studies, and was the first to characterize the in vivo role of RXRa in skin during epidermal homeostasis. This contribution is significant and the results are expected to have a positive impact on human health, because the outcome of the work will provide the molecular cornerstone for the development of future pharmacological strategies designed to treat, and ultimately cure malignant melanoma. PUBLIC HEALTH RELEVANCE: Melanoma is generally recognized as an aggressive skin cancer that can metastasize early in the course of the disease and is highly resistant to most current therapeutic interventions. Understanding the genetic and environmental factors driving melanoma formation is essential for the development of new therapies to treat this disease. The present study involves the use of a novel melanoma mouse model to study the molecular mechanism underlying the role of skin keratinocytes to control melanocyte mitogenesis and melanomagenesis.
DESCRIPTION (provided by applicant):
Exposure to a wide range of environmental agents can cause dramatic changes in gene expression. In theory, these changes should revert back to normal after exposure has ceased. It appears, however, that changes in gene expression can persist after acute or chronic exposures suggesting epigenetic changes, and it has been suggested that these changes can have pathological consequences. For example, silencing of critical genes is commonly observed in environmentally induced cancers. The goal of the work proposed in this exploratory R21 application is to test the hypothesis that reductions in gene expression occurring in response to environmental exposures will sensitize mammalian promoters to undergo silencing. A corollary of this hypothesis is that selective pressure, which propels the development and progression of cancerous cells, can also propel the silencing process. Three specific aims are offered. For the first aim, expression of the selectable mouse Aprt (adenosine phosphoribosyl transferase) coding region will be controlled with the tet on/off system in cultured mouse cells and the relation between chronic or acute reductions in expression and stable silencing will be examined. The role of a pre-existing focus of DNA methylation in facilitating the silencing process will also be examined. For the second specific aim, Aprt will be expressed from nickel (Ni) repressible promoters and the ability of this common environmental carcinogen to trigger stable silencing by repressing transcription will be examined in mouse cells. For the third specific aim, the ability of a variety of environmental carcinogens to trigger silencing via promoter repression will be examined in the MCF-7 human breast cancer cell line. The work for this aim will use Hprt as the selectable marker for silencing. Successful completion of the proposed work will firmly link environmental exposure with gene silencing and demonstrate that one mechanism for this link is a significant reduction in promoter function.
Crisp Terms/Key Words: epigenetics, environmental exposure, gene environment interaction, MCF7 cell, cell line, DNA methylation, chemical carcinogenesis, environment related neoplasm /cancer, chemical related neoplasm /cancer, nickel, hypoxanthine phosphoribosyltransferase, gene induction /repression, genetic transcription, genetic promoter element, genetic regulatory element, gene expression, transfection, tetracycline
DESCRIPTION (provided by applicant): The long-term objectives are to explain biochemically how human mismatch-repair (MMR) systems act in vivo to suppress induction of mutation by DNA lesions, yet promote lesion-triggered cell-cycle arrest and apoptosis. The focus here is on two representative classes of environmentally-induced mutagenic and carcinogenic lesions, UV photoproducts and polycyclicaromatic-hydrocarbon (PAH) adducts. The aim of the specific components of this exploratory work is to provide a well-defined basis for future studies-both expanded biochemical analyses and work with cultured cells and transgenic mice. Aim 1 is to analyze (ATP-sensitive) binding, by the (purified) human MMR-recognition proteins hMutS1 and hMutS2, of DNA containing defined cyclobutane-pyrimidine-dimer (CPD) photoproducts or PAH-purine adducts-opposite "matching" or "mismatching" nucleotides. The MMR targets here are, respectively, T[CPD]T/AG vs. T[CPD]T/AA in various contexts, and B[a]P-N2G:C vs. B[a]P-N2G:T and B[c]Ph-N6A:T vs. B[c]Ph-N6A:C. Targets bound twice as well as homoduplex DNA in electrophoretic-mobility-shift arrays will be used for further experiments. Aim 2 is to determine, using complete cell-free extracts, which Aim 1 lesion targets activate incision, by the essential MMR protein hMutL1, of model circular substrates (containing preexisting defined nicks in non-lesion strands) and concomitantly provoke 3'-5' excision along the shorter paths from substrate nicks to targets. Ability to activate MutL1 distinguishes "Class I" MMR targets (base- mispair prototype) from "Class II" (T[CPD]T/AG prototype) targets. Putative Class II targets will be tested, by surface-plasmon-resonance techniques, for abilities to form ternary complexes with (unactivated) hMutL1 and hMutS(1/2). Aim 3 is to test PAH-purine and the prototypic T[CPD]T/AG targets for the defining Class II property-activation of the MMR-associated hExoI protein for 5'-3' excision of model nicked-circular substrates by purified-protein mixtures and cell-free extracts. Aim 4 is to compare forward Hprt mutation induced in MMR-deficient vs. MMR-proficient cells in culture by B[a]P and B[C]Ph diol epoxides. Efficient MMR responses to DNA lesions can both reduce cancer risk and promote killing of tumor cells by some chemotherapeutic drugs. Environmental mutagens may pose unsuspected risks to individuals harboring one or (especially) multiple polymorphic partial MMR deficiencies. Additional partial deficiencies in legion-removal system may further. Future biochemical studies will analyze the efficiency and accuracy of DNA resynthesis past template lesions that have provoked 3'-5' (Aim 2) or 5'-3' (Aim 3) excision of (non-lesion) strands in extracts and recruitment (in the absence of excision) of signaling proteins in these extracts. Future genetic studies with various transgenic mice will examine effects of MMR-protein "knockouts" on specific mutation pathways induced by B[a]P and B[c]Ph diol epxidos. PUBLIC HEALTH RELEVANCE: This exploratory work will provide the basis for more later more extensive studies. These will help identify individuals at increased risk for cancer induced by environmental agents.
DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs), including benzo(a)pyrene (BP), form a major class of environmental pollutants suggested to be causative factors in a variety of disease susceptibilities, including cancer. Virtually all PAH mixtures contain BP; a model compound that causes the formation of BP-DNA-adducts. Levels of BP-DNA adducts in cigarette smokers are decreased by vitamin E (a-tocopherol) administration. Although a-tocopherol's antioxidant activity has been the proposed mechanism for its protective effects, our recent provocative findings indicate that a-tocopherol also has a regulatory function in liver. Thus, a-tocopherol's action in eliminating BP-induced DNA damage likely involves regulation of hepatic detoxification and biliary excretion. There is, therefore, a need to evaluate a-tocopherol-dependent modulation of hepatic xenobiotic metabolism and disposition as mechanisms for the detoxification and elimination of PAHs. Our long-range goal is to determine the efficacy of prophylactic high dose vitamin E supplementation for prevention of DNA-adduct formation during occupational exposure to PAHs. Our objective in this R21 application is to identify the key mechanism(s) by which a-tocopherol supplementation alters the response of hepatic, lung and kidney tissues to PAHs utilizing BP as a model compound. Our central hypothesis is that pharmacologic a-tocopherol supplementation, in addition to providing increased antioxidant protection, increases xenobiotic metabolism and excretion pathways, thereby protecting the liver and other organs from PAH-induced DNA adduct formation by increasing detoxification and/or elimination of PAHs and their metabolites from the body. We propose to: Aim 1. Determine modulation of BP metabolism and excretion by a-tocopherol in rats. Our working hypothesis is that elevated levels of a-tocopherol will significantly increase: (1) metabolism of BP to non-DNA reactive metabolites and (2) increase BP and/or BP metabolite excretion. Aim 2. Identify the protective effects of a-tocopherol supplementation against BP-induced DNA damage. Our working hypothesis is that elevated levels of a-tocopherol will decrease BP-induced DNA damage in liver, lung and kidney by two synergistic mechanisms: (1) increased antioxidant protection against oxidative stress- induced damage and (2) decreased formation of covalent BP-DNA adducts. This proposal is innovative because it challenges the current paradigm that -tocopherol acts almost exclusively as an antioxidant, while supporting the paradigm that nutrition and dietary regiments can modulate toxicological insults and resultant pathologies. The public health relevance of these studies is that evidence that pathways other than antioxidant activity are functionally operative in a-tocopherol-mediated protection against environmental pollutants such as PAHs would be of considerable value in the ultimate development of protective strategies for acute occupational exposures to these and other environmental pollutants. Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure. PUBLIC HEALTH RELEVANCE: Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure.
DESCRIPTION (provided by applicant): Exposure to short wave ultraviolet light has been demonstrated to be the causal factor in nonmelanoma skin cancers and a strong risk factor in melanomas. While human cells only use nucleotide excision repair to repair the UV-induced dipyrimidine DNA photoproducts, other organisms initiate the base excision repair pathway by DNA glycosylases that catalyze incision at the 5' base of pyrimidine dimers. Developing an understanding of the function of enzymes is critical, since T4 pyrimidine dimer glycosylase (T4-Pdg) is being used in human clinical trials. Although topical delivery of wild-type T4-Pdg on xeroderma pigmentosum patients has demonstrated efficacy in cancer reduction, all investigations to date using wild-type mammalian cells reveal that T4-Pdg results in decreased, rather than increased survival after UV. It is hypothesized that the ability of T4-Pdg to incise all dimer sites within DNA domains leads to cytotoxic double-strand breaks where dimers are in close proximity in complementary strands. Thus, it is hypothesized that forms of T4-Pdg that have lost the ability to incise dimers in clusters will enhance repair and decrease mutagenesis without creating cytotoxic double-strand breaks. To accomplish this goal, it is proposed to engineer T4-Pdg to be less efficient in the precatalytic steps of DNA bending and nucleotide flipping, with the net result being a decrease in the ability of these altered enzymes to form a Michaelis complex and incise dimers in clusters. These studies will be guided by our recent determination of the cocrystal structure of T4-Pdg covalently trapped as a reduced imine intermediate at an abasic site in duplex DNA. This structure reveals key amino acids necessary for achieving an active complex, and these data have led to a series of hypotheses that implicate at least three different portions of the enzyme in this process. Using the knowledge derived from the cocrystal structure, and given the challenges of enhancing dimer repair in wild-type mammalian cells, Specific Aims are proposed to 1) biochemically characterize mutants of T4-Pdg in their ability to carry out bending, flipping, catalysis, and clustered incisions in vitro; 2) express control and mutant T4-Pdgs in keratinocytes to determine effects on double-strand break formation, survival, and mutagenesis; and 3) activate base excision repair of UV-photoproducts in mitochondria and determine the role of dimers in cytotoxicity.
DESCRIPTION (provided by applicant)
The Environmental Health Sciences (EHS) Center at Oregon State University is an interdisciplinary unit of 35 Center investigators and now in its 39th year of existence. The mission of the EHS Center is to foster excellent research and technology development into the fundamental causes and progression of environmentally related diseases; to advance our ability to predict, prevent, and mitigate environmental insults and promote health; and to disseminate this knowledge to educate the government and public to make informed decisions. The theme for the Oregon State University (OSU) EHS Center is to advance our knowledge concerning the actions of environmental agents at the molecular and cellular level and to understand how we can modulate our individual susceptibility to improve health. To achieve these objectives, the Center continues to develop pioneering analytical capabilities, investigate model systems, and apply the results to realworld problems. The results of this research enabled by the Center contribute to the scientific basis for the prediction of health risks due to exposure to environmental chemicals, aid in the development of innovative approaches for use in risk assessment, and to minimize the impact of environmental stresses on human health. The broad intellectual base of expertise, research, and teaching allows the Center to conduct innovative environmental health-related studies across campus through collaborations and sharing of expertise. Three Research Cores focus collaborative research into the broad themes of: (1) Environmental Mutagenesis and Carcinogenesis, (2) Biomolecular and Environmental Chemistry, and (3) Signaling and Oxidative Stress. Four Facility Cores provide scientists with access to expertise, services, and major equipment in specific research technologies. (1) Aquatic Models, (2) Mass Spectrometry, (3) Cell Imaging and Analysis, and (4) Integrated Human Health Core-newly formed from the Statistics Core and a clinical study coordinator. The EHS Center grant also supports the Administration Core and an expanded Pilot Project Program. Because of Center guideline changes, this Center will be merged with the OSU Marine and Freshwater Biomedical Sciences Center, enabling the largest vertebrate animal studies (with 40,000 trout) on carcinogenesis and cancer prevention in the Aquatic Models Facility Core. New capabilities to conduct large-scale toxicology studies using zebrafish are being developed.
BACKGROUND
This Center, which is one of the original six NIEHS Centers, is applying for years 39-43. This is a revised application of a competing continuation application. The Center has undergone substantial reorganization because of retirements, and new hires, and, of course, the new Center guidelines. The overall theme remains advancing knowledge concerning the actions of environmental agents at the molecular and cellular level and understanding how we can modulate individual susceptibility to improve health. The Center has three long-range goals: 1) to understand the mechanisms for reducing individual susceptibility; 2) to assess health risks at low exposures (with emphasis on large numbers through their aquatic capabilities; and 3) macromolecular interactions. During the last period of support, the Center members obtained one Program Project grant, a Training grant and a Short-Term Minority Undergraduate Training grant, as well as individual grants. Additionally, two new Center-affiliated Program Project grants and 1 Training grant were awarded. There has been a restructuring from the previous structure of seven Facility Cores to the current four: 1) Aquatic Models; 2) Mass Spectrometry; 3) Cell Imaging and Analysis; and 4) Integrated Human Health Core. The fourth Core is a merger of the original Statistics Core and a clinical study coordinator. A formal Community Outreach and Education Core is not proposed in this application. The Center also has an Administrative Core and a Pilot Project Program.
ESSENTIAL CHARACTERISTICS
Strategic Vision and Impact on Environmental Health
DESCRIPTION (provided by applicant): Extrapolation of dose-response carcinogen data from animals to establish "safe" levels for human exposures (1 in a million) is challenging as it requires modeling of dose-response over at least 4 orders of magnitude. In many cases, the conservative approach is assumed linearity. The largest tumor study in a rodent model used 24,192 mice to detect 1 cancer in 100. The trout tumor model has proven valuable in identification of carcinogens and their mechanism of action. Trout are very sensitive to the hepatocarcinogenicity of aflatoxin B1 (AFB1), the only IARC human carcinogen where exposure is through the food supply. Hepatocellular carcinoma (HCC) is responsible for over 600,000 deaths a year worldwide and accounts for 10-15% of all deaths in certain regions. HCC is the most rapidly increasing solid tumor in the U.S. For AFB1, the target organ, metabolism, DNA adduction and gene targets are similar in trout and human and, in this example, the trout model is superior to mouse. The trout model can utilize large numbers of animals to evaluate cancer across a wide range of doses. This approach is possible due to a number of advantages of this model including low spontaneous tumor incidence and low per diem costs. We have recently completed the largest cancer study in any animal model, utilizing 42,000 trout to assess carcinogenicity of dibenzo[a,l]pyrene (DBP) at ultra-low doses. The target was an order of magnitude lower than the mouse ED01 study, to one cancer in 1000. Our data established a dose of DBP that resulted in 1 cancer in 5,000 trout and the dose-response was non-linear. We now propose to utilize this ultra-low dose model to test the hypothesis that the non-linearity of cancer incidence at ultra-low dose also applies to AFB1. Tumor incidence data will be coupled with measurements of molecular dosimetry, cell proliferation, apoptosis and gene expression utilizing a custom microarray in order to test the second hypothesis, that in contrast to tumor incidence, these biomarkers of carcinogenicity exhibit linearity across the entire tumor dose-response range.
DESCRIPTION (provided by applicant): Organophosphorus pesticides (OPs) are the most commonly used pesticides in the U.S. and worldwide. Evidence from human and animal studies clearly identifies neurotoxicity as the primary endpoint of concern. However, it has been difficult to predict the risk that repeated low-dose exposure to OPs pose to humans because: 1) a relationship between OP dose and neurobehavioral deficits has yet to be established in humans; 2) biomarkers that reliably predict OP-induced neurobehavioral deficits are not available: and 3) the potential for genetic variation to modify exposure sensitivity has not been thoroughly investigated. The proposed studies will test the hypotheses that OP-induced neurobehavioral deficits are dose-related and that measures of oxidative stress and inflammation are better predictors of neurobehavioral deficit than cholinesterase inhibition. These hypotheses will be tested by studying a cohort of pesticide application workers in Egypt's Menoufia Governorate previously reported to exhibit the broadest range of neurobehavioral deficits in humans following OP exposure. This Egyptian cohort is uniquely suited for these studies because, unlike most pesticide exposures, the exposure is simple (a single OP, chlorpyrifos) and consistent within job categories, but with substantial differences between job categories. In aim 1, OP doses will be estimated using PBPK/PD modeling of urinary OP metabolite data collected from 255 Egyptian workers over the application cycle. These workers will also be genotyped for polymorphisms of key enzymes involved in OP metabolism (CYP2B6, CYP2C19 and PON1) to evaluate the potential for genetic variation to modify internal dose. In aim 2, behavioral deficits will be determined in a subset of workers exhibiting a range of OP exposures. Data from aims 1 and 2 will be integrated to determine the relationship between OP dose and neurobehavioral deficits. Rat studies will be conducted in parallel (aim 3) to test candidate biomarkers as predictors of OP-induced neurobehavioral deficits. The specific biomarkers that will be examined include cholinesterase inhibition, urinary isoprostanes as a measure of oxidative stress, and serum levels of C-reactive protein and inflammatory cytokines as measures of inflammation. In aim 4, those biomarkers that predict OP-induced neurobehavioral deficits in rats will be tested to determine if they similarly predict deficits in behavioral performance in Egyptian pesticide workers. The proposed studies will provide critical data needed to develop effective biomarkers of OP exposure, biological response and genetic susceptibility. The availability of such biomarkers would facilitate the identification of at-risk individuals as well as the testing of intervention and treatment strategies, and the need to develop these strategies is underscored by evidence of widespread human exposure to OPs and the credible threat of OPs as chemical agents of terrorism. Project Summary/Abstract - Relevance The goal of the proposed studies is to identify biomarkers of exposure and effect that are predictive of neurobehavioral deficits in humans exposed to organophosphorus pesticides (OPs). In addition, we will examine human genetic variants of the enzymes CYP2B6 and CYP2C19 that influence OP metabolism to not only inform interpretation of OP exposure data, but also provide insights into genetic susceptibilities that modulate neurotoxic responses to OPs. These studies will provide data critically needed to identify at-risk individuals and will provide tools to facilitate the development and evaluation of intervention and treatment strategies for exposure to not only OP pesticides, which are the most commonly used pesticides in the U.S. and worldwide, but also to nerve agents that are considered a credible terrorist threat.
DESCRIPTION (provided by applicant): We have published papers demonstrating that organophosphates (OPs) induce airway hyperreactivity that is dose related, associated with loss of inhibitory neuronal M2 receptor function that normally limit acetylcholine release, and occurs at doses significantly lower than those that inhibit acetylcholinesterase. Here, we show that sensitized animals (sensitized to an antigen but never challenged with antigen) are significantly more sensitive to OPs than non sensitized controls. 0.001 mg/kg of the OP parathion did not cause hyperreactivity in non-sensitized guinea pigs but it doubled vagally-induced bronchoconstriction in sensitized animals. Higher doses of OPs, that did affect non sensitized animals, had a significantly greater effect in sensitized animals. In addition, we show that the mechanism for OP induced hyperreactivity does not depend on eosinophils in non sensitized animals, but is switched to require eosinophils after sensitization. We have developed a model for eosinophil-nerve interactions that includes active recruitment and adhesion of eosinophils to parasympathetic nerves followed by activation and release of eosinophil major basic protein that is an endogenous antagonist for the M2 receptors. It is our hypothesis that OP-induced hyperreactivity in sensitized animals is mediated by OPs affecting chemotactic factors and adhesion molecules that enhance eosinophil recruitment to nerves, and also OP induced eosinophil activation. We will test this in vitro inhuman and guinea pig parasympathetic nerves and in vivo in guinea pigs. There are 4 specific aims: We will test whether increased sensitivity to OPs extends to the OP class and will include other non OP insecticides as controls (aim 1). Aim 2 will examine the ability of OPs to alter expression of chemotactic factors, their receptors and adhesion molecules and alter eosinophil-nerve interactions at a cellular level. Aim 3 will examine how OPs activate eosinophils and aim 4 will determine the physiological relevance pathways identified in aims 2 and 3 in vivo. Human exposures to OPs is great in the United States and worldwide, given that more than 80% of children with asthma are also sensitized to antigen, these studies could directly impact levels of OP exposure considered safe and provide targets for intervention after exposure.
DESCRIPTION (provided by applicant):
Oregon State University (OSU) in Corvallis is a land-, sea-, and space-grant institution. OSU, with a long history of excellence in environmental toxicology research, has partnered with the Center for Occupational and Environmental Toxicology (CROET) at the Oregon Health and Sciences University (OHSU) in Portland to provide a comprehensive and interdisciplinary training program for pre- and postdoctoral students in environmental health and toxicology.
OSU is home to two NIEHS-funded Centers as well as the prestigious Linus Pauling Institute (LPI). Additionally, there is a NIEHS funded Superfund grant and an NIEHS Toxicogenomics Center within CROET at OHSU. These Centers and Institutes, with their associated facilities and services cores, provide outstanding opportunities for research and training in an environment that heavily favors collaborative programs. The NIEHS Training grant at OSU, along with the associated OSU Centers and Institutes, has experienced significant institutional commitment over the years, which further enhances training opportunities on campus. Additionally, the Training Grant faculty members have very active extramural research programs which are reflected in their individual research grant funding.
The top applicants to the Department of Environmental and Molecular Toxicology and associated graduate programs are aggressively recruited as predoctoral trainees, and postdoctoral trainees recruited through national searches. An important goal of these recruitments is the achievement of diversity among qualified candidates. The productivity of the Training grant's trainees is solid, and alumni of this training program are currently occupying important positions in academia, government, and industry.
Over the next funding period, the training program will be further fine-tuned to improve what is already an outstanding program. The administrative structure is being designed to provide more opportunities for oversight and evaluation of the program, and support for predoctoral trainees will be limited to a maximum of two years, rather than four. There will be important new training opportunities in areas such as proteomics and microarrays. The primary goal of the proposed training program is to produce highly qualified and motivated future leaders in the science of environmental health and toxicology.
DESCRIPTION (provided by applicant): Circadian clocks allow organisms to adapt biochemical and physiological processes to their environment in rhythms entrained by the solar day. There is intriguing evidence that the toxicological response to a number of xenobiotic compounds varies with time of day in many species, including humans. From these reports, it can be inferred that organisms may protect themselves from environmental toxins by increasing molecular defenses when daily exposure is most expected. We will test this novel hypothesis by monitoring mortality of Drosophila melanogaster exposed to pyrethroids at different times of day. Preliminary microarray data have revealed putative rhythmic expression patterns in genes responsible for detoxifying pyrethroids. We will characterize these patterns and examine the involvement of these genes in rhythmic susceptibility to pyrethroids. Using the tools of systems biology, existing microarray data, and our own results, we will construct a model of the convergence of circadian and toxicological networks in order to highlight common regulatory mechanisms. Humans are inevitably exposed to pyrethroids and other pesticides, and this interdisciplinary investigation is likely to lead to novel strategies protective of human health.
DESCRIPTION (provided by applicant): Of the many suspected mediators of asthma, organophosphate (OP) pesticides such as parathion are recently implicated to cause or excacerbate asthma. OP exposure is ubiquitous and probably significant in children since OP metabolites have been reported in breast milk and children's urine. OP exposure may predispose atopic individuals to airway hyperreactivity through increased interactions of eosinophils on the airway nerves. The specific aims are to test the hypothesis that 1. OPs promote the release of major basic protien (MBP) from eosinophils leading to a loss of M2 muscarinic function and an increase in bronchoconstriction to vagal stimulation in sensitized guinea pigs, 2. OPs induce the expression of the adhesion molecules ICAM-1 and/or VCAM-1 and the chemotactant eotaxin in lung nerves, and 3. OPs induce the expression of CD11/CD18, VLA-4, and/or CCR3, the respective counerligands, on the eosinophils. Sensitized, parathion-exposed guinea pigs will be treated to block MBP and used in physiological studies to measure changes in bronchocontstriction after vagal stimulation. The observed effects of OPs on eosinophils and nerves will be measured in isolated cells.
DESCRIPTION (provided by applicant)
The prevalence and incidence of obesity is a serious threat to public health in the United States, and has reached epidemic proportions. Additional concerns are the associations of overweight and obesity with cardiovascular disease, diabetes, cancer, and other debilitating conditions. This proposed project responds to the call for efforts to identify and measure potential causal associations between the built environment and obesity, and related comorbidities. This investigation proposes a longitudinal, multilevel project to examine how the physical and built environment may influence levels of overweight and obesity, physical inactivity, and blood pressure in neighborhoods of older residents. The primary aims are to: (a) simultaneously examine neighborhood- and resident-level change in body mass index, physical activity, and blood pressure over a three-year period, and (b) identify neighborhood-level physical and built environment correlates of change in the proposed outcomes while controlling for covariates at the resident-level.
Using a multistage sampling design, the study will recruit 1,800 community residents aged 60 years and older from a random sample of 120 census-block groups (defined as a proxy for neighborhoods - the primary sampling unit) in Multinomial County, Oregon. Data to be gathered include surveys, assessments, census and Geographic Information Systems data, and dependent outcome measures of body mass index, physical activity, and blood pressure. Key physical and built environment measures will include hilly terrain, urban form, and density of fast-food restaurants. The resulting environmental and personal factors data will be integrated into a three-level statistical model involving temporal measures (Level 1), that are nested within residents (Level 2), who are themselves nested within neighborhoods (Level 3). The hierarchically structured data, to be analyzed through multilevel modeling methodologies, will examine both inter-neighborhood and inter-resident variability in change in the proposed outcomes, as well as the degree to which neighborhood-level built environment variables are related to variation in change in the outcomes over time.
This proposed investigation extends the current individual oriented paradigm to an ecological, multilevel paradigm for assessing the extent to which built environment factors influence obesity and obesity-related outcomes over time in the neighborhoods of older adults. The results of this study are likely to increase understanding of the unique influences of physical and built environment factors which directly and indirectly affect neighborhood-level overweight and obesity in older adults, and will provide information to guide future pubic health investigations to slow the pace of this growing epidemic.
DESCRIPTION (provided by applicant): Nanotechnology is an enabling platform that will provide a broad range of novel applications and improved technologies for biomedical science due to the unique physical and chemical properties inherent to nanomaterials. Pertinent to the development of promising biomedical nanotechnologies, and to the safety of nanomaterials in general, is a thorough understanding of nanomaterial-biological interactions. Yet, the principal characteristics that may be predictive of nanomaterial interactions with biological systems have not been elucidated because of the current lack of data, the enormous diversity of nanomaterials, and the lack of coordinated efforts to share findings and translate data into knowledge. The embryonic zebrafish model is a dynamic in vivo system that offers the power of whole-animal investigations with the convenience of cell culture to rapidly evaluate interactions between engineered nanomaterials and biological systems. Investigations using this model system can reveal subtle interactions at multiple levels of biological organization, i.e. molecular, cellular, systems, organismal. Our approach couples the many advantages of the embryonic zebrafish assay with an ideal nanoparticle platform in order to systematically assess the relative influence of various physiochemical parameters on overall biological responses to nanomaterial exposure. High-purity, ligand-functionalized gold nanoparticles (AuNPs) synthesized in aqueous environments can be precisely engineered such that individual aspects of the material can be evaluated independently. It is well understood that data from this emerging field will be extremely diverse including a multitude of widely varying nanomaterials that are being/or will be tested in a broad array of animal systems and in vitro assays. Knowledge of nanomaterial-biological interactions will likely only be arrived at upon inclusion and consideration of the entire body of data produced from global efforts in this research area. To address these needs in the nascent field of nanobiotechnology, our group has developed a collaborative knowledgebase of Nanomaterial-Biological Interactions (NB). The NBI knowledgebase serves as a repository for annotated data on nanomaterial characterization, synthesis methods, and nanomaterial-biological interactions define at multiple levels of biological organization. Relevant computational, analytic and data mining tools will be incorporated into NBI to the framework for species, route, dose and scenario extrapolations and for identification of key data required to predict the biological interactions of nanomaterials. PUBLIC HEALTH RELEVANCE: New nanomaterials are rapidly being developed for a wide range of biomedical applications (e.g. high-performance diagnostic probes, site-selective therapeutics, prosthetics, regenerative medicine, imaging, etc.), so it is surprising that so little is known about how or why nanomaterials interact with biological systems and even less is known about how to design them to exhibit a desired effect in whole animals. The immediate need to gain comprehensive information on biological-nanomaterial interactions requires systematic, collaborative scientific investigation to define nanomaterial-biological interactions and describe how specific properties of nanomaterials govern biological responses. Timely evaluation and dissemination of information on nanomaterial-biological interactions will provide much needed data, improve public trust of the nanotechnology industry, and provide nanomaterial designers in academia and industry with information to direct the development of high-performance, safe nanomaterials and resulting biomedical technologies.