Publications by authors named "Elwood Linney"

DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood.

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Oxidative stress is an important mechanism of chemical toxicity, contributing to teratogenesis and to cardiovascular and neurodegenerative diseases. Developing animals may be especially sensitive to chemicals causing oxidative stress. The developmental expression and inducibility of anti-oxidant defenses through activation of NF-E2-related factor 2 (NRF2) affect susceptibility to oxidants, but the embryonic response to oxidants is not well understood.

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Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood.

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Zebrafish are increasingly used for developmental neurotoxicity testing because early embryonic events are easy to visualize, exposures are done without affecting the mother and the rapid development of zebrafish allows for high throughput testing. We used zebrafish to examine how exposures to three different organophosphorus pesticides (chlorpyrifos, diazinon and parathion) over the first five days of embryonic and larval development of zebrafish affected their survival, acetylcholinesterase (AChE) activity and behavior. We show that at non-lethal, equimolar concentrations, chlorpyrifos (CPF) is more effective at equimolar concentrations than diazinon (DZN) and parathion (PA) in producing AChE inhibition.

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This is a review of research that supports a hypothesis regarding early restriction of gene expression in the vertebrate embryo. We hypothesize that vertebrate retinoic acid receptors (RARs for several vertebrates but rars for zebrafish) are part of an embryonic, epigenetic switch whose default position, at the time of fertilization is "OFF". This is due to the assemblage of a rar-corepressor-histone deacetylase complex on retinoic acid response elements (RAREs) in regulatory regions of a subset of genes.

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The retinoic acid receptors (RARs or rars) and the thyroid hormone receptors are members of the steroid receptor superfamily that interact with their DNA response elements (for RARs: retinoic acid response elements or RAREs) in the regulatory regions of promoters in the absence of their ligand. In this ligand minus configuration, it has been suggested that the RAR provides a binding site for a corepressor (SMRT or N-CoR) that also brings in other proteins to repress the gene. In the presence of the ligand, the receptor goes through an allosteric change eliminating the corepressor binding site and providing a coactivator binding site.

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Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavioral impairment. In a parallel series of studies with zebrafish, we have also found persisting behavioral dysfunction after developmental CPF exposure. We have developed a battery of measures of zebrafish behavior, which are reliable and sensitive to toxicant-induced damage.

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As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to exposure during early development if people taking the medication become pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity.

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Background: In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio) interactome based on orthologs and interaction data from other eukaryotes.

Methodology/principal Findings: Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times.

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The understanding of how environmental exposures interact with genetics in central nervous system dysfunction has gained great momentum in the last decade. Seminal findings have been uncovered in both mammalian and non-mammalian model in large result of the extraordinary conservation of both genetic elements and differentiation processes between mammals and non-mammalians. Emerging model organisms, such as the nematode and zebrafish have made it possible to assess the effects of small molecules rapidly, inexpensively, and on a miniaturized scale.

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The increased use of silver nanoparticles in consumer and medical products has led to elevated human and environmental exposures. Silver nanoparticles act as antibacterial/antifungal agents by releasing Ag(+) and recent studies show that Ag(+) impairs neural cell replication and differentiation in culture, suggesting that in vivo exposures could compromise neurodevelopment. To determine whether Ag(+) impairs development in vivo, we examined the effects of exposure on survival, morphological, and behavioral parameters in zebrafish embryos and larvae.

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Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely.

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Chlorpyrifos (CPF) an organophosphate pesticide causes persisting behavioral dysfunction in rat models when exposure is during early development. In earlier work zebrafish were used as a complementary model to study mechanisms of CPF-induced neurotoxicity induced during early development. We found that developmental (first five days after fertilization) chlorpyrifos exposure significantly impaired learning in zebrafish.

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Early piscine life stages are sensitive to polycyclic aromatic hydrocarbon (PAH) exposure, which can cause pericardial effusion and craniofacial malformations. We previously reported that certain combinations of PAHs cause synergistic developmental toxicity, as observed with coexposure to the aryl hydrocarbon receptor agonist beta-naphthoflavone (BNF) and cytochrome P4501A inhibitor alpha-naphthoflavone (ANF). Herein, we hypothesized that oxidative stress is a component of this toxicity.

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Cyp26A1 is a major enzyme that controls retinoic acid (RA) homeostasis by metabolizing RA into bio-inactive metabolites. Previous research revealed that the mouse Cyp26A1 promoter has two canonical RA response elements (RAREs) that underlie the regulation of the gene by RA. Analyzing the 2,533-base pairs (2.

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Estradiol is produced from testosterone by the aromatase gene, cyp19. In the zebrafish Danio rerio, brain aromatase, cyp19a1b, is highly expressed during development. We report the developmental expression pattern of cyp19a1b using whole mount in situ hybridization and describe hormonal effects on the gene using RT-PCR.

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Background: The zebrafish Danio rerio is an important model system for drug discovery and to study cardiovascular development. Using a laser-scanning confocal microscope, we have developed a non-invasive method of measuring cardiac performance in zebrafish embryos and larvae that obtains cardiovascular parameters similar to those obtained using Doppler echocardiography in mammals. A laser scan line placed parallel to the path of blood in the dorsal aorta measures blood cell velocity, from which cardiac output and indices of vascular resistance and contractility are calculated.

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Gene expression profiling is a widely used technique with data from the majority of published microarray studies being publicly available. These data are being used for meta-analyses and in silico discovery; however, the comparability of toxicogenomic data generated in multiple laboratories has not been critically evaluated. Using the power of prospective multilaboratory investigations, seven centers individually conducted a common toxicogenomics experiment designed to advance understanding of molecular pathways perturbed in liver by an acute toxic dose of N-acetyl-p-aminophenol (APAP) and to uncover reproducible genomic signatures of APAP-induced toxicity.

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Although recent studies have extended our understanding of agrin's function during development, its function in the central nervous system (CNS) is not clearly understood. To address this question, zebrafish agrin was identified and characterized. Zebrafish agrin is expressed in the developing CNS and in nonneural structures such as somites and notochord.

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Background: Vitamin A (retinol), in the form of retinoic acid (RA), is essential for normal development of the human embryo. Studies in the mouse and zebrafish have shown that retinol is metabolized in the developing spinal cord and must be maintained in a precise balance along the anteroposterior axis. Both excess and deficiency of RA can affect morphogenesis, including failures of neural tube closure.

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Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell-cell interactions, and may play a role in the formation and closure of the neural tube.

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We have cloned the zebrafish ortholog of the mammalian cyp26b1 gene. The predicted zebrafish cyp26b1 protein shares greater than 73% identity with mammalian homologues. cDNA transfection assays showed that like human cyp26b1, zebrafish cyp26b1 is involved in limiting the activity of retinoic acid.

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We analyzed 15,512 unique transcripts from wild-type Danio rerio using a long oligonucleotide microarray containing >16,000 65-mers probes. Total RNA was isolated from staged embryos at 2 h intervals over a 24-h period. On average, at any given time point, 27% of the probe set detected corresponding transcripts in embryonic RNA.

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Chlorpyrifos (CPF), a widely used organophosphate insecticide and potent acetylcholinesterase inhibitor, interferes with neurobehavioral development. Rat models have been key in demonstrating that developmental CPF exposure causes learning deficits and locomotor activity alterations, which persist into adulthood. Complementary nonmammalian models can be useful in determining the neurodevelopmental mechanisms underlying these persisting behavioral effects.

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At a time when common regulatory pathways are being identified in several different species and genomics is beginning to allow comparisons of genes, how they are arranged on chromosomes and how they are regulated, zebrafish has emerged as a valuable and complementary vertebrate model. Some of the characteristics that prove of value are described and illustrated. Fluorescent transgenic lines of zebrafish embryos are presented for time-line studies with neurotoxicants.

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