Search PubMed⌕ Search

Biomedical subjects

William Slikker

Publications and source records attributed to William Slikker.

At least 19 recordsLinked to original sources
PubMed2006

Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the robustness of ketamine-induced developmental neurotoxicity using rhesus monkey frontal cortical cultures and also to determine if dysregulation of NMDA receptor subunits promotes ketamine-induced cell death. Frontal cortical cells collected from the neonatal monkey were incubated for 24 h with 1, 10, or 20 microM ketamine alone or with ketamine plus either NR1 antisense oligonucleotides or the nuclear factor kB translocation inhibitor, SN-50. Ketamine caused a marked reduction in the neuronal marker polysialic acid neural cell adhesion molecule and mitochondrial metabolism, as well as an increase in DNA fragmentation and release of lactate dehydrogenase. Ketamine-induced effects were blocked by NR1 antisenses and SN-50. These data suggest that NR1 antisenses and SN-50 offer neuroprotection from the enhanced degeneration induced by ketamine in vitro.

Animals↗
PubMed2005

Biomarkers of adult and developmental neurotoxicity.

Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessary for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s), (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations.

Amphetamine↗
PubMed2005

A microarray study of MPP+-treated PC12 Cells: Mechanisms of toxicity (MOT) analysis using bioinformatics tools.

BACKGROUND: This paper describes a microarray study including data quality control, data analysis and the analysis of the mechanism of toxicity (MOT) induced by 1-methyl-4-phenylpyridinium (MPP+) in a rat adrenal pheochromocytoma cell line (PC12 cells) using bioinformatics tools. MPP+ depletes dopamine content and elicits cell death in PC12 cells. However, the mechanism of MPP+-induced neurotoxicity is still unclear. RESULTS: In this study, Agilent rat oligo 22K microarrays were used to examine alterations in gene expression of PC12 cells after 500 muM MPP+ treatment. Relative gene expression of control and treated cells represented by spot intensities on the array chips was analyzed using bioinformatics tools. Raw data from each array were input into the NCTR ArrayTrack database, and normalized using a Lowess normalization method. Data quality was monitored in ArrayTrack. The means of the averaged log ratio of the paired samples were used to identify the fold changes of gene expression in PC12 cells after MPP+ treatment. Our data showed that 106 genes and ESTs (Expressed Sequence Tags) were changed 2-fold and above with MPP+ treatment; among these, 75 genes had gene symbols and 59 genes had known functions according to the Agilent gene Refguide and ArrayTrack-linked gene library. The mechanism of MPP+-induced toxicity in PC12 cells was analyzed based on their genes functions, biological process, pathways and previous published literatures. CONCLUSION: Multiple pathways were suggested to be involved in the mechanism of MPP+-induced toxicity, including oxidative stress, DNA and protein damage, cell cycling arrest, and apoptosis.

1-Methyl-4-phenylpyridinium↗
PubMed2005

Behavioral test methods workshop.

A one and a half day workshop on behavioral testing was conducted in order to discuss experimental procedures and practices that may help enhance the utility of behavioral data as a reliable index of neurotoxicity and in the safety evaluation of chemical substances. The workshop was open to participation by all sectors of the neuroscience community including academia, government, testing laboratories, and industry. The level of confidence with which changes in behavior can reliably signal adverse effects on the nervous system depends, in part, on the scientific quality of the data generated. With an emphasis on education and problem solving, the workshop focused on the practical aspects and scientific rationale underlying valid and high quality testing. In behavioral testing, there are numerous experimental factors that may impact on the quality of data. These include such elements as experimental design, selection of test methods, the care and precision in the conduct of behavioral testing, procedures to minimize bias and potential confounds, appropriateness of statistical analyses, and data interpretation. In plenary session investigators experienced in behavioral testing discussed the significance of these various experimental factors to data quality, outlined problematic issues, and presented a synopsis of approaches for addressing each of the factors as outlined in a draft of a primer developed by the Interagency Committee on Neurotoxicology (ICON). During the remainder of the workshop, open discussions in small breakout groups were used to address the problematic issues identified by the plenary speakers and explore alternative approaches for dealing with them. Finally, all workshop participants were reconvened in plenary session for summation of breakout group discussions and final recommendations. Information from the workshop was used to form the basis of this manuscript and will be used to help finalize a behavioral test methods primer being drafted by the ICON. The overall conclusions from the workshop were that consensus can be reached on the fundamentals of behavioral assessment, and that aspects of behavioral assessment including experimental design, test method selection, training, validation, control of confounds, data variability, data analysis, and data interpretation need to be carefully considered in the planning and conduct of behavioral safety assessments.

Animals↗
PubMed2005

The differential JunB responses to inhibition of succinate dehydrogenase in rat hippocampus and liver.

The inhibitor of mitochondrial enzyme succinate dehydrogenase, 3-nitropropionic acid (3-NPA), induces cellular energy deficit followed by oxidative stress, secondary excitotoxicity and neuronal degeneration. The fast activation of Jun and Fos proteins and other proteins encoding inducible transcription factors (ITFs) occurs in most tissues upon exposure to a variety of stressors including exposure to mitochondrial inhibitors. However, the consequences of this activation can differ dramatically in different organs. For example, while activation of the same ITFs may lead to apoptosis and necrosis in neurons it may stimulate liver regeneration. Here, we report the alterations in mRNAs levels of c-Fos, JunB, and Krox20 proteins induced in the rat brain and liver by the acute exposure to 3-NPA at 30 mg/kg, s.c. While the increase of c-fos transcripts was observed in both the hippocampus and liver, the junb transcript increased in the hippocampus but decreased in the liver. No changes were observed in krox-20 mRNA in the hippocampus. Interestingly, there was a large variation in krox-20 mRNA levels in the liver among animals within the same experimental group. In conclusion, out of the three ITFs transcripts examined here junb may activate different pathways depending on the tissue as indicated by differential responses to mitochondrial inhibition in the hippocampus and liver.

Animals↗
PubMed2005

Sex differences in cytochrome P450 1B1, an estrogen-metabolizing enzyme, in the rhesus monkey telencephalon.

The metabolic enzyme CYP1B1 is a recently cloned member of the cytochrome P450 superfamily, expressed widely throughout primate tissue, including the CNS. Although CYP1B1 protein is known to metabolize estradiol to catecholestrogens in the uterus, its localization and function in brain have not yet been described. To better understand CYP1B1 distribution, we have combined in situ hybridization (ISH) for its mRNA with immunohistochemistry (IHC) for the CYP1B1 protein in selected brain regions of male and female adult rhesus monkeys (Macaca mulatta). Blocks of formalin-fixed tissue obtained from the frontal cortex, hippocampus, thalamus, and amygdala were processed and embedded in paraffin. They were then sectioned and stained as described for human tissue [Muskhelishvili, L., Thompson, P.A., Kusewitt, D.F., Wang, C., Kadlubar, F.F., 2001. In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. J. Histochem. Cytochem. 49, 229-236]. Results indicated widespread distribution of CYP1B1 mRNA in both male and female monkey frontal cortex, hippocampus, thalamus, and amygdala. In contrast, although CYP1B1 protein was co-localized with its mRNA in the female brains, it was primarily restricted to hippocampal pyramidal neurons in the male brains. These results suggest that CYP1B1 may subserve widespread metabolic functions in the female primate brain but have more restricted actions within the hippocampal pyramidal neurons of the male.

Animals↗
PubMed2005

Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.

Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although Thimerosal has been recently removed from most children's vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations.

Acetylcysteine↗
PubMed2005

Improving predictive modeling in pediatric drug development: pharmacokinetics, pharmacodynamics, and mechanistic modeling.

A workshop was conducted on November 18-19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adult-like in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

Adult↗
PubMed2004

Dose-dependent transitions in mechanisms of toxicity.

Scientists and decision makers from all sectors agree that risk assessments should be based on the best available science. Several years ago, the Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), identified the need for better scientific understanding of dose-dependent transitions in mechanisms of toxicity as one avenue by which the best and latest science can be integrated into the decision making process. In July 2001, the HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity established a group of academic, government, and industry scientists to engage in active technical discourse on the issue of dose-dependent transitions in mechanisms of toxicity. Over the next 18 months, case studies were examined. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, the peroxisome proliferator-activated receptor, progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc (Slikker, W., Jr., Andersen, M.E., Bogdanffy, M.S., Bus, J.S., Cohen, S.D., Conolly, R.B., David, R.M., Doerrer, N.G., Dorman, D.C., Gaylor, D.W., Hattis, D., Rogers, J.M., Setzer, R.W., Swenberg, J.A., Wallace, K., 2004. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol. Appl. Pharmacol. 201(3), 226-294 (this issue)). The HESI Project Committee sponsored two technical workshops in 2003. The first of these workshops took place on February 12-13, 2003, and was co-sponsored by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency. Additional support was provided by Health Canada. Invited experts from government, academia, and industry provided scientific perspectives and recommendations at the workshop. The purpose of the workshop was to examine approaches to dose-response analysis, learn from the case study examples, and gather feedback from invited participants on the impact of dose-dependent transitions on the risk assessment process. The second forum consisted of a workshop in March 2003 at the Society of Toxicology Annual Meeting in Salt Lake City, UT. This paper addresses the issues discussed at both workshops, and presents the consensus conclusions drawn by expert participants.

Animals↗
PubMed2004

Dose-dependent transitions in mechanisms of toxicity: case studies.

Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposures, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose-dependent transitions in principal mechanisms of toxicity may occur, and could have significant impact on the interpretation of reference data sets for risk assessment. To illustrate the existence of dose-dependent transitions in mechanisms of toxicity, a group of academic, government, and industry scientists, formed under the leadership of the ILSI Health and Environmental Sciences Institute (HESI), developed a series of case studies. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, peroxisome proliferator-activated receptor (PPAR), progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc. The case studies formed the basis for technical discourse at two scientific workshops in 2003.

Acetaminophen↗
PubMed2004

N-ethyl-N-nitrosourea (ENU) increased brain mutations in prenatal and neonatal mice but not in the adults.

The incidence of childhood cancer is increasing. One of the most common cancers for children under 15 years of age, gliomas for example, has been reported to have increased in incidence over the last 20 years by approximately 40%. The rising trend of childhood cancer in brain may be associated with environmental exposure to genotoxins and susceptibility to mutation in early development. To investigate age-dependent mutagenic sensitivity of brain tissue to genotoxins, the Big Blue mouse model was utilized in this study. Groups of five male mice were treated with a single dose of 120 mg/kg ENU transplacentally at three days before birth (prenatal), eight days (neonate) or eighteen weeks (adult) after birth. The animals were sacrificed six weeks after the treatment. The mutant frequencies and types of mutations in the brain cII gene from ENU-treated and concurrent control mice were determined. A significant increase in mutant frequencies over control was found in the prenatal and neonatal groups whereas there was no significant difference between the adult group and its control. Molecular analysis of the mutants also indicated that the mutational spectra from the ENU-treated mice were age-dependent. The percentage of A:T --> T:A transversion, the typical type of mutation induced by ENU, was inversely related to the treatment age, whereas G:C --> A:T transition was the main type of mutation in the adult group, the same as the control. These results demonstrate a differential mutagenic effect of ENU on the mouse brain depending on the stages of development and suggest an enhanced susceptibility of brain cancer hazard for perinatal exposure to genotoxicants.

Aging↗
PubMed2004

Neuroimaging: new approaches for neurotoxicology.

Over the last 20 years, the impact of imaging on the clinical sciences is unquestionable. It has revolutionized the diagnosis and treatment of disease. Interestingly, the use of imaging in preclinical neurotoxicology has been relatively negligible. This has been in part due to the lack of knowledge or understanding of the capabilities of these powerful technologies. However, some of the more immediately applicable imaging approaches could impact the present approach to neurotoxicology. In addition, the recent advent of the development of imagers specifically for application to small animals will provide the opportunity of obtaining information for neurotoxicological risk assessment in a more timely and relevant manner. The ability to visualize changes in structure and function due to neurotoxic insult in a noninvasive manner is a promising direction. Changes in anatomy of soft and hard tissue, metabolism, function and gene expression can now be done in both a preclinical and a clinical setting using such technologies as magnetic resonance imaging (MRI), magnetic resonance imaging microscopy (MRM), and positron emission tomography (PET). This type of information is not readily accessible using conventional preclinical neurotoxicological procedures and usually requires total destruction of the intrinsic structure of the sample of interest. Imaging provides an opportunity to produce much of these data in a nondestructive manner and presents the data in a three-dimensional format. This permits longitudinal studies of the same subject subsequently reducing the number of animals required for studies while providing more information. In addition, as these technologies have been primarily developed for clinical purposes, they provide an outstanding opportunity for cross-species and animal-to-human extrapolation and testing.

Animals↗
PubMed2004

Introduction.

Explore the source record for details and available documents.

Journal Article↗
PubMed2004

Role of the standard deviation in the estimation of benchmark doses with continuous data.

For continuous data, risk is defined here as the proportion of animals with values above a large percentile, e.g., the 99th percentile or below the 1st percentile, for the distribution of values among control animals. It is known that reducing the standard deviation of measurements through improved experimental techniques will result in less stringent (higher) doses for the lower confidence limit on the benchmark dose that is estimated to produce a specified risk of animals with abnormal levels for a biological effect. Thus, a somewhat larger (less stringent) lower confidence limit is obtained that may be used as a point of departure for low-dose risk assessment. It is shown in this article that it is important for the benchmark dose to be based primarily on the standard deviation among animals, s(a), apart from the standard deviation of measurement errors, s(m), within animals. If the benchmark dose is incorrectly based on the overall standard deviation among average values for animals, which includes measurement error variation, the benchmark dose will be overestimated and the risk will be underestimated. The bias increases as s(m) increases relative to s(a). The bias is relatively small if s(m) is less than one-third of s(a), a condition achieved in most experimental designs.

Animals↗
PubMed2004

Incorporating children's toxicokinetics into a risk framework.

Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper.

Adult↗