New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Subchronic Toxicities of Industrial and Agricultural Chemicals to Fathead Minnows (Pimephales promelas)

The utility of chemical toxicity testing as an environmental protection strategy has been an accepted practice since the mid 1900s. Extensive aquatic toxicity testing began in the 1960s and tests were categorized into three different formats according to duration and measured parameters. The acute toxicity test generally ran 48-96 hr and was a measurement of survival. The subchronic test lasted 30-60 days and measured organism hatchability, larval/juvenile survival, and growth parameters of surviving test organisms. Full life cycle tests required six months to two years for completion and measured reproductive effects of toxicants in addition to the aforenamed parameters

Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) Volume V

The completion of this fifth volume of Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) marks a milestone for our QSAR research program. The five volumes contain original data from 777 acute toxicity tests using 651 different chemicals and encompassing 12 years of effort. In April, 1989, a new data file called ATOC (Acute Toxicity of Organic Chemicals) was added to the AQUIRE (Aquatic Information Retrieval) data base currently available on-line to government agencies. The ATOC file contains test data on 525 of the 651 chemicals contained in volumes I-V of Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas). Other supplemental information has been added to the data base in the past two years and is reflected in the present volume. Individual tests from volumes I-V were reanalyzed for 24-, 48- and 72-hr LC50s (concentrations causing 50% mortality of the fish) and EC50s (concen­trations causing 50% of the fish to show an adverse effect). The results are recorded in Appendix C. Another component of the QSAR research program at ERL-D has been the study of behavioral toxicity syndromes. Of the chemicals contained in volumes I-V, 309 were evaluated using behavioral and morphological signs of stress which occurred during acute toxicity testing (Drwnmond and Russom 1990). The goal of that study was to classify chemicals according to general mode of action, and the chemicals used are listed in Appendix A. Cumulative appendices containing molecular formulas, GAS numbers and chemical names have been updated and are reported herein (Appendices A and B). Fathead minnow acute toxicity testing conducted at ERL-D and the University of Wisconsin-Superior has slowed somewhat in the last couple ofyears due to changing emphases in research. Emphasis has shifted towards early-life stage tests and the use of the medaka (Oryzias latipes) as a test organism. Volume V of the toxicity data base series incorporates all additional fathead minnow acute toxicity test data to date. It is anticipated that the future volumes will be published less frequently because the number of chemicals tested each year will decline. Although the level of fathead minnow acute toxicity testing has changed, the commitment of supplying the scientific community with high quality data will remain steadfast. Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas). Other supplemental information has been added to the data base in the past two years and is reflected in the present volume. Individual tests from volumes I-V were reanalyzed for 24-, 48- and 72-hr LC50s (concentrations causing 50% mortality of the fish) and EC50s (concen­ trations causing 50% of the fish to show an adverse effect). The results are recorded in Appendix C. Another component of the QSAR research program at ERL-D has been the study of behavioral toxicity syndromes. Of the chemicals contained in volumes I-V, 309 were evaluated using behavioral and morphological signs of stress which occurred during acute toxicity testing (Drwnmond and Russom 1990). The goal of that study was to classify chemicals according to general mode of action, and the chemicals used are listed in Appendix A. Cumulative appendices containing molecular formulas, GAS numbers and chemical names have been updated and are reported herein (Appendices A and B). Fathead minnow acute toxicity testing conducted at ERL-D and th

Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) Volume IV

In this, the fourth volume of acute toxicity data on organic chemi­cals, we pay tribute to the species which has made this possible. The fathead minnow (Pimephales promelas) is well suited to laboratory studies and was chosen for several reasons, including: (1) ease of cul­turing, (2) widespread occurrence, (3) rapid growth, (4) ecological importance, and (5) mid-range in tolerance for freshwater organisms to environmental pollutants. The cover shows the fathead minnow in its natural habitat. The male, with his nuptial tubercles, is actively tending his nest by agitating the water and grooming the eggs on the underside of a piece of wood. At the right, a female is shown waiting to add to the eggs already in the nest. The fathead minnow is in the Cyprinidae family of modern bony fishes. It is widespread in North America, ranging from the Great Slave Lake and Hudson Bay in Canada in the north to the State of Chihu­ahua, Mexico in the south, and from the State of Maine in the east to the Rocky Mountains in the west (Scott and Crossman 1973). Its pres­ence in the Sacramento Valley in the State of California was indicated by Becker (1983). Several common names have been applied to the species. It has been referred to as northern fathead minnow, blackhead minnow, Tuffy minnow and fathead (Becker 1983, Scott and Crossman 1973). It derives its scientific name from the breeding male having an enlarged blackish head relative to the dark remainder of the body

Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) Volume III

Acute toxicity values for aquatic life continue to be useful for pre­liminary assessment of the potential for harm in the environment by chemicals. The end-point for an Lc50 (concentration of chemical necessary to kill 50 per­ cent of the test organisms in a specified time limit) is rigorous and defini­tive. This end-point lends itself well to comparative testing and is useful in preliminary screening for hazardous chemicals. The literature contains many papers dealing with acute toxicity to aquatic organisms. The Aquatic Information Retrieval (AQUIRE) data base, for example, presently contains information on approximately 4,600 chemicals using 2,245 test species (Anne Pilli, personal communication).1 These species include various fresh and saltwater organisms from fungi to fish. The Columbia National Fisheries Research Laboratory data base (Johnson and Finley, 1980) contains acute toxicity test results for 271 chemicals using 58 aquatic species of test organisms. The large data bases contain data gleaned from the literature and derived from diverse test conditions. In contrast, the data base presented here is derived using standardized conditions of chemical exposure and a single test species. (fathead minnow, Pimephales promelas) of a given age class (26 to 37 day old juveniles at start of exposures). All tests have been conducted using either Lake Superior water or water from the municipal supply for the City of Superior, Wisconsin, which is derived from wells beneath Lake Superior and is very similar in its natural chemical characteristics to Lake Superior water. Volume III adds 151 tests to the data base, bringing the total number of tests to 500 and the number of chemicals tested to 425. New chemical classes are contained in this volume which are not in Volumes I and II. Testing is still underway for many new chemicals and chemical classes. The results of these tests will be reported in future volumes

Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) Volume I

Over 60,000 chemicals exist in United States commerce (U.S. EPA, 1982). This inventory expands each year as 200 to l,000 new chemicals are advanced into commercial production (Muir, 1980). Fortunately, most of these chemicals have not posed any known threats to the environment. However, several chemicals have presented serious environmental hazards, and an increased awareness of these hazards developed in the 1960 1 s and 1970 1 s. This resulted in passage by the U.S. Congress in 1976 of the Toxic Substances Control Act (TSCA). The governmental focus via TSCA has been on the prevention of potentially harmful situations (Kissman and Wexler, 1983). Thus, the act attempts to control the introduction, production, distribution or use in commerce of any chemical that presents an unreasonable risk to human health or the environment, which is not adequately regulated by other laws. This act has empowered the U.S. Environmental Protection Agency (EPA) with authority over the regulation, reporting and testing of these chemicals (Muir, 198.0). Because of the large and ever-increasing number of chemicals in the TSCA inventory, resources simply are not available to test the vast majority of these chemicals for their hazard potential in the environment. Therefore, approaches have been adopted by EPA which are designed to result in the selection for further study of chemicals with real hazard potential and the elimination from further study of those which are judged to be relatively innocuous. The area of predictive environmental toxicology has been used in this process of chemical selection. Principles of quantitative structure-activity relationships (QSAR) are applied in predictive toxicology. For development of toxicity prediction models, a subset of chemicals from a given class or from a group with a common mode of toxic action are tested for their toxicities to the test organism. Structural or physicochemical features of the test compounds are correlated with toxicity test endpoints to determine the strength of relationships. QSAR models which exhibit high correlations between basic molecular properties and toxicity may be used to predict toxicity with a certain degree of accuracy. Very few aquatic toxicology data bases exist which can be applied to. QSAR model development. Ideally, such data bases should consist of tests conducted with the same species in the same water under identical test conditions. Concentrations of toxicants in the exposure chambers should be measured. In cooperation with EPA, the University of Wisconsin­ Superior has been developing a data base for application in predictive toxicology model development. This volume provides the methods and results from 198 acute toxicity tests conducted with the fathead minnow (Pimephales promelas) in Lake Superior water

Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) Volume II

The contents of the second volume of Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas} provide additional infor­mation for the ongoing development of an aquatic toxicology data base. Listed herein are the methods and results from 151 acute toxicity tests con­ ducted with the fathead minnow (Pimephales promelas} in Lake Superior water. Some chemical classes included in Volume 1 have. been expanded in this volume, with the data lending further support to quantitative structure­ activity relationship CQSAR) model development. Test compounds have been added from several chemical classes not in Volume 1. Behavioral observations have been enhanced through the use of a coded, systemized checklist. These behavioral observations in conjunction with the 96 hr toxicity data, have added to the understanding of a prediction model for narcotic chemicals (Veith et tl·, 1983). Future volumes of Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales promelas) will emphasize test results from non-narcotic chemi.ca1 s.