Analysis of incidence data in developmental toxicity studies: Statistical tests to account for litter effects in fetal defect data.

Background: When analyzing fetal defect incidence in laboratory animal studies, correlation in responses within litters (i.e., litter effects) can lead to increased false-positive rates if litter effects are not incorporated into the analysis.

Comprehensive Analyses and Prioritization of Tox21 10K Chemicals Affecting Mitochondrial Function by in-Depth Mechanistic Studies.

Background: A central challenge in toxicity testing is the large number of chemicals in commerce that lack toxicological assessment. In response, the Tox21 program is re-focusing toxicity testing from animal studies to less expensive and higher throughput methods using target/pathway-specific, mechanism-driven assays.

Objectives: Our objective was to use an in-depth mechanistic study approach to prioritize and characterize the chemicals affecting mitochondrial function.

Developmental Effects of the ToxCast™ Phase I and Phase II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits.

Background: Modern toxicology is shifting from an observational to a mechanistic science. As part of this shift, high-throughput toxicity assays are being developed using alternative, nonmammalian species to prioritize chemicals and develop prediction models of human toxicity.

Methods: The nematode Caenorhabditis elegans (C.

Comparative toxicogenomic responses of mercuric and methyl-mercury.

Background: Mercury is a ubiquitous environmental toxicant that exists in multiple chemical forms. A paucity of information exists regarding the differences or similarities by which different mercurials act at the molecular level.

Results: Transcriptomes of mixed-stage C.

Comparison of the toxicity of fluoridation compounds in the nematode Caenorhabditis elegans.

Fluorides are commonly added to drinking water in the United States to decrease the incidence of dental caries. Silicofluorides, such as sodium hexafluorosilicate (Na2 SiF6 ) and fluorosilicic acid (H2 SiF6 ), are mainly used for fluoridation, although fluoride salts such as sodium fluoride (NaF) are also used. Interestingly, only the toxicity of NaF has been examined and not that of the more often used silicofluorides.

Caenorhabditis elegans as a model in developmental toxicology.

A number of practical advantages have made the nematode Caenorhabditis elegans a useful model for genetic and developmental biological research. These same advantages, along with conservation of disease and stress response pathways, availability of mutant and transgenic strains, and wealth of biological information, have led to the increased use of C. elegans in toxicological studies.

Amelioration of metal-induced toxicity in Caenorhabditis elegans: utility of chelating agents in the bioremediation of metals.

The presence of toxic amounts of transition metals in the environment may originate from a range of human activities and natural processes. One method for the removal of toxic levels of metals is through chelation by small molecules. However, chelation is not synonymous with detoxification and may not affect the bioavailability of the metal.

A discrete time model for the analysis of medium-throughput C. elegans growth data.

Background: As part of a program to predict the toxicity of environmental agents on human health using alternative methods, several in vivo high- and medium-throughput assays are being developed that use C. elegans as a model organism. C.

Application of a mathematical model to describe the effects of chlorpyrifos on Caenorhabditis elegans development.

Background: The nematode Caenorhabditis elegans is being assessed as an alternative model organism as part of an interagency effort to develop better means to test potentially toxic substances. As part of this effort, assays that use the COPAS Biosort flow sorting technology to record optical measurements (time of flight (TOF) and extinction (EXT)) of individual nematodes under various chemical exposure conditions are being developed. A mathematical model has been created that uses Biosort data to quantitatively and qualitatively describe C.

Medium- and high-throughput screening of neurotoxicants using C. elegans.

The U.S. National Toxicology Program, the U.

Characterization of the proneural gene regulatory network during mouse telencephalon development.

Background: The proneural proteins Mash1 and Ngn2 are key cell autonomous regulators of neurogenesis in the mammalian central nervous system, yet little is known about the molecular pathways regulated by these transcription factors.

Results: Here we identify the downstream effectors of proneural genes in the telencephalon using a genomic approach to analyze the transcriptome of mice that are either lacking or overexpressing proneural genes. Novel targets of Ngn2 and/or Mash1 were identified, such as members of the Notch and Wnt pathways, and proteins involved in adhesion and signal transduction.