ABSTRACT
An IQ DruSafe working group evaluated the concordance of 3 alternative teratogenicity assays (rat whole embryo culture, rWEC; zebrafish embryo culture, ZEC; and murine embryonic stem cells, mESC) with findings from rat or rabbit embryo-fetal development (EFD) studies. Data for 90 individual compounds from 9 companies were entered into a database. In vivo findings were deemed positive if malformations or embryo-fetal lethality were reported in either species. Each company used their own criteria for deciding whether the alternative assay predicted the in vivo findings. Standard concordance parameters were calculated, positive and negative predictive values (PPV and NPV) were adjusted for the aggregate portfolio prevalence of positive compounds (established by a survey of participating companies), and positive and negative likelihood ratios (LR+ and iLR-) were calculated. Of the 3 assays, only rWEC data were robustly predictive, particularly for negative predictions (NPVadj = 92%). However, both LR+ (4.92) and iLR- (4.72) were statistically significant for the rWEC assay. When analyzed separately for rats, the NPVadj and iLR-values for the rWEC assay increased to 96% and 9.75, respectively. These data suggest that a negative rWEC outcome could defer or replace a rat EFD study in certain regulatory settings.
Subject(s)
Animal Testing Alternatives/methods , Teratogenesis/drug effects , Teratogens/toxicity , Animals , Cells, Cultured , Embryo, Mammalian , Embryo, Nonmammalian , Female , Fetal Development , Mice , Mouse Embryonic Stem Cells , Primary Cell Culture , Rats , ZebrafishABSTRACT
Currently, in pre and postnatal development studies or in juvenile rat studies, bone growth is assessed "for cause" by simple measurements of long bone length in vivo and at termination. This manuscript compares two radiographic methods for in vivo assessment of long bones in suckling rats; 2D imaging using a Faxitron™ and 3D imaging using µCT. This paper illustrates that it is possible to image the unanaesthetised postnatal day 1 rat by Faxitron™ using a simple Micropore™ tape restraint method. With isoflurane anaesthesia, it was possible to obtain high quality µCT images of pups from day of birth. No pups were rejected by their mothers following either technique. The Faxitron™ was straightforward and fast, however the µCT 3D images were of greater overall utility. Either method could be used for longitudinal investigation of long bone observations made previously in embryofetal development studies, or for other mechanistic work.
Subject(s)
Bone and Bones/diagnostic imaging , Radiography/methods , Animals , Animals, Newborn , Bone and Bones/abnormalities , Female , Forelimb/abnormalities , Forelimb/diagnostic imaging , Pregnancy , Radiography/instrumentation , RatsABSTRACT
The brain is a functionally complex organ, the patterning and development of which are key to adult health. To help elucidate the genetic networks underlying mammalian brain patterning, we conducted detailed transcriptional profiling during embryonic development of the mouse brain. A total of 2,400 genes were identified as showing differential expression between three developmental stages. Analysis of the data identified nine gene clusters to demonstrate analogous expression profiles. A significant group of novel genes of as yet undiscovered biological function were detected as being potentially relevant to brain development and function, in addition to genes that have previously identified roles in the brain. Furthermore, analysis for genes that display asymmetric expression between the left and right brain hemispheres during development revealed 35 genes as putatively asymmetric from a combined data set. Our data constitute a valuable new resource for neuroscience and neurodevelopment, exposing possible functional associations between genes, including novel loci, and encouraging their further investigation in human neurological and behavioural disorders.
