A human induced pluripotent stem cell-based in vitro assay predicts developmental toxicity through a retinoic acid receptor-mediated pathway for a series of related retinoid analogues.

The relative developmental toxicity potency of a series of retinoid analogues was evaluated using a human induced pluripotent stem (iPS) cell assay that measures changes in the biomarkers ornithine and cystine. Analogue potency was predicted, based on the assay endpoint of the ornithine/cystine (o/c) ratio, to be all-trans-retinoic acid>TTNPB>13-cis-retinoic acid≈9-cis-retinoic acid>acitretin>etretinate>retinol. These rankings correlate with in vivo data and demonstrate successful application of the assay to rank a series of related toxic and non-toxic compounds.

Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children.

Background: The diagnosis of autism spectrum disorder (ASD) at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age.

Establishment and assessment of a new human embryonic stem cell-based biomarker assay for developmental toxicity screening.

A metabolic biomarker-based in vitro assay utilizing human embryonic stem (hES) cells was developed to identify the concentration of test compounds that perturbs cellular metabolism in a manner indicative of teratogenicity. This assay is designed to aid the early discovery-phase detection of potential human developmental toxicants. In this study, metabolomic data from hES cell culture media were used to assess potential biomarkers for development of a rapid in vitro teratogenicity assay.

Metabonomic identification of two distinct phenotypes in Sprague-Dawley (Crl:CD(SD)) rats.

Genetic drift in animal populations has been a recognized concern for many years. Less understood is the potential for phenotypic "drift" or variation that is not related to any genetic change. Recently, stock Sprague-Dawley (Crl:CD(SD)) rats obtained from the Charles River Raleigh facility demonstrated a distinct endogenous urinary metabonomic profile that differed from historical control SD urine spectral profiles obtained over the past several years in our laboratory.

Comparison of heterogeneous and homogeneous radioactivity flow detectors for simultaneous profiling and LC-MS/MS characterization of metabolites.

Methods for simultaneous liquid chromatography-radioactivity monitor (LC-RAM) metabolite profiling and LC-tandem mass spectrometry (MS/MS) characterization of metabolites are described. Profiling and characterization of metabolites from three drug candidates from different therapeutic areas were compared using in-line heterogeneous LC-RAM-MS/MS and homogeneous LC-RAM-MS/MS methods. Although comparison shows that simultaneous metabolite profiling and characterization can be achieved using either heterogeneous or homogeneous-LC-RAM-MS/MS systems, a homogeneous system has the advantage in the following aspects, (1) sensitivity; (2) ease of method transfer; (3) less peak broadening problems due to the drug or metabolites adhering to the RAM cell; (4) accuracy in quantitation of the metabolites; and (5) the ability to load larger volumes of unprocessed biological fluids.