Current assays employed to assess the potential of drugs and environmental agents for their potential to cause birth defects involve the use of animal models. Not only are these models costly and time consuming, but they also have poor concordance to human data. SteminaTM Biomarker Discovery (Stemina) has developed a screening assay that utilizes human embryonic stem (hES) cells and metabolomics to study the secretome of hES cells exposed to test compounds in an all human model system to identify compounds with teratogenic potential. Integrated Laboratory Systems (ILS) and Stemina have formalized a partnership to advance devTOXTM, Stemina's stem cell-based toxicology testing platform. This SBIR will deepen and extend the unique devTOXTM platform by interrogating impact on the human genome and epigenome of hES cells from toxicant exposures. Toxicity testing screens focused on effects to the epigenome are aspect of toxicity based screening that with a few exceptions is virtually absent in high content cellular based toxicity assays. The focus of this SBIR is to: 1. conduct time course and dose-response studies directed at evaluating known and investigative epigenetic biomarkers indicative of aberrant hES cell function using the devTOXTM platform and 2. integrate toxicogenomics-based mRNA and miRNA biomarkers to the devTOXTM platform to assess the impact of toxicants on the genome and epigenome in three specific aims.
Specific Aim 1 is to assess stability of biomarker genes and miRNAS associated with maintaining self- renewal and pluripotency of hES cells during cell culture expansion.
Specific aim 2 Assess the impact of a reference set of test compounds on genomic and epigenomic response biomarkers in hES cells.
Specific aim 3 will test 10 blinded chemicals provided by DOW Chemical Company in DevTOXTM integrated with genomic and epigenomic response biomarkers, then compare results to Dow """"""""in-house"""""""" test results from other developmental toxicology screens. We anticipate that the integration of the gene expression and epigenomic profiling with the devTOXTM will increase the predictivity of the devTOXTM platform increasing its use as a weight- of-evidence tool in predicting potential development and reproductive toxicity.
Stem cells have the unique ability among all of the cells of the human body of self- renewal, that is, they can remain in a primitive unspecialized state. Under the right conditions, they can give rise to specialized cells of the body (differentiation) like th heart, liver, or pancreas. Human embryonic stem cells are being developed as a toxicity testing platform for the assessment of developmental toxicity. These cells present a unique model system to understand and assess the effects of environmental agents and new drug candidates to predict or anticipate toxicity in humans.
