Environmental toxicity due to chemicals and pesticides also require screening, in particular neurotoxicity and endocrine disruption (EDSP) screening. Since there are thousands of compounds already commercially used and many new chemicals coming on to the market, effective high throughput in vitro assays must be developed. Industry as well as groups at the NIH, EPA and Tox21 are collaborating to develop more relevant in vitro models and more predictive in vivo models for human toxicity.
For example, exposure to pesticides such as maneb and paraquat increase the risk of developing Parkinson’s disease. Unfortunately, there is no optimal in vitro model system to assess the neurotoxic potential of compounds. As result, exposure to poorly characterized compounds represents a significant contributor to the development of environmentally-induced diseases. There is a compelling unmet need for in vitro models and endpoint assays that are cost-effective, accurate, predictive, and sensitive that would also be amenable to high throughput screening.
Thyroidal hormones modulate gene expression as hormone activated transcription factors. Screening to identify endocrine disrupters known to effect these hormones is essential for drug discovery and environmental toxicity purposes. However, very little high or even medium through put methods have been developed to address this concern.
Genome editing is being employed to develop homogeneous in vitro screens that can be used in quantitative high-throughput screening to query large libraries of chemical compounds such as the ‘Tox21 10K’ chemical library. Reporter cell lines under the control of endogenous toxicant-responsive genes or their promoters provide a cost effective, rapid system for neurotoxicity testing. It has also been demonstrated that gene mutations are associated with an increasing number of diseases. The creation of disease and patient specific edited cells on the background of a specific toxicity reporter cell line is being explored and developed for ‘precision toxicity’ testing.