In Vitro Techniques and Predictive Toxicology

 Chemicals exert their toxicity via interacting with proteins, termed the molecular initiating event. If the organism is unable to respond to this toxic insult, then the individual's health may be impacted, leading to effects at a population level. Understanding the factors that determine how a chemical interacts at the molecular initiating event is a key component for predictive toxicology at the individual species level.   

 Species sensitivity is derived from toxicity tests. There is recognition that it is unethical to continue killing organisms, and there is a push to find alternative strategies such as in vitro methods (data derived without the use of animals) and in-silico approaches (the use of computer programmes) to generate the data necessary to set standards to protect all species, a novel approach called New Approach Methodology.

 The aim of the project is to develop a computer-based approach to predict individual species sensitivity by focusing on fish stress receptors, called the corticosteroid receptors which comprise the glucocorticoid and mineralocorticoid receptors. This is because:

1. There are assays available to assess receptor functionality and thus the sensitivity of the molecular initiating event to man-made chemicals.  
2. There is evidence of differences in the sensitivity of the receptors to steroids in a few species, but not others.  
3. There is a suite of computer-based tools to identity the key sequence motifs in receptors that confer sensitivity to a chemical.  
4. Altered corticosteroid receptors' function is detrimental to health and man-made corticosteroids are a growing environmental concern.  

The deliverable of the project will be the ability to identify fish species that are sensitive to man-made corticosteroids, other corticosteroid endocrine disrupting chemicals, progestins and stress based on receptor amino acid sequence alone.