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Toxicity pathway-specific protein expression models for chemical screening and prioritization

Project Purpose:
Toxicity pathway-specific protein expression models for chemical screening and prioritization.

Project Description(s):
Plasma (in vivo) or culture media (in vitro) from control and MOA agonist exposed treatments are applied to ProteinChip arrays, processed and then analyzed by Mass Spectrometry (to produce protein expression profiles for each sample. Differences in protein expression between control and treatment groups are used to identify protein biomarkers uniquely expressed in the agonist treatment samples. A model to classify samples according to MOA activity is then derived. In addition, short-term in vivo fish exposures using multiple species and in vitro fish hepatocyte exposures are used to link diagnostic protein biomarkers between whole organism and tissue level assays, and across multiple fish species. As proof of concept, research efforts have been focused on developing diagnostic models using well-characterized estrogen and androgen agonists. We are currently extending the technique to anti-estrogenic, androgenic and anti-androgenic MOA's. Future efforts will be directed toward a physiological systems approach using development of MOA-specific biomarker libraries predictive of multiple chemical classes capable of causing adverse effects on the reproductive system.

Project Outcomes:
Development of analytical protocols and plasma protein expression models enabling in vivo screening of chemicals for estrogenic activity has been completed. To further validate the method, contracts have been awarded for an inter-laboratory evaluation of the performance of the estrogenic activity protocol and model and will be completed in early FY07. These results support the possibility that libraries of MOA-specific protein biomarkers and patterns may be developed. Detection of multiple MOAs through protein expression libraries presents a viable option for ultimately replacing many of the single MOA based in vivo mammalian tests currently used in safety assessment and would greatly reduce the animal numbers needed for such assessments. This research addresses OPPTS needs for increased efficiency and effectiveness of screening and testing programs by providing a targeted, hypothesis-based approach for chemical risk assessments.

Calvin Walker at walker.calvin@epa.gov

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