Citation:

Moser, V. C., N. Stewart, D. Freeborn, J. Crooks, D. MacMillan, J. Hedge, C. Wood, R. McMahen, M. Strynar, AND D. Herr. Assessment of Serum Biomarkers in Rats After Exposure to Pesticides of Different Chemical Classes. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 282(2):161-174, (2014).

Impact/Purpose:

There is great promise in the use of blood-based biomarkers as indicators of adverse health outcomes in safety assessment, environmental exposure, and translational research. The search for bioindicators of toxicity has been aided with expanding technologies capable of measurements of hundreds to thousands of analytes, from mRNA and microRNA transcripts to proteins and metabolites (Collings and Vaidya, 2008). In clinical trials, there is a critical need for biomarkers of effect that can serve as predictors or surrogate endpoints for adverse outcomes, especially if such monitoring can detect toxicity at an early, preclinical stage (Biomarkers Definitions Working Group, 2001). To be relevant for human monitoring, such markers must be measurable in accessible sample types such as serum/blood or urine. In safety pharmacology and toxicology studies, biomarker research has been used to provide a basis for understanding mechanisms and adverse outcome pathways for specific manifestations of toxicity. These efforts highlight the continuing need for biomarker discovery, evaluation, and interpretation.

Description:

There is increasing emphasis on the use of biomarkers of adverse outcomes in safety assessment and translational research. We evaluated serum biomarkers and targeted metabolite profiles after exposure to pesticides (permethrin, deltamethrin, imidacloprid, carbaryl, triadimefon, fipronil) with different neurotoxic actions. Adult male Long-Evans rats were evaluated after acute exposure to vehicle or one of two doses of each pesticide at the time of peak effect. The doses were selected to produce similar magnitude of behavioral effects across chemicals. Serum or plasma was analyzed using commercial cytokine/protein panels and targeted metabolomics. Additional studies of fipronil used lower doses (lacking behavioral effects) singly or for 14 days, and included additional markers of exposure and biological activity. Biomarker profiles varied in the number of altered analytes and patterns of change across pesticide classes and discriminant analysis could separate the treatment groups from control. Low doses of fipronil produced greater effects when given for 14 days compared to a signle dose. Changes in thyroid hormones and relative amounts of fipronil and its sulfone metabolite also differed between the dosing regimens. Most cytokine changes reflected alterational in inflammatory responses, hormone levels, and products of phospholipid, fatty acid, and amino acid metabolism. These findings demonstrate distinct blood-based analyte profiles across different pesticide classes, dose levels, and exposure duration. These results show promise for detailed analyses of these biomarkers and their linkages to biological pathways.

Record Details: