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USE OF GENOMIC TECHNOLOGIES AND ISOTONIC DOSE-RESPONSE MODELING IN THE DEVELOPMENT OF A BIOCHEMICAL MARKER OF EFFECT FOR PYRETHROID INSECTICIDE.
Citation:
HARRILL, J., F. A. WRIGHT, AND K. M. CROFTON. USE OF GENOMIC TECHNOLOGIES AND ISOTONIC DOSE-RESPONSE MODELING IN THE DEVELOPMENT OF A BIOCHEMICAL MARKER OF EFFECT FOR PYRETHROID INSECTICIDE. Presented at Society for Risk Analysis, Baltimore, MD, December 03 - 06, 2006.
Description:
Pyrethroids are pesticides that disrupt nervous system function by prolongation of sodium currents
through voltage-sensitive sodium channels present in nerve membranes. Pyrethroid usage has
increased as use of other pesticides has declined. A sensitive, dose-responsive and class specific
biomarker of effect is not available for pyrethroids. Developing this type of endpoint will aid the
risk analysis process by providing a rapid quantitative assay for use in characterizing the cumulative
risk of mixtures of pyrethroids. The present study uses genomic technologies, quantitative real-time
PCR and protein expression to identify candidate biomarkers of effect. Long-Evans rats (n = 8-12 /
group) were orally dosed with either permethrin (1, 10, 100 mg/kg), deltamethrin (0.3, 1.0, 3.0
mg/kg) or vehicle and global gene expression profiles were created using Affymetrix Rat 230 2.0
microarrays hybridized with labeled cRNA derived from CNS cortical tissue. Identification of
dose-responsive transcripts was performed using a novel combination of statistical techniques. An
isotonic regression statistic (M-score, Hu et al. 2005) was used to identify transcripts in the
microarray study that display significant dose-related alterations in expression for each model
compound. This method assumes a monotone dose-response relationship, but otherwise makes no
assumptions about the precise form of the dose-response curve. We used this approach in
conjunction with permutation calculations of false discovery rates (FDR) as outlined in Storey &
Tibshirani (2003) to provide multiple-comparison error control. Genes are prioritized for
confirmation by qRT-PCR based on the strength of the dose-response, commonality of the response
profile between compounds and the estimated FDR. Several transcripts have been identified as
potential dose-responsive biomarkers of effect and have been confirmed by qRT-PCR. Future
studies will test the reliability and specificity of the identified biomarkers by using a variety of
pyrethroid and non-pyrethroid compounds. (This is an abstract of a proposed presentation and
does not reflect EPA policy)