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Using the Drosophila Melanogaster Genetics Reference Panel to Identify Toxicity Pathways for Toluene
Citation:
Bushnell, P., T. Morozova, S. Hester, W. Oshiro, J. Mckee, M. Higuchi, W. Boyes, R. Judson, K. Tatum-Gibbs, D. Reif, AND T. MacKay. Using the Drosophila Melanogaster Genetics Reference Panel to Identify Toxicity Pathways for Toluene. Society of Toxicology (SOT) Annual Meeting, San Diego, CA, March 23 - 27, 2015.
Impact/Purpose:
Will be presented at the Society of Toxicology (SOT) Annual Meeting, March 23-27, 2015, San Diego, CA Note: New RAP Products have not been loaded in STICS. When they are loaded I will go back and add them to the record. -J. Williams This product is CSS 12.23
Description:
Mechanistic information is needed to link effects of chemicals at molecular targets in high throughput screening assays to adverse outcomes in whole organisms. This study was designed to use the Drosophila Genetic Reference Panel (DGRP), a set of genetically well-characterized lines of fruit flies, to identify adverse outcome pathways associated with toluene. We generated a profile of behavioral response to toluene across 123 strains ofDGRP flies and mapped the genetic markers of this profile. Single flies were placed in 5 mm dia glass tubes and exposed to 750 ppm of toluene vapor (n= 24-50 I line); paired controls received air. Real-time locomotor activity was observed at10-minute intervals for 1 hr before, 4 hr during, and 15 hr after exposure. Toluene reduced activityduring exposure. This acute effect differed quantitatively across DGRP lines, demonstrating variation in susceptibility to this narcotic vapor. We carried out a genome-wide association analysis for sensitivity to toluene using the DGRP web portal (http://dgrp2.gnets.ncsu.edu/). Mean activity counts during exposure were adjusted for effects of Wolbachia infection and major inversions, and then used to fit a mixed-effects model accounting for relatedness among the lines to estimate the effects of individual sequence variants. We tested 1,891,456 DNA variants with minor allele frequencies> 0.05 and P-values < 10-5• We performed separate single marker analyses for toluene, air and the response to toluene (toluene - air). We found 11 variants in 6 genes associated with the acute effect of toluene, 21 variants located in or near 15 genes associated with activity in toluene, and 19 variants in or near 13 genes associated with activity in air. Whether pathways associated with these genes are consistent with the narcotic effect of toluene remains to be determined. This abstract does not reflect US. EPA policy.