Identifying the genetic determinants of insecticide response variation to advance human risk assessment

About This Grant

PROJECT SUMMARY Vector-borne diseases such as malaria cause approximately 700,000 deaths each year. To support insect vector control, pyrethroid insecticides are widely deployed. However, the rise of resistance has reduced their effectiveness, prompting the use of combination treatments that pair pyrethroids with chlorfenapyr—an insecticide with a distinct mode of action. Evidence suggests that specific pyrethroid resistance alleles can modulate responses to chlorfenapyr, potentially driving synergistic effects when the two insecticides are combined. This interaction raises concern that similar or novel gene-by-treatment interactions could also influence human responses, complicating chemical risk assessment for genetically diverse human populations. The overall objective of this proposal is to integrate low-cost, high-throughput quantitative genetics in C. elegans with human cell culture to investigate the genes and molecular pathways that influence responses to insecticides alone and in combination. The rationale for the proposed research is that identifying the conserved genes and molecular pathways that harbor natural variants influencing responses to combined insecticide exposure can help inform risk assessment for humans. In Aim 1, we will map quantitative trait loci (QTL) that influence responses to chlorfenapyr and four pyrethroids, both individually and in combination, using wild strains and recombinant inbred lines of C. elegans. In Aim 2, we will identify specific genes and variants within QTL that cause differences in insecticide responses using experimental crosses and CRISPR/Cas9 genome-editing. In Aim 3, we will profile transcriptomic responses to insecticides in C. elegans strains with causal edits and in human HEK293 and HepG2 cells to identify conserved pathways associated with responses to combined insecticide exposure. The innovation of this proposal stems from the integration of high-throughput quantitative genetics in C. elegans with cross-species comparative transcriptomics. This approach has never been used to investigate the effects of natural variation on combined insecticide susceptibility. The proposed research is significant because it will uncover molecular mechanisms underlying natural variation in susceptibility to combined pyrethroid and chlorfenapyr exposures, and identify candidate genes that may harbor susceptibility alleles relevant to human populations. Importantly, this proposal aligns with the objectives of the AREA R15 mechanism by (1) increasing undergraduate involvement in toxicology and genetics research, and (2) strengthening the research infrastructure at the Florida Institute of Technology.