A Genome-Wide Screen Identifies Yeast Genes Required for Tolerance to Technical Toxaphene, an Organochlorinated Pesticide Mixture

Brandon D Gaytán,Sebastián Chávez,Nancy D Denslow,Alex V Loguinov,Xenia Peñate,Jan-Michael Lerot,Chris D Vulpe,Aamir Nazir

doi:10.1371/journal.pone.0081253

Abstract

Exposure to toxaphene, an environmentally persistent mixture of chlorinated terpenes previously utilized as an insecticide, has been associated with various cancers and diseases such as amyotrophic lateral sclerosis. Nevertheless, the cellular and molecular mechanisms responsible for these toxic effects have not been established. In this study, we used a functional approach in the model eukaryote Saccharomyces cerevisiae to demonstrate that toxaphene affects yeast mutants defective in (1) processes associated with transcription elongation and (2) nutrient utilization. Synergistic growth defects are observed upon exposure to both toxaphene and the known transcription elongation inhibitor mycophenolic acid (MPA). However, unlike MPA, toxaphene does not deplete nucleotides and additionally has no detectable effect on transcription elongation. Many of the yeast genes identified in this study have human homologs, warranting further investigations into the potentially conserved mechanisms of toxaphene toxicity.

Highlights

Toxaphene is a complex mixture of polychlorinated camphenes and bornanes primarily used to control insects on cotton during the 1960-80s (Figure 1A) [1]
Functional profiling in yeast identifies genes required for toxaphene tolerance The IC20, the concentration at which growth is inhibited by 20%, is a dose frequently utilized in functional screens, as it elicits a response without being overly toxic [17]
Overrepresentation analyses identify biological attributes needed for toxaphene resistance All toxaphene-sensitive strains identified by differential strain sensitivity analysis (DSSA) (n = 122; Table S2) were analyzed with Functional Specification (FunSpec) for significantly overrepresented biological attributes at a corrected p value of

Summary

Introduction

Toxaphene is a complex mixture of polychlorinated camphenes and bornanes primarily used to control insects on cotton during the 1960-80s (Figure 1A) [1]. After the ban of DDT in 1972, toxaphene became the most heavily applied pesticide in the United States, but all registered uses were cancelled by the U.S Environmental Protection Agency (EPA) in 1989 over concerns related to its toxicity and persistence [2]. Toxaphene remains a problematic environmental contaminant, ranking 32nd on the Agency for Toxic Substances and Disease Registry (ATSDR) Priority List of Hazardous Substances, a list of compounds that possibly threaten human health via their toxicity and possibility for exposure at EPA National Priorities List hazardous waste sites. Toxaphene's most persistent congeners and degradation products have been detected in water, air, and sediment, and are known to bioaccumulate in wildlife and humans [1]. The cellular and molecular processes that toxaphene perturbs to result in these toxicities and disease states remain unclear

Methods

Results

Conclusion