Abstract
The increased presence of chemical contaminants in the environment is an undeniable concern to human health and ecosystems. Historically, by relying heavily upon costly and laborious animal-based toxicity assays, the field of toxicology has often neglected examinations of the cellular and molecular mechanisms of toxicity for the majority of compounds—information that, if available, would strengthen risk assessment analyses. Functional toxicology, where cells or organisms with gene deletions or depleted proteins are used to assess genetic requirements for chemical tolerance, can advance the field of toxicity testing by contributing data regarding chemical mechanisms of toxicity. Functional toxicology can be accomplished using available genetic tools in yeasts, other fungi and bacteria, and eukaryotes of increased complexity, including zebrafish, fruit flies, rodents, and human cell lines. Underscored is the value of using less complex systems such as yeasts to direct further studies in more complex systems such as human cell lines. Functional techniques can yield (1) novel insights into chemical toxicity; (2) pathways and mechanisms deserving of further study; and (3) candidate human toxicant susceptibility or resistance genes.
Highlights
Advantages of functional toxicologyFlies, zebrafish, and human cell lines (Table 2), can (1) contribute novel insight into chemical mechanisms of action; (2) define more specific toxicological endpoints; and (3) inform further mechanistic-based assays
The increased presence of chemical contaminants in the environment is an undeniable concern to human health and ecosystems
Many chemicals are managed through the Toxic Substances Control Act (TSCA), but several independent analyses have concluded that these regulations seriously hinder (1) toxicity testing and hazard assessment; (2) control of chemicals of concern; and (3) investment in safer alternatives, such as those generated by the tenets of green chemistry (Wilson and Schwarzman, 2009)
Summary
Flies, zebrafish, and human cell lines (Table 2), can (1) contribute novel insight into chemical mechanisms of action; (2) define more specific toxicological endpoints; and (3) inform further mechanistic-based assays. Barcoded mutant collections have been generated in budding (Giaever et al, 1999, 2002) and fission yeast (Kennedy et al, 2008; Kim et al, 2010; Chen et al, 2012), allowing assessment of individual strain fitness in pooled cultures under selective conditions (reviewed by North and Vulpe, 2010; dos Santos et al, 2012) This technique, known as functional profiling, functional genomics, chemical genomics, or chemical-genetic profiling, can identify the genetic requirements for tolerance to any substance that causes measurable growth inhibition in yeast. The functional tools available in yeast provide unmatched resources for inquiries into potential cellular and molecular mechanisms of toxicity Such analyses have informed functional experimentation in more complex organisms such as zebrafish or human cell lines. POTENTIAL FOR FUNCTIONAL TOXICOLOGY IN OTHER FUNGI AND BACTERIA The recent development of the TagModule collection (Oh et al, 2010a), building upon the work of Xu et al (2007), takes
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call