Abstract

Formaldehyde (FA) is a commercially important chemical with numerous and diverse uses. Accordingly, occupational and environmental exposure to FA is prevalent worldwide. Various adverse effects, including nasopharyngeal, sinonasal, and lymphohematopoietic cancers, have been linked to FA exposure, prompting designation of FA as a human carcinogen by U.S. and international scientific entities. Although the mechanism(s) of FA toxicity have been well studied, additional insight is needed in regard to the genetic requirements for FA tolerance. In this study, a functional toxicogenomics approach was utilized in the model eukaryotic yeast Saccharomyces cerevisiae to identify genes and cellular processes modulating the cellular toxicity of FA. Our results demonstrate mutant strains deficient in multiple DNA repair pathways–including homologous recombination, single strand annealing, and postreplication repair–were sensitive to FA, indicating FA may cause various forms of DNA damage in yeast. The SKI complex and its associated factors, which regulate mRNA degradation by the exosome, were also required for FA tolerance, suggesting FA may have unappreciated effects on RNA stability. Furthermore, various strains involved in osmoregulation and stress response were sensitive to FA. Together, our results are generally consistent with FA-mediated damage to both DNA and RNA. Considering DNA repair and RNA degradation pathways are evolutionarily conserved from yeast to humans, mechanisms of FA toxicity identified in yeast may be relevant to human disease and genetic susceptibility.

Highlights

  • Extensive industrial and commercial uses of formaldehyde (FA) results in both high production volumes and consequent exposure potential (National Toxicology Program (NTP), 2010)

  • To determine the FA IC20, growth curves were performed with wild-type yeast and increasing concentrations of FA (Figure 1A), with the IC20 calculated as 0.6 mM (Figure 1B)

  • Non-essential deletion mutant pools were grown in 0.6 mM (IC20), 0.3 mM (50% IC20), and 0.15 mM (25% IC20) FA for either 5 or 15 generations (5G and 15G) to identify genes required for optimal growth in FA

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Summary

Introduction

Extensive industrial and commercial uses of formaldehyde (FA) results in both high production volumes and consequent exposure potential (National Toxicology Program (NTP), 2010). FA is utilized to produce industrial resins and adhesives and can serve as a disinfectant or preservative (IARC, 2012a). In addition to its industrial production, combustion, smoking of cigarettes, and secondary photochemical reactions of hydrocarbon pollutants can generate FA. FA is produced endogenously through metabolic processes in humans and animals. FA’s ubiquity results in broad potential for occupational and environmental exposure (IARC, 2012a). Workplace exposure to FA has been linked to nasopharyngeal, sinonasal, and lymphohematopoietic cancers, leading both the International Agency for Research on Cancer

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