Toxicity of Methanol and Formaldehyde Towards Saccharomyces cerevisiae as Assessed by DNA Microarray Analysis

Abstract

To assess the toxicity of the C1 compounds methanol and formaldehyde, gene expression profiles of treated baker's yeast were analyzed using DNA microarrays. Among approximately 6,000 open reading frames (ORFs), 314 were repressed and 375 were induced in response to methanol. The gene process category "energy" comprised the greatest number of induced genes while "protein synthesis" comprised the greatest number of repressed genes. Products of genes induced by methanol were mainly integral membrane proteins or were localized to the plasma membrane. A total of 622 and 610 ORFs were induced or repressed by formaldehyde, respectively. More than one-third of the genes found to be strongly repressed by formaldehyde belonged to the "protein synthesis" functional category. Conversely, genes in the subcategory of "nitrogen, sulfur, and selenium metabolism" within "metabolism" and in the category of "cell rescue, defense, and virulence" were up-regulated by exposure to formaldehyde. Our data suggest that membrane structure is a major target of methanol toxicity, while proteins were major targets of formaldehyde toxicity.

Homocysteine Methyltransferases Mht1 and Sam4 Prevent the Accumulation of Age-damaged (R,S)-AdoMet in the Yeast Saccharomyces cerevisiae

“…Additionally, Sam4 protein levels were found to be increased under menadione-induced oxidative stress (41). Both MHT1 and SAM4 have been linked to the arsenic response network (42), and MHT1 was found to be up-regulated 2-fold in response to methanol (43). Finally, SAM4 mRNA has been shown to decrease in aging yeast (44).…”

Functional Toxicogenomic Profiling Expands Insight into Modulators of Formaldehyde Toxicity in Yeast

“…Lending support to these results, we demonstrate PRR mutants are sensitive to FA (Figure 8); however, we did not identify NER as required following FA treatment. Others have utilized genomic tools to assess FA toxicity in yeast, including Yasokawa et al (2010), who examined gene expression via microarrays following exposure to 1.8 mM FA, finding metabolism and cell rescue (including DNA repair) genes were up-regulated, whereas protein synthesis genes were down-regulated. In a study comparable to ours, but using higher doses in solid media, de Graaf et al (2009) performed a screen of the yeast deletion collection to identify mutants affected by acute (60 mM) and chronic (1.5 mM) FA exposure.…”

Commentary: mechanistic considerations for associations between formaldehyde exposure and nasopharyngeal carcinoma

“…Considering that the functions of many proteins may be modulated by S -nitrosylation, it is conceivable that excess formaldehyde exposure may further alter protein functions in EBV-positive cells. Additionally, formaldehyde itself can deplete GSH levels and can react with proteins and peptides [68-70]. Recent genomics analyses in yeast cells clearly indicate that oxidative stress pathways are induced by formaldehyde exposure [70].…”

“…Additionally, formaldehyde itself can deplete GSH levels and can react with proteins and peptides [68-70]. Recent genomics analyses in yeast cells clearly indicate that oxidative stress pathways are induced by formaldehyde exposure [70]. These analyses also identified protein fate (processing and degradation, folding and stabilization, and ubiquitination pathways) as a major category of altered gene expression; formaldehyde induced 14-19% of genes involved in ubiquitination processes, whereas methanol (which is oxidized to formaldehyde) induced only 1% of these genes [70].…”

“…Recent genomics analyses in yeast cells clearly indicate that oxidative stress pathways are induced by formaldehyde exposure [70]. These analyses also identified protein fate (processing and degradation, folding and stabilization, and ubiquitination pathways) as a major category of altered gene expression; formaldehyde induced 14-19% of genes involved in ubiquitination processes, whereas methanol (which is oxidized to formaldehyde) induced only 1% of these genes [70]. While this simple eukaryotic system may not directly inform in vivo mammalian tissue responses, there is little reason to believe that it cannot provide sentinel information as to how formaldehyde interacts with cellular macromolecules.…”