Application of toxicogenomic profiling to evaluate effects of benzene and formaldehyde: from yeast to human

Abstract

Genetic variation underlies a significant proportion of the individual variation in human susceptibility to toxicants. The primary current approaches to identify gene–environment (GxE) associations, genome-wide association studies (GWAS) and candidate gene association studies, require large exposed and control populations and an understanding of toxicity genes and pathways, respectively. This limits their application in the study of GxE associations for the leukemogens benzene and formaldehyde, whose toxicity has long been a focus of our research. As an alternative approach, we applied innovative in vitro functional genomics testing systems, including unbiased functional screening assays in yeast and a near-haploid human bone marrow cell line (KBM7). Through comparative genomic and computational analyses of the resulting data, we have identified human genes and pathways that may modulate susceptibility to benzene and formaldehyde. We have validated the roles of several genes in mammalian cell models. In populations occupationally exposed to low levels of benzene, we applied peripheral blood mononuclear cell transcriptomics and chromosome-wide aneuploidy studies (CWAS) in lymphocytes. In this review of the literature, we describe our comprehensive toxicogenomic approach and the potential mechanisms of toxicity and susceptibility genes identified for benzene and formaldehyde, as well as related studies conducted by other researchers.

Re-evaluation of the WHO (2010) formaldehyde indoor air quality guideline for cancer risk assessment

“…Repair of the FA–DNA mono-adducts may include the base excision repair (BER) pathway, and the intra-strand cross-links may be by the nucleotide excision repair (NER) pathway (Kawanishi et al 2014). FA-induced DPX may be repaired by the NER repair and by the homologous recombination (HR) pathways (de Graaf et al 2009; Kawanishi et al 2014; McHale et al 2014). Furthermore, DPX may partly be broken down by specific proteolytic enzymes, allowing translesion synthesis polymerases (a potentially mutagenic pathway) to replicate across DNA-peptide lesions.…”

“…Additionally, a tolerance pathway also exists, allowing replication across unrepaired DPX lesions that may include strand breaks (potentially causing genomic rearrangements) followed by strand ligation (Stingele et al 2015). Not least, the Fanconi anaemia pathway is important in the repair of inter-strand DNA cross-links and DPX (Ren et al 2013; Kirsch-Volders et al 2014; McHale et al 2014; Schneider et al 2015). …”

Connecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges

“…Budding yeast can be used for toxicogenomic screens in a highly time and cost-efficient way, given the existence of barcoded genome-wide gene deletion collections. 142 Candidate susceptibility genes identied in this simple eukaryotic model organism can subsequently be validated in human cell culture models, if human homologs of the yeast genes exist. Humanised yeast models relevant for Parkinson's disease research have been created through overexpression in the yeast model of the human protein alphasynuclein 143 and have already successfully been used for highthroughput genetic 144 and drug screens.…”

The Next Generation of Risk Assessment Multi-Year Study—Highlights of Findings, Applications to Risk Assessment, and Future Directions

“…EPA 2014; French et al 2015; Godderis et al 2012; Hatch et al 2014; McCullough et al 2014; McHale et al 2014; Mendrick 2011; Perkins et al 2013; Smith 2010; Smith et al 2011; Thomas R et al 2014; Thomas RS et al 2012b; Tice et al 2013; Zeise et al 2013). Identifying causal events without tight control of variability can be difficult even knowing the adverse outcome, reinforcing the importance for careful experimentation and interpretation when potential outcomes are unknown (U.S.…”