Genome-Wide Functional Profiling Reveals Genes Required for Tolerance to Benzene Metabolites in Yeast

Benzene is a ubiquitous environmental contaminant and is widely used in industry. Exposure to benzene causes a number of serious health problems, including blood disorders and leukemia. Benzene undergoes complex metabolism in humans, making mechanistic determination of benzene toxicity difficult. We used a functional genomics approach to identify the genes that modulate the cellular toxicity of three of the phenolic metabolites of benzene, hydroquinone (HQ), catechol (CAT) and 1,2,4-benzenetriol (BT), in the model eukaryote Saccharomyces cerevisiae. Benzene metabolites generate oxidative and cytoskeletal stress, and tolerance requires correct regulation of iron homeostasis and the vacuolar ATPase. We have identified a conserved bZIP transcription factor, Yap3p, as important for a HQ-specific response pathway, as well as two genes that encode putative NAD(P)H:quinone oxidoreductases, PST2 and YCP4. Many of the yeast genes identified have human orthologs that may modulate human benzene toxicity in a similar manner and could play a role in benzene exposure-related disease

Effect of indoor air quality of day care centers in children with different predisposition for asthma

BACKGROUND: Scarce information is available about the relationships between indoor air quality (IAQ) at day care centers (DCC), the estimated predisposition for asthma and the actual wheezing susceptibility. METHODS: In the Phase II of ENVIRH study, 19 DCC were recruited after cluster analysis. Children were evaluated firstly using the ISAAC questionnaire and later by a follow up questionnaire about recent wheezing. A positive asthma predictive index (API) was considered as predisposition for asthma. Every DCC was audited for IAQ and monitored for chemical and biological contaminants. RESULTS: We included 1,191 children, with a median age of 43 (P25 -P75 : 25-58) months. Considering the overall sample, in the first questionnaire, associations were found between CO2 concentration (increments of 200 ppm) and diagnosis of asthma (OR: 1.10; 95% CI: 1.00 - 1.20). Each increment of 100 μg.m-3 of total volatile organic compounds (TVOC) and 1 μg of Der p1/g of dust were associated with wheezing in the previous 12 months (OR: 1.06; 95% CI: 1.01-1.11 and OR: 1.06; 95% CI: 0.99-1.12, respectively). In the follow-up questionnaire, TVOC were again associated with wheezing (OR: 1.05; 95% CI: 1.00-1.11). Children exposed to fungal concentration above the 75th percentile had also higher odds of wheezing at follow-up. TVOC were associated with wheezing in children with either negative or positive API. CONCLUSIONS: IAQ in DCC seems to be associated with wheezing, in children with and without predisposition for asthma. This article is protected by copyright. All rights reserved.FC

Metabolic polymorphisms and biomarkers of effect in the biomonitoring of occupational exposure to low-levels of benzene: state of the art

Current levels of occupational exposure to benzene, a genotoxic human carcinogen, in Western countries are reduced by two-three orders of magnitude (from ppm to ppb) as compared to the past. However, as benzene toxicity is strongly dependent on biotransformation and recent evidence underlines a higher efficiency of bio-activation pathways at lower levels of exposure, toxic effects at low doses could be higher than expected, particularly in susceptible individuals. Currently, biological monitoring can allow accurate exposure assessment, relying on sensitive and specific enough biomarkers of internal dose. The availability of similarly reliable biomarkers of early effect or susceptibility could greatly improve the risk assessment process to such an extent that risk could even be assessed at the individual level. As to susceptibility biomarkers, functional genetic polymorphisms of relevant biotransformation enzymes may modulate the risk of adverse effects (NQO1) and the levels of biomarkers of internal dose, in particular S-phenylmercapturic acid (GSTM1, GSTT1, GSTA1). Among biomarkers of early effect, genotoxicity indicators, although sensitive in some cases, are too aspecific for routine use in occupational health surveillance programmes. Currently only the periodical blood cell count seems suitable enough to be applied in the longitudinal monitoring of effects from benzene exposure. Novel biomarkers of early effect are expected from higher collaboration among toxicologists and clinicians, also using advanced "omics" techniques

Applications of the comet assay in particle toxicology: air pollution and engineered nanomaterials exposure

Exposure to ambient air particles is associated with elevated levels of DNA strand breaks (SBs) and endonuclease III, formamidopyrimidine DNA glycosylase (FPG) and oxoguanine DNA glycosylase-sensitive sites in cell cultures, animals and humans. In both animals and cell cultures, increases in SB and in oxidatively damaged DNA are seen after exposure to a range of engineered nanomaterials (ENMs), including carbon black, carbon nanotubes, fullerene C60, ZnO, silver and gold. Exposure to TiO2 has generated mixed data with regard to SB and oxidatively damaged DNA in cell cultures. Nanosilica does not seem to be associated with generation of FPG-sensitive sites in cell cultures, while large differences in SB generation between studies have been noted. Single-dose airway exposure to nanosized carbon black and multi-walled carbon nanotubes in animal models seems to be associated with elevated DNA damage levels in lung tissue in comparison to similar exposure toTiO2 and fullerene C60. Oral exposure has been associated with augmented DNA damage levels in cells of internal organs, although the doses have been typically very high. Intraveneous and intraperitoneal injection of ENMs have shown contradictory results dependent on the type of ENM and dose in each set of experiments. In conclusion, the exposure to both combustion-derived particles and ENMs is associated with increased levels of DNA damage in the comet assay. Particle size, composition and crystal structure of ENM are considered important determinants of toxicity, whereas their combined contributions to genotoxicity in the comet assay are yet to be thoroughly investigated