Perturbation of metabolic pathways mediates the association of air pollutants with asthma and cardiovascular diseases

BACKGROUND: Epidemiologic evidence indicates common risk factors, including air pollution exposure, for respiratory and cardiovascular diseases, suggesting the involvement of common altered molecular pathways. OBJECTIVES: The goal was to find intermediate metabolites or metabolic pathways that could be associated with both air pollutants and health outcomes ("meeting-in-the-middle"), thus shedding light on mechanisms and reinforcing causality. METHODS: We applied a statistical approach named 'meet-in-the-middle' to untargeted metabolomics in two independent case-control studies nested in cohorts on adult-onset asthma (AOA) and cardio-cerebrovascular diseases (CCVD). We compared the results to identify both common and disease-specific altered metabolic pathways. RESULTS: A novel finding was a strong association of AOA with ultrafine particles (UFP; odds ratio 1.80 [1.26, 2.55] per increase by 5000 particles/cm3). Further, we have identified several metabolic pathways that potentially mediate the effect of air pollution on health outcomes. Among those, perturbation of Linoleate metabolism pathway was associated with air pollution exposure, AOA and CCVD. CONCLUSIONS: Our results suggest common pathway perturbations may occur as a consequence of chronic exposure to air pollution leading to increased risk for both AOA and CCVD

Key Role of Mfd in the Development of Fluoroquinolone Resistance in Campylobacter jejuni

Campylobacter jejuni is a major food-borne pathogen and a common causative agent of human enterocolitis. Fluoroquinolones are a key class of antibiotics prescribed for clinical treatment of enteric infections including campylobacteriosis, but fluoroquinolone-resistant Campylobacter readily emerges under the antibiotic selection pressure. To understand the mechanisms involved in the development of fluoroquinolone-resistant Campylobacter, we compared the gene expression profiles of C. jejuni in the presence and absence of ciprofloxacin using DNA microarray. Our analysis revealed that multiple genes showed significant changes in expression in the presence of a suprainhibitory concentration of ciprofloxacin. Most importantly, ciprofloxacin induced the expression of mfd, which encodes a transcription-repair coupling factor involved in strand-specific DNA repair. Mutation of the mfd gene resulted in an approximately 100-fold reduction in the rate of spontaneous mutation to ciprofloxacin resistance, while overexpression of mfd elevated the mutation frequency. In addition, loss of mfd in C. jejuni significantly reduced the development of fluoroquinolone-resistant Campylobacter in culture media or chickens treated with fluoroquinolones. These findings indicate that Mfd is important for the development of fluoroquinolone resistance in Campylobacter, reveal a previously unrecognized function of Mfd in promoting mutation frequencies, and identify a potential molecular target for reducing the emergence of fluoroquinolone-resistant Campylobacter

Novi pogledi na Joakima Stullija (1730-1817), hrvatskog leksikografa, povodom 250. obljetnice rođenja

EXPOsOMICS is a European Union funded project that aims to develop a novel approach to the assessment of exposure to high priority environmental pollutants, by characterizing the external and the internal components of the exposome. It focuses on air and water contaminants during critical periods of life. To this end, the project centres on 1) exposure assessment at the personal and population levels within existing European short and long-term population studies, exploiting available tools and methods which have been developed for personal exposure monitoring (PEM); and 2) multiple “omic” technologies for the analysis of biological samples (internal markers of external exposures). The search for the relationships between external exposures and global profiles of molecular features in the same individuals constitutes a novel advancement towards the development of “next generation exposure assessment” for environmental chemicals and their mixtures. The linkage with disease risks opens the way to what are defined here as ‘exposome-wide association studies’ (EWAS)

Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens

Combinations of estrogen receptor agonists have been shown to exert more potent effects than single compounds in many single-endpoint bioassays. However, to our knowledge, it has never been tested how genome-wide expression programs are shaped by the interplay of multiple estrogenic stimuli. In view of the abundance of dietary phytoestrogens, we selected binary mixtures of these phytochemicals to determine their global impact using high-density DNA microarrays. MCF7 cells, a frequent in vitro model for molecular processes associated with breast cancer, were exposed to a sub-saturating concentration of coumestrol either alone or in combination with analogs that exhibit 1000-fold lower estrogen receptor activity. As expected, in the presence of coumestrol, the induction of many estrogen-sensitive genes was not further increased by the addition of resveratrol or enterolactone. However, it was surprising to find that these weak phytoestrogens, when combined with coumestrol in equal concentrations, were able to more than double the number of significantly regulated transcripts. Thus, phytoestrogens with low receptor affinity interact with other estrogenic agonists to generate more widespread expression fingerprints. This effect involving the number of susceptible transcripts instead of their amplitude of induction remains undetected if mixtures are evaluated with conventional bioassays

Transcriptomic profile indicative of immunotoxic exposure: in vitro studies in peripheral blood mononuclear cells.

Investigating the immunotoxic effects of exposure to chemicals usually comprises evaluation of weight and histopathology of lymphoid tissues, various lymphocyte parameters in the circulation and immune function. Immunotoxicity assessment is time consuming in humans or requires a high number of animals, making it expensive. Furthermore, reducing the use of animals in research is an important ethical and political issue. Immunotoxicogenomics represents a novel approach to investigate immunotoxicity able of overcoming these limitations. The current research, embedded in the EU project NewGeneris, aimed to retrieve gene expression profiles that are indicative of exposure to immunotoxicants. To this end, whole genome gene expression was investigated in human peripheral blood mononuclear cells (PBMC) in response to in vitro exposure to a range of immunotoxic chemicals (4-hydroxy-2-nonenal, aflatoxin B1, benzo[a]pyrene, deoxynivalenol, ethanol, malondialdehyde, polychlorinated biphenyl 153, 2,3,7,8-tetrachlorodibenzo-p-dioxin) and non-immunotoxic chemicals (acrylamide, dimethylnitrosamine, 2-amino-3-methyl-3H-imidazo[4,5-F]quinoline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine). Using Agilent oligonucleotide microarrays, whole genome gene expression profiles were generated, which were analysed using Genedata's Expressionist((R)) software. Using Recursive Feature Elimination and Support Vector Machine, a set of 48 genes was identified that distinguishes the immunotoxic from the non-immunotoxic compounds. Analysis for enrichment of biological processes showed the gene set to be highly biologically and immunologically relevant. We conclude that we have identified a promising transcriptomic profile indicative of immunotoxic exposure