Project description:Cesium-137 is a fission product of uranium and plutonium in nuclear reactors and is released in large quantities during nuclear explosions or detonation of an improvised device containing this isotope. This environmentally persistent radionuclide undergoes radioactive decay with the emission of beta particles as well as gamma radiation. Exposure to (137)Cs at high doses can cause acute radiation sickness and increase risk for cancer and death. The serious health risks associated with (137)Cs exposure makes it critical to understand how it affects human metabolism and whether minimally invasive and easily accessible samples such as urine and serum can be used to triage patients in case of a nuclear disaster or a radiologic event. In this study, we have focused on establishing a time-dependent metabolomic profile for urine collected from mice injected with (137)CsCl. The samples were collected from control and exposed mice on days 2, 5, 20 and 30 after injection. The samples were then analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC/TOFMS) and processed by an array of informatics and statistical tools. A total of 1,412 features were identified in ESI(+) and ESI(-) modes from which 200 were determined to contribute significantly to the separation of metabolomic profiles of controls from those of the different treatment time points. The results of this study highlight the ease of use of the UPLC/TOFMS platform in finding urinary biomarkers for (137)Cs exposure. Pathway analysis of the statistically significant metabolites suggests perturbations in several amino acid and fatty acid metabolism pathways. The results also indicate that (137)Cs exposure causes: similar changes in the urinary excretion levels of taurine and citrate as seen with external-beam gamma radiation; causes no attenuation in the levels of hexanoylglycine and N-acetylspermidine; and has unique effects on the levels of isovalerylglycine and tiglylglycine.

Project description:School children may be exposed to secondhand smoke (SHS) either at home, in transit or in social gatherings permitting smoking in their presence. Questionnaires about SHS often underestimate prevalence and extent of exposure. A more accurate tool is the use of biomarkers such as cotinine (COT) and trans-3'-hydrocycotinine (3HC) as biomarkers of SHS exposure, alongside 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a reduction product in the body of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), both potent carcinogens. We measured urinary COT, 3HC and total NNAL using sensitive and specific high-performance LC-MS/MS methods. The limit of quantification (LOQ) for each assay were 0.05 ng/mL, 0.1 ng/mL and 0.25 pg/mL respectively. The aim of this study was to evaluate the exposure to SHS of school children (9-11 years), from five public schools in the island of Malta, from questionnaire information about smoking at home and verify it by urinary biomarker data of COT, 3HC and NNAL. These biomarkers were measurable in 99.4%, 95.4% and 98.3% of the participating children respectively. From the children reporting smoking at home, 11% had a history of asthma and had COT, 3HC and NNAL geometric mean concentrations double compared to the non-asthmatic group. In has been confirmed that non-smokers exposed to SHS and THS have a higher NNAL/COT ratio than the group identified as smokers according to specific and defined COT threshold levels (despite the fact that a priori, the entire study group was composed of non-smokers). The implication of high measured levels of urinary NNAL in children should be of concern given its potency. A main effects multifactor ANOVA model was developed and the children's house and school locations and the smoking frequency were statistically significant to predict the levels of the three metabolites. For 3HC only, the status of the employment of the mother was also an important predictor.

Project description:This study presents a comprehensive multi-omic analysis of upper urinary tract urothelial tumours (UTUC) and urines of patients with past exposure to carcinogenic aristolochic acid (AA). We determined complex miRNA:mRNA tumor networks and their key protein components. Tumor exome and transcriptome sequencing revealed a burden of AA-specific mutations in UTUC and identified deleteriously mutated genes and their mRNA transcripts. A subset of identified urinary miRNAs presents potential biomarkers of UTUC development or presence. Recurrent upper urinary tract carcinomas (UTUC) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). We aimed to delineate the detailed biological programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe, by using an integrative multi-omics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative miRNA and mRNA expression profiling, immunohistochemical analysis by tissue microarrays, and exome and transcriptome sequencing were performed in UTUC and non-tumor tissues. Urinary miRNAsof cases undergoing surgery were profiled before and after UTUC resection. RNA and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1862 target mRNAs and involving deregulation of cell cycle, DNA damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcriptome components were confirmed at the protein level. Exome and transcriptome sequencing of UTUC revealed AA-specific COSMIC mutational signature 22, with 68-76% AA-specific, deleterious mutations propagated at the mRNA level. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients’ urine prior to tumor resection. The gene regulation programs of AAN-associated UTUC tumors are highly complex and involve regulatory miRNAs prospectively applicable to non-invasive urine-based screening of AAN patients for cancer recurrence.

Dataset Information

Unraveling biomarkers of exposure for tenuazonic acid through urinary metabolomics.

Publications

Unraveling biomarkers of exposure for tenuazonic acid through urinary metabolomics.

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