Chemicals have improved our quality of life, but the resulting environmental pollution has the potential to cause detrimental effects on humans and the environment. People and biota are chronically ...exposed to thousands of chemicals from various environmental sources through multiple pathways. Environmental chemists and toxicologists have moved beyond detecting and quantifying single chemicals to characterizing complex mixtures of chemicals in indoor and outdoor environments and biological matrices. We highlight analytical and bioanalytical approaches to isolating, characterizing, and tracking groups of chemicals of concern in complex matrices. Techniques that combine chemical analysis and bioassays have the potential to facilitate the identification of mixtures of chemicals that pose a combined risk.
The exposome and health: Where chemistry meets biology Vermeulen, Roel; Schymanski, Emma L; Barabási, Albert-László ...
Science (American Association for the Advancement of Science),
01/2020, Letnik:
367, Številka:
6476
Journal Article
Recenzirano
Odprti dostop
Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. ...To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
The vast, diverse universe of organic pollutants is a formidable challenge for environmental sciences, engineering, and regulation. Nontarget screening (NTS) based on high resolution mass ...spectrometry (HRMS) has enormous potential to help characterize this universe, but is it ready to go for real world applications? In this Feature article we argue that development of mass spectrometers with increasingly high resolution and novel couplings to both liquid and gas chromatography, combined with the integration of high performance computing, have significantly widened our analytical window and have enabled increasingly sophisticated data processing strategies, indicating a bright future for NTS. NTS has great potential for treatment assessment and pollutant prioritization within regulatory applications, as highlighted here by the case of real-time pollutant monitoring on the River Rhine. We discuss challenges for the future, including the transition from research toward solution-centered and robust, harmonized applications.
Background
The
in silico
fragmenter MetFrag, launched in 2010, was one of the first approaches combining compound database searching and fragmentation prediction for small molecule identification ...from tandem mass spectrometry data. Since then many new approaches have evolved, as has MetFrag itself. This article details the latest developments to MetFrag and its use in small molecule identification since the original publication.
Results
MetFrag has gone through algorithmic and scoring refinements. New features include the retrieval of reference, data source and patent information via ChemSpider and PubChem web services, as well as InChIKey filtering to reduce candidate redundancy due to stereoisomerism. Candidates can be filtered or scored differently based on criteria like occurence of certain elements and/or substructures prior to fragmentation, or presence in so-called “suspect lists”. Retention time information can now be calculated either within MetFrag with a sufficient amount of user-provided retention times, or incorporated separately as “user-defined scores” to be included in candidate ranking. The changes to MetFrag were evaluated on the original dataset as well as a dataset of 473 merged high resolution tandem mass spectra (HR-MS/MS) and compared with another open source
in silico
fragmenter, CFM-ID. Using HR-MS/MS information only, MetFrag2.2 and CFM-ID had 30 and 43 Top 1 ranks, respectively, using PubChem as a database. Including reference and retention information in MetFrag2.2 improved this to 420 and 336 Top 1 ranks with ChemSpider and PubChem (89 and 71 %), respectively, and even up to 343 Top 1 ranks (PubChem) when combining with CFM-ID. The optimal parameters and weights were verified using three additional datasets of 824 merged HR-MS/MS spectra in total. Further examples are given to demonstrate flexibility of the enhanced features.
Conclusions
In many cases additional information is available from the experimental context to add to small molecule identification, which is especially useful where the mass spectrum alone is not sufficient for candidate selection from a large number of candidates. The results achieved with MetFrag2.2 clearly show the benefit of considering this additional information. The new functions greatly enhance the chance of identification success and have been incorporated into a command line interface in a flexible way designed to be integrated into high throughput workflows. Feedback on the command line version of MetFrag2.2 available at
http://c-ruttkies.github.io/MetFrag/
is welcome.
•Mass spectral databases play a key role in metabolomics.•Advantages and limitations of public and commercial databases are underlined.•The overlap of compounds in public and commercial databases is ...calculated.•Future prospects of mass spectral databases are discussed.
At present, mass spectrometry (MS)-based metabolomics has been widely used to obtain new insights into human, plant, and microbial biochemistry; drug and biomarker discovery; nutrition research; and food control. Despite the high research interest, identifying and characterizing the structure of metabolites has become a major drawback for converting raw MS data into biological knowledge. Comprehensive and well-annotated MS-based spectral databases play a key role in serving this purpose via the formation of metabolite annotations. The main characteristics of the mass spectral databases currently used in MS-based metabolomics are reviewed in this study, underlining their advantages and limitations. In addition, the overlap of compounds with MSn (n ≥ 2) spectra from authentic chemical standards in most public and commercial databases has been calculated for the first time. Finally, future prospects of mass spectral databases are discussed in terms of the needs posed by novel applications and instrumental advancements.
Wastewater effluents contain a multitude of organic contaminants and transformation products, which cannot be captured by target analysis alone. High accuracy, high resolution mass spectrometric data ...were explored with novel untargeted data processing approaches (enviMass, nontarget, and RMassBank) to complement an extensive target analysis in initial “all in one” measurements. On average 1.2% of the detected peaks from 10 Swiss wastewater treatment plant samples were assigned to target compounds, with 376 reference standards available. Corrosion inhibitors, artificial sweeteners, and pharmaceuticals exhibited the highest concentrations. After blank and noise subtraction, 70% of the peaks remained and were grouped into components; 20% of these components had adduct and/or isotope information available. An intensity-based prioritization revealed that only 4 targets were among the top 30 most intense peaks (negative mode), while 15 of these peaks contained sulfur. Of the 26 nontarget peaks, 7 were tentatively identified via suspect screening for sulfur-containing surfactants and one peak was identified and confirmed as 1,3-benzothiazole-2-sulfonate, an oxidation product of a vulcanization accelerator. High accuracy, high resolution data combined with tailor-made nontarget processing methods (all available online) provided vital information for the identification of a wider range of heteroatom-containing compounds in the environment.
There is an increasing need for comparable and harmonized retention times (t R) in liquid chromatography (LC) among different laboratories, to provide supplementary evidence for the identity of ...compounds in high-resolution mass spectrometry (HRMS)-based suspect and nontarget screening investigations. In this study, a rigorously tested, flexible, and less system-dependent unified retention time index (RTI) approach for LC is presented, based on the calibration of the elution pattern. Two sets of 18 calibrants were selected for each of ESI+ and ESI-based on the maximum overlap with the retention times and chemical similarity indices from a total set of 2123 compounds. The resulting calibration set, with RTI set to range between 1 and 1000, was proposed as the most appropriate RTI system after rigorous evaluation, coordinated by the NORMAN network. The validation of the proposed RTI system was done externally on different instrumentation and LC conditions. The RTI can also be used to check the reproducibility and quality of LC conditions. Two quantitative structure–retention relationship (QSRR)-based models were built based on the developed RTI systems, which assist in the removal of false-positive annotations. The applicability domains of the QSRR models allowed completing the identification process with higher confidence for substances within the domain, while indicating those substances for which results should be treated with caution. The proposed RTI system was used to improve confidence in suspect and nontarget screening and increase the comparability between laboratories as demonstrated for two examples. All RTI-related calculations can be performed online at http://rti.chem.uoa.gr/.
•CECscreen is an annotation database for CECs in human biological samples.•CECscreen includes 70,397 structures, 306,071 simulated metabolites, and metadata.•CECscreen is openly accessible and is ...incorporated into Metfrag.•CECscreen facilitates large-scale detection of chemicals in exposome research.
Chemicals of Emerging Concern (CECs) include a very wide group of chemicals that are suspected to be responsible for adverse effects on health, but for which very limited information is available. Chromatographic techniques coupled with high-resolution mass spectrometry (HRMS) can be used for non-targeted screening and detection of CECs, by using comprehensive annotation databases. Establishing a database focused on the annotation of CECs in human samples will provide new insight into the distribution and extent of exposures to a wide range of CECs in humans.
This study describes an approach for the aggregation and curation of an annotation database (CECscreen) for the identification of CECs in human biological samples.
The approach consists of three main parts. First, CECs compound lists from various sources were aggregated and duplications and inorganic compounds were removed. Subsequently, the list was curated by standardization of structures to create “MS-ready” and “QSAR-ready” SMILES, as well as calculation of exact masses (monoisotopic and adducts) and molecular formulas. The second step included the simulation of Phase I metabolites. The third and final step included the calculation of QSAR predictions related to physicochemical properties, environmental fate, toxicity and Absorption, Distribution, Metabolism, Excretion (ADME) processes and the retrieval of information from the US EPA CompTox Chemicals Dashboard.
All CECscreen database and property files are publicly available (DOI: https://doi.org/10.5281/zenodo.3956586). In total, 145,284 entries were aggregated from various CECs data sources. After elimination of duplicates and curation, the pipeline produced 70,397 unique “MS-ready” structures and 66,071 unique QSAR-ready structures, corresponding with 69,526 CAS numbers. Simulation of Phase I metabolites resulted in 306,279 unique metabolites. QSAR predictions could be performed for 64,684 of the QSAR-ready structures, whereas information was retrieved from the CompTox Chemicals Dashboard for 59,739 CAS numbers out of 69,526 inquiries. CECscreen is incorporated in the in silico fragmentation approach MetFrag.
The CECscreen database can be used to prioritize annotation of CECs measured in non-targeted HRMS, facilitating the large-scale detection of CECs in human samples for exposome research. Large-scale detection of CECs can be further improved by integrating the present database with resources that contain CECs (metabolites) and meta-data measurements, further expansion towards in silico and experimental (e.g., MassBank) generation of MS/MS spectra, and development of bioinformatics approaches capable of using correlation patterns in the measured chemical features.
An integrated workflow based on liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer (LC-QTOF-MS) was developed and applied to detect and identify suspect and unknown ...contaminants in Greek wastewater. Tentative identifications were initially based on mass accuracy, isotopic pattern, plausibility of the chromatographic retention time and MS/MS spectral interpretation (comparison with spectral libraries, in silico fragmentation). Moreover, new specific strategies for the identification of metabolites were applied to obtain extra confidence including the comparison of diurnal and/or weekly concentration trends of the metabolite and parent compounds and the complementary use of HILIC. Thirteen of 284 predicted and literature metabolites of selected pharmaceuticals and nicotine were tentatively identified in influent samples from Athens and seven were finally confirmed with reference standards. Thirty four nontarget compounds were tentatively identified, four were also confirmed. The sulfonated surfactant diglycol ether sulfate was identified along with others in the homologous series (SO4C2H4(OC2H4) x OH), which have not been previously reported in wastewater. As many surfactants were originally found as nontargets, these compounds were studied in detail through retrospective analysis.
PDF
