RTP: One Effective Platform to Probe Reactive Compound Transformation Products and Its Applications for a Reactive Plasticizer BADGE.

Reactive compounds, such as covalent toxicants/drugs, have their ubiquitous occurrences and are known to react with protein or DNA in human beings, but their reactions with endogenous metabolites are rarely understood. Currently, a viable platform is demanded for discovering their reaction products since their efficacy/toxicity may be altered after the reaction. We aim to develop a platform for identifying unknown abiotic or biotransformation products for these reactive compounds. Based on stable isotope-labeling (SIL) metabolomics, we have developed a novel and robust analytical platform, reactive compound transformation profiler (RTP), which can automatically analyze preannotated high-resolution mass spectrometry (LC-HRMS) data sets and uncover probable transformation products. Generally, RTP consists of four complementary steps: (1) selecting peak pairs of light and heavy-labeled products, (2) defining the "core structure mass" for possible reaction search, (3) constructing an endogenous metabolite reaction database, and (4) developing algorithms to propose the potential transformation products by searching against the database with a single-/multiple-site reaction. Its performance was validated using the reactive plasticizer bisphenol A diglycidyl ether (BADGE) in several sample matrices. This platform enabled the identification of novel transformation products while also demonstrating its capacity to filter out the false-positive signals and provide product annotation. The RTP is freely accessible at https://github.com/FangLabNTU/Reactive-Compound-Transformation-Profiler-RTP-.

[1]  Guanyong Su,et al.  Reactive Flame Retardants: Are They Safer Replacements? , 2021, Environmental science & technology.

[2]  Min Liu,et al.  A comprehensive review on the analytical method, occurrence, transformation and toxicity of a reactive pollutant: BADGE. , 2021, Environment international.

[3]  Hui Peng,et al.  Proteome-wide effects of naphthalene-derived secondary organic aerosol in BEAS-2B cells are caused by short-lived unsaturated carbonyls , 2020, Proceedings of the National Academy of Sciences.

[4]  Min Liu,et al.  Competitive Biotransformation among Phenolic Xenobiotic Mixtures: Underestimated Risks for Toxicity Assessment. , 2019, Environmental science & technology.

[5]  Fengxiu Zhang,et al.  Highly efficient flame-retardant and soft cotton fabric prepared by a novel reactive flame retardant , 2019, Cellulose.

[6]  J. Gan,et al.  Stable Isotope Labeling-Assisted Metabolite Probing for Emerging Contaminants in Plants. , 2018, Analytical chemistry.

[7]  G. Thallinger,et al.  MetExtract II: A Software Suite for Stable Isotope-Assisted Untargeted Metabolomics , 2017, Analytical chemistry.

[8]  Soha Hassoun,et al.  PROXIMAL: a method for Prediction of Xenobiotic Metabolism , 2015, BMC Systems Biology.

[9]  Mukesh Kathalewar,et al.  Improvement in flame retardancy of polyurethane dispersions by newer reactive flame retardant , 2015 .

[10]  M. Grillo.  Detecting reactive drug metabolites for reducing the potential for drug toxicity , 2015, Expert opinion on drug metabolism & toxicology.

[11]  H. Stapleton,et al.  Characterizing the Peroxisome Proliferator-Activated Receptor (PPARγ) Ligand Binding Potential of Several Major Flame Retardants, Their Metabolites, and Chemical Mixtures in House Dust , 2014, Environmental health perspectives.

[12]  P. Batterham,et al.  Dissecting the insect metabolic machinery using twin ion mass spectrometry: a single P450 enzyme metabolizing the insecticide imidacloprid in vivo. , 2014, Analytical chemistry.

[13]  Rainer Breitling,et al.  Stable isotope-labeling studies in metabolomics: new insights into structure and dynamics of metabolic networks. , 2014, Bioanalysis.

[14]  L. Wackett,et al.  Evaluating Pesticide Degradation in the Environment: Blind Spots and Emerging Opportunities , 2013, Science.

[15]  L. P. Mašič,et al.  Bioactivation of bisphenol A and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[16]  R. Krska,et al.  Stable isotopic labelling-assisted untargeted metabolic profiling reveals novel conjugates of the mycotoxin deoxynivalenol in wheat , 2012, Analytical and Bioanalytical Chemistry.

[17]  S. Neumann,et al.  CAMERA: an integrated strategy for compound spectra extraction and annotation of liquid chromatography/mass spectrometry data sets. , 2012, Analytical chemistry.

[18]  J. Swenberg,et al.  Distribution of DNA adducts caused by inhaled formaldehyde is consistent with induction of nasal carcinoma but not leukemia. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[19]  K. Verhoeckx,et al.  Analysis of reaction products of food contaminants and ingredients: bisphenol A diglycidyl ether (BADGE) in canned foods. , 2010, Journal of agricultural and food chemistry.

[20]  L. Willmitzer,et al.  13C isotope-labeled metabolomes allowing for improved compound annotation and relative quantification in liquid chromatography-mass spectrometry-based metabolomic research. , 2009, Analytical chemistry.

[21]  H. Steinhart,et al.  Bisphenol A diglycidyl ether (BADGE) migrating from packaging material ‘disappears’ in food: reaction with food components , 2008, Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment.

[22]  M T D Cronin,et al.  A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity , 2006, SAR and QSAR in environmental research.

[23]  J. Vieites,et al.  Cytotoxic effects of BADGE (bisphenol A diglycidyl ether) and BFDGE (bisphenol F diglycidyl ether) on Caco-2 cells in vitro , 2006, Archives of Toxicology.

[24]  A. DeCaprio,et al.  Protein adduct formation as a molecular mechanism in neurotoxicity. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  Gary W Caldwell,et al.  Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. , 2004, Analytical chemistry.

[26]  T. Baillie,et al.  Integration of knowledge-based metabolic predictions with liquid chromatography data-dependent tandem mass spectrometry for drug metabolism studies: application to studies on the biotransformation of indinavir. , 2004, Analytical chemistry.

[27]  Guengerich Fp,et al.  Reaction of aflatoxin B1 exo-8,9-epoxide with DNA: kinetic analysis of covalent binding and DNA-induced hydrolysis. , 1997 .

[28]  D. Mansuy,et al.  Thiophene S-oxides as new reactive metabolites: formation by cytochrome P-450 dependent oxidation and reaction with nucleophiles , 1991 .

[29]  G. Siuzdak,et al.  Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. , 2018, Nature chemical biology.

[30]  P. Venuvanalingam,et al.  Sequence selectivity of azinomycin B in DNA alkylation and cross-linking: a QM/MM study , 2012, Journal of Molecular Modeling.

[31]  L. Ehrenberg,et al.  Alkylation of macromolecules for detecting mutagenic agents. , 1980, Teratogenesis, carcinogenesis, and mutagenesis.