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The present study assessed the residue levels of six parent neonicotinoids (p-NEOs) and four metabolites (m-NEOs) in indoor dust collected from 12 cities of China. Acetamiprid (ACE) and imidacloprid (IMI) were the predominated p-NEOs (detection rates: 98%) with the median values at 4.54 and 7.48 ng/g dry weight (dw), respectively. N-demethyl-acetamiprid (N-dm-ACE) was the most important m-NEO with the median value at 0.69 ng/g dw, while other m-NEOs were rarely detected (detection rates:15%). Significant correlation between ACE and thiacloprid (THD) was observed (p 0.01), indicating their probably concurrent applications. ACE was significantly correlated to N-dm-ACE (p 0.01), implicating the degradation of ACE in indoor environment. The estimated daily intake (EDI

Analytical techniques with high sensitivity and selectivity are essential to the quantitative analysis of clinical samples. Liquid chromatography coupled to tandem mass spectrometry is the gold standard in clinical chemistry. However, tandem mass spectrometers come at high capital expenditure and maintenance costs. We recently showed that it is possible to generate very similar results using a much simpler single mass spectrometry detector by performing enhanced in-source fragmentation/annotation (EISA) combined with correlated ion monitoring. Here we provide a step-by-step protocol for optimizing the analytical conditions for EISA, so anyone properly trained in liquid chromatography-mass spectrometry can follow and apply this technique for any given analyte. We exemplify the approach by using 2-hydroxyglutarate (2-HG) which is a clinically relevant metabolite whose d-enantiomer is considered an 'oncometabolite', characteristic of cancers associated with mutated isocitrate dehydrogenases 1 or 2 (IDH1/2). We include procedures for determining quantitative robustness, and show results of these relating to the analysis of dl-2-hydroxyglutarate in cells, as well as in serum samples from patients with acute myeloid leukemia that contain the IDH1/2 mutation. This EISA-mass spectrometry protocol is a broadly applicable and low-cost approach for the quantification of small molecules that has been developed to work well for both single-quadrupole and time-of-flight mass analyzers.The tandem mass spectrometers used in clinical chemistry are expensive. This protocol describes how to generate similar results using a single mass spectrometry detector by optimizing in-source fragmentation and data analysis via correlated ion monitoring.

Limited information is available about prenatal exposure to per- and polyfluoroalkyl substances (PFAS) in electronic waste (e-waste) recycling sites. In this study, we determined 21 emerging PFAS and 13 legacy PFAS in 94 paired maternal and cord serum samples collected from an e-waste dismantling site in Southern China. We found 6:2 fluorotelomer sulfonate (6:2 FTSA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and perfluorooctanephosphonate (PFOPA) as the major emerging PFAS, regardless of matrices, at median concentrations of 2.40, 1.78, and 0.69 ng/mL, respectively, in maternal serum samples, and 2.30, 0.73, and 0.72 ng/mL, respectively, in cord serum samples. Our results provide evidence that e-waste dismantling activities contribute to human exposure to 6:2 FTSA, 6:2 Cl-PFESA, and PFOPA. The trans-placental transfer efficiencies of emerging PFAS (0.42-0.94) were higher than that of perfluorooctanesulfonic acid (0.37) and were structure-dependent. The substitution of fluorine with chlorine or hydrogen and/or hydrophilic functional groups may alter trans-placental transfer efficiencies. Multiple linear regression analysis indicated significant associations between maternal serum concentrations of emerging PFAS and maternal clinical parameters, especially liver function and erythrocyte-related biomarkers. This study provides new insights into prenatal exposure to multiple PFAS in e-waste dismantling areas and the prevalence of emerging PFAS in people living near the sites.

Electrospray ionization (ESI) in-source fragmentation (ISF) has traditionally been minimized to promote precursor molecular ion formation, and therefore its value in molecular identification is underappreciated. In-source annotation algorithms have been shown to increase confidence in putative identifications by using ubiquitous in-source fragments. However, these in-source annotation algorithms are limited by ESI sources that are generally designed to minimize ISF. In this study, enhanced in-source fragmentation annotation (eISA) was created by tuning the ISF conditions to generate in-source fragmentation patterns comparable with higher energy fragments generated at higher collision energies as deposited in the METLIN MS/MS library, without compromising the intensity of precursor ions (median loss ≤10% in both positive and negative ionization modes). The analysis of 50 molecules was used to validate the approach in comparison to MS/MS spectra produced via data dependent acquisition (DDA) and data independent acquisition (DIA) mode with quadrupole time-of-flight mass spectrometry (QTOF-MS). Enhanced ISF as compared to QTOF DDA enabled higher peak intensities for the precursor ions (median: 18 times in negative mode and 210 times in positive mode), with the eISA fragmentation patterns consistent with METLIN for over 90% of the molecules with respect to fragment relative intensity and m/z. eISA also provides higher peak intensity as opposed to QTOF DIA for over 60% of the precursor ions in negative mode (median increase: 20%) and for 88% of the precursor ions in positive mode (median increase: 80%). Molecular identification with eISA was also successfully validated from the analysis of a metabolic extract from macrophages. An interesting side benefit of enhanced ISF is that it significantly improved molecular identification confidence with low resolution single quadrupole mass-spectrometry-based untargeted LC/MS experiments. Overall, enhanced ISF allowed for eISA to be used as a more sensitive alternative to other QTOF DIA and DDA approaches, and further, it enabled the acquisition of ESI TOF and ESI single quadrupole mass spectrometry instrumentation spectra with improved molecular identification confidence.

Mounting evidence has linked gut microbiome to health benefits of various functional foods. We previously reported that administration of a diet rich in black raspberry (BRB) changed the composition and diverse functional pathways in the mouse gut microbiome. To further characterize the functional profile in the gut microbiome of mice on BRB diet, in this follow-up study, we examined the metabolome differences in the gut microbiome driven by BRB consumption via targeted and untargeted metabolomic approaches. A distinct metabolite profile was observed in the gut microbiome of the mice on BRB diet, likely resulting from a combination of microbiome functional changes and unique precursors in BRBs. A number of functional metabolites, such as tetrahydrobiopterin and butyrate that were significantly increased in the gut microbiome may be linked to the beneficial health effects of BRB consumption. These findings suggest the important role of the gut microbiome in the health effects of BRBs and provide a connection among the health benefits of functional foods and the gut microbiome.

We have reviewed a paper titled “Bioaccumulation of Methyl Siloxanes in Common Carp (Cyprinus carpio) and in an Estuarine Food Web in Northeastern China” by Xue et al., which was published in the Archives of Environmental Contamination and Toxicology in 2019. In the paper, the authors presented and discussed the measured bioconcentration factors (BCFs), biomagnification factors (BMFs), and trophic magnification factors (TMFs) of selected volatile methylsiloxanes in Shuangtaizi estuary in China. Although we appreciate their efforts for sample collection and data analysis, we have identified significant errors in calculations of BCFs, TMFs, and BMFs, as well as animal welfare issues and food web trophic level assumptions. Based on the data, we have attempted to correct some of the analysis and offered a more complete and robust interpretation of the related data, when possible. Collectively, these errors would likely lead to very different conclusions than yours in the paper.

Deep-sea environment, characterized by high pressures, extremely high/low temperatures, limited photosynthesis-generated organic matter, darkness, and high levels of corrosion, is home to flourishing special ecosystems in the world. Here, we illustrate how the deep-sea equipment offers insights into the study of life in the deep sea based on the work in the past five decades. We first describe how organisms in the deep sea are studied, even though it is highly difficult to get access to such extreme environments. We then explain the role of deep-sea technologies in advancing research on the evolution of organisms in hydrothermal vents, cold seeps, seamounts, oceanic trenches, and whale falls from the following perspectives: biological diversity, mechanisms of environmental adaptation, biological evolution, and ecosystem connectivity. Finally, to better understand the function and service of deep-sea organisms, and further conserve the special creatures under anthropologic activity and climate change, we highlight the importance of innovative deep-sea technologies to promote cutting-edge research on deep-sea organisms, and note the remaining challenges and developing directions for deep-sea equipment.

Despite the restrictions on polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDDs), these chemicals are still ubiquitous environmental pollutants. In this study, we measured the concentrations and profiles of 17 PBDE congeners and 3 HBCDD isomers in indoor dust samples collected from 23 provinces and cities across China. The summed concentrations of PBDEs (Σ

Enhanced in-source fragmentation/annotation (EISA) has recently been shown to produce fragment ions that match tandem mass spectrometry data across a wide range of small molecules. EISA has been developed to facilitate data-dependent acquisition (DDA), data-independent acquisiton ( DIA), and multiple-reaction monitoring (MRM), enabling molecular identifications in untargeted metabolomics and targeted quantitative single-quadrupole MRM (Q-MRM) analyses. Here, EISA has been applied to peptide-based proteomic analysis using optimized insource fragmentation to generate fragmentation patterns for a mixture of 38 peptides, which were comparable to the b- and y-type fragment ions typically observed in tandem MS experiments. The optimal in-source fragmentation conditions at which high-abundance peptide fragments and precursor ions coexist were compared with automated data-dependent acquisition (DDA) in the same quadrupole time-of-flight (QTOF-MS) mass spectrometer, generating a significantly higher fragment percentage of peptides from both singly and doubly charged b- and y-type fragment (b(+), y(+), b(2+), and y(2+)) ions. Higher fragment percentages were also observed for these fragment ion series over linear ion trap instrumentation. An XCMS-EISA annotation/deconvolution program was developed, making use of the retention time and peak shape continuity between precursor fragment ions, to perform automated proteomic data analysis on the enhanced in-source fragments. Post-translational modification (PTM) characterization on peptides was demonstrated with EISA, producing fragment ions corresponding to a neutral loss of phosphoric acid with greater intensity than observed with DDA on a QTOF-MS. Moreover, Q-MRM demonstrated the ability to use EISA for peptide quantification. The availability of more sophisticated in-source fragmentation informatics, beyond XCMS-EISA, will further enable EISA for sensitive autonomous identification and Q-MRM quantitative analyses in proteomics.

Single-chemical thresholds cannot comprehensively evaluate the risk of chemical mixture exposure in indoor air. Moreover, a large number of researches have focused on short-term and high-concentration co-exposure scenarios related to different species, based on diverse endpoints, which hampers the application and improvement of existing risk evaluation models of chemical mixture exposures. More importantly, current risk evaluation models are not user-friendly for construction practitioners who do not have sufficient toxicological knowledge. Therefore, in this study, an inhalation experiment system and a hazard index (HI) were developed to investigate the risks associated with low-concentration and long-term inhalation exposure scenarios of formaldehyde and benzene, individually and combined, based on Drosophila melanogaster mortality. The results showed that the system exhibited good reproducibility in providing stable exposure concentrations during D. melanogaster life cycle. Furthermore, in a range of experimental concentrations, the interaction between formaldehyde and benzene was additive or synergistic, which was concentration- and ratio-dependent. This study is of great significance in harmonising and providing toxicity data under long-term and low-concentration exposure scenarios, which is beneficial for establishing a new user-friendly risk evaluation model for indoor chemical mixture exposures. It should be noted that the proposed HI value could indicate the hazard degrees of long-term inhalation exposures of formaldehyde and benzene, individually and combined, to D. melanogaster. However, the applicability of this index requires further experiments to evaluate the exposure risks of other volatile organic compounds (VOCs) to D. melanogaster.

To uncover metal toxicity targets and defense mechanisms of the facultative anaerobe Pantoea sp. strain MT58 (MT58), we used a multiomic strategy combining two global techniques, random bar code transposon site sequencing (RB-TnSeq) and activity-based metabolomics. MT58 is a metal-tolerant Oak Ridge Reservation (ORR) environmental isolate that was enriched in the presence of metals at concentrations measured in contaminated groundwater at an ORR nuclear waste site. The effects of three chemically different metals found at elevated concentrations in the ORR contaminated environment were investigated: the cation Al(3+), the oxyanion CrO(4)(2−), and the oxycation UO(2)(2+). Both global techniques were applied using all three metals under both aerobic and anaerobic conditions to elucidate metal interactions mediated through the activity of metabolites and key genes/proteins. These revealed that Al(3+) binds intracellular arginine, CrO(4)(2−) enters the cell through sulfate transporters and oxidizes intracellular reduced thiols, and membrane-bound lipopolysaccharides protect the cell from UO(2)(2+) toxicity. In addition, the Tol outer membrane system contributed to the protection of cellular integrity from the toxic effects of all three metals. Likewise, we found evidence of regulation of lipid content in membranes under metal stress. Individually, RB-TnSeq and metabolomics are powerful tools to explore the impact various stresses have on biological systems. Here, we show that together they can be used synergistically to identify the molecular actors and mechanisms of these pertubations to an organism, furthering our understanding of how living systems interact with their environment. IMPORTANCE Studying microbial interactions with their environment can lead to a deeper understanding of biological molecular mechanisms. In this study, two global techniques, RB-TnSeq and activity metabolomics, were successfully used to probe the interactions between a metal-resistant microorganism, Pantoea sp. strain MT58, and metals contaminating a site where the organism can be located. A number of novel metal-microbe interactions were uncovered, including Al(3+) toxicity targeting arginine synthesis, which could lead to a deeper understanding of the impact Al(3+) contamination has on microbial communities as well as its impact on higher-level organisms, including plants for whom Al(3+) contamination is an issue. Using multiomic approaches like the one described here is a way to further our understanding of microbial interactions and their impacts on the environment overall.

Single quadrupole mass spectrometry (MS) with enhanced in-source multiple fragment ion monitoring was designed to perform high sensitivity quantitative mass analyses. Enhanced in-source fragmentation amplifies fragmentation from traditional soft electrospray ionization producing fragment ions that have been found to be identical to those generated in tandem MS. We have combined enhanced in-source fragmentation data with criteria established by the European Union Commission Directive 2002/657/EC for electron ionization single quadrupole quantitative analysis to perform quantitative analyses. These experiments were performed on multiple types of complex samples that included a mixture of 50 standards, as well as cell and plasma extracts. The dynamic range for these quantitative analyses was comparable to triple quadrupole multiple reaction monitoring (MRM) analyses at up to 5 orders of magnitude with the cell and plasma extracts showing similar matrix effects across both platforms. Amino acid and fatty acid measurements performed from certified NIST 1950 plasma with isotopically labelled standards demonstrated accuracy in the range of 91–110% for the amino acids, 76–129% for the fatty acids, and good precision (coefficient of variation < 10%). To enhance specificity, a newly developed correlated ion monitoring algorithm was designed to facilitate these analyses. This algorithm autonomously processes, aligns, filters, and compiles multiple ions within one chromatogram enabling both precursor and in-source fragment ions to be correlated within a single chromatogram, also enabling the detection of co-eluting species based on precursor and fragment ion ratios. Single quadrupole instrumentation can provide MRM level quantitative performance by monitoring/correlating precursor and fragment ions facilitating high sensitivity analysis on existing single quadrupole instrumentation that are generally inexpensive, easy to operate, and technically less complex.

Phthalates are plasticizers in various products and regarded as endocrine disruptors due to their anti-androgen effects. Environmental occurrence and toxicities of parent phthalates have been widely reported, while the current state of knowledge on their metabolites is rarely summarized. Based on the available literature, the present review mainly aims to 1) characterize the potential metabolites of phthalates (mPAEs) using the pharmacokinetics evidences acquired via animal or human models; 2) examine the molecular and cellular mechanism involved in toxicity for mPAEs; 3) investigate the exposure levels of mPAEs in different human specimens (e.g., urine, blood, seminal fluid, breast milk, amniotic fluid and others) across the globe; 4) discuss the models and related parameters for phthalate exposure assessment. We suggest there is subtle difference in toxic mechanisms for mPAEs compared to their parent phthalates due to their alternative chemical structures. Human monitoring studies performed in Asia, America and Europe have provided the population exposure baseline levels for typical phthalates in different regions. Urine is the preferred matrix than other specimens for phthalate exposure study. Among ten urinary mPAEs, the largest proportions of di-(2-ethylhexyl) phthalate (DEHP) metabolites (40%), monoethyl phthalate (mEP) (43%) and DEHP metabolites/mEP (both 29%) were observed in Asia, America and Europe respectively, and mono-5-carboxy-2-ethypentyl phthalate was the most abundant compounds among DEHP metabolites. Daily intakes of phthalates can be accurately calculated via urinary mPAEs if the proper exposure parameters were determined. Further work should focus on combining epidemiological and biological evidences to establish links between phthalates exposure and biological phenotypes. More accurate molar fractions (FUE) of the urinary excreted monoester related to the ingested diesters should be collected in epidemiological or pharmacokinetic studies for different population.

A single quadrupole combined with enhanced in-source fragmentation/annotation (EISA) was used to perform multiple reaction monitoring (Q-MRM) for quantitative mass spectrometry analysis. EISA amplifies fragmentation of traditional soft electrospray ionization to produce fragment ions that have been found to be identical to those generated in tandem mass spectrometry. We have combined EISA fragmentation data with criteria established by the European Union Commission Directive 2002/657/EC for electron ionization single quadrupole quantitative analysis to perform quantitative Q-MRM experiments. These experiments were performed on multiple types of complex samples that included a mixture of 50 standards, as well as cell and plasma extracts. The dynamic range for Q-MRM quantitative analysis was comparable to triple quadrupole multiple reaction monitoring (QqQ-MRM) analyses at up to 5 orders of magnitude with the cell and plasma extracts showing similar matrix effects across both platforms. Amino acid and fatty acid measurements performed from certified NIST 1950 plasma with isotopically labelled standards demonstrated Q-MRM accuracy in the range of 91-110% for the amino acids, 76-129% for the fatty acids, and good precision (coefficient of variation < 10%). In order to enhance specificity, a newly developed Correlated Ion Monitoring (CIM) algorithm was designed to facilitate these analyses. CIM autonomously processes, aligns, filters, and compiles multiple ions within one chromatogram enabling both precursor and in-source fragment ions to be correlated within a single chromatogram, also enabling the detection of co-eluting species based on precursor and fragment ion ratios. Q-MRM and CIM with single quadrupole instrumentation has been designed as an alternative to QqQ-MRM technology by correlating precursor and fragment ions to facilitate high sensitivity Q-MRM quantitative analysis on existing instrumentation that are generally inexpensive, easy to operate, and technically less complex. @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:3 0 0 0 1 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman",serif; mso-fareast-font-family:"Times New Roman";}.MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:11.0pt; mso-ansi-font-size:11.0pt; mso-bidi-font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:DengXian; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-fareast-language:ZH-CN;}.MsoPapDefault {mso-style-type:export-only; margin-bottom:8.0pt; line-height:107%;}div.WordSection1 {page:WordSection1;}

Sucralose, one kind of "sugar-free" artificial sweeteners, is widely used as food and drinks additives. It is generally considered that sucralose is safe because majority of ingested sucralose is not metabolized and absorbed by human body. However, increasing evidence shows the negative effects of artificial sweeteners in perturbations of gut microbiota which plays an important role in a variety of processes related to host health such as immune system development. Specifically, sucralose uptake can alter the homeostasis of mouse gut microbiota, resulting in the significant changes of gut bacterial genera diversity, metabolic patterns, and fecal metabolite profiles as well as inducing host liver inflammation. Therefore, there is a need to study liver proteome changes which may be potentially affected by sucralose-induced dysbiosis. In this study, isobaric labeling-based quantitative proteomics was performed to reveal the liver functional proteome changes in male C57BL/6J mice with sucralose administration in drinking water for six-month period. The labeled tryptic peptides were off-line fractionated before LC-MS/MS analysis to improve proteome coverage detected. SIGNIFICANCE: We demonstrated the first quantitative proteomics for mice liver proteome to evaluate the effect of sucralose consumption. In total, >5700 protein groups were identified from 18 mouse liver tissues (9 from control group; 9 from sucralose-treated group), and 4327 protein groups were quantified in all samples without any missing values. Among them, 113 protein groups were identified with statistical significance (q value

Bisphenol A diglycidy ether (BADGE) and its derivatives are epoxy resins and widely used as emerging plasticizers in food packages and material coating. Though known as endocrine disruptors, little information is available on their occurrence, exposure routes and toxicity. Besides, the analysis of BADGE and its derivatives has always been a challenge due to their reactive chemical properties and the background contamination. Therefore, we firstly developed a novel water-free method to analyze BADGE and its derivatives in dust samples together with other two typical plasticizers bisphenol A (BPA) and bisphenol S (BPS). In order to investigate the levels in paired dust and urine samples, 33 paired samples were collected from Singapore. In both dust and urine samples, the predominant compounds were BPA, BADGE-2H2O and BPS. A significantly positive correlation of BPA levels in paired dust and urine samples was observed in this small-scale study. To tentatively explore the human health effect from exposure to these bisphenol plasticizers, we assessed the correlation between the urinary concentrations of these compounds and oxo-2’-deoxyguanosine (8-OHdG), an oxidative stress biomarker. The result showed that 8-OHdG levels in urine samples was positively correlated with urinary BPA level and body mass index (BMI), suggesting that elevated oxidative stress might be associated with BPA exposure and obesity. In the future, a larger scale study is warranted due to the limited sample size in this study. Building and Construction Authority (BCA) Ministry of Education (MOE) Nanyang Technological University National Environmental Agency (NEA) We appreciate the contributions of all volunteers in this study. This work was funded by Singapore Ministry of Education Academic Research Fund Tier 1 (M4011732.030), Start-Up Grant of Nanyang Technological University (M4081915, M060030008), Singapore National Environment Agency (M4061617) and Singapore Building and Construction Authority (M4062065).

Despite high production and usage of bisphenols including bisphenol A (BPA) as well as bisphenol A diglycidyl ether and its derivatives (BADGEs), little is known about the occurrence and fate of these substances in wastewater treatment plants (WWTPs) in the U.S. In this study, we investigated the occurrence, removal, mass flows, and fate of eight bisphenol analogues and six BADGEs based on the concentrations measured in influent, primary effluent, final effluent, and sludge from two WWTPs (WWTPA and WWTPB) in the Albany area of New York State, USA. BPA, bisphenol F, bisphenol S, and BADGE·2H2O were the predominant compounds found in influents of both WWTPs, at respective geometric mean (GM) concentrations of 90.0, 90.2, 31.2, and 6.48 ng/L in WWTPA, and 53.3

Parabens have been of global concern due to their endocrine disrupting properties. However, few studies have reported tissue-specific distribution of parabens in wildlife. In this study, we measured parabens and their metabolites in organs and tissues (blubber, muscle, melon, stomach, kidney, liver, gonad, brain, uterus, and umbilical cord, total n = 94) of common dolphins (Delphinus capensis) and finless porpoises (Neophocaena asiaeorientalis), to investigate tissue-specific accumulation and body burden. Among the target compounds, methyl paraben (MeP) and para-hydroxybenzoic acid (4-HB) were detected in all organs. Compared to common dolphins, finless porpoises had significantly higher concentrations of MeP and 4-HB due to their near-shore habitat. Higher concentrations of MeP and 4-HB were found in the kidney, liver, and stomach than in other organs, indicating selective accumulation of parabens in certain organs. Significant correlations between MeP and 4-HB in liver/kidney suggested metabolic transformation of the former to the latter. Detection of parabens in brains, umbilical cords, and uteri suggests that these chemicals cross biological barriers such as the blood-brain and placental barriers. The body burdens of total parabens were in the ranges of 13000-90600 mu g and 19800-81500 mu g for common dolphins and finless porpoises, respectively.

We evaluated whether bisphenol-A (BPA) could be quantified in breast adipose tissue samples provided by 36 breast cancer mastectomy patients and 14 reduction mammoplasty patients. Samples of breast adipose tissue were collected and BPA concentration was quantified using HPLC-ESI-MS/MS. BPA was detectable above the limit of quantitation of 0.38 ng/g in 30.6% of samples. BPA concentrations varied within- and between breasts and were similar between cases and controls (0.39 vs 0.41 ng/g, p = 0.74).

The mammalian gut microbiome (GM) plays a critical role in xenobiotic biotransformation and can profoundly affect the toxic effects of xenobiotics. Previous in vitro studies have demonstrated that gut bacteria have the capability to metabolize arsenic (As); however, the specific roles of the gut microbiota in As metabolism in vivo and the toxic effects of As are largely unknown. Here, we administered sodium arsenite to conventionally raised mice (with normal microbiomes) and GM-disrupted mice with antibiotics to investigate the role of the gut microbiota in As biotransformation and its toxicity. We found that the urinary total As levels of GM-disrupted mice were much higher, but the fecal total As levels were lower, than the levels in the conventionally raised mice. In vitro experiments, in which the GM was incubated with As, also demonstrated that the gut bacteria could adsorb or take up As and thus reduce the free As levels in the culture medium. With the disruption of the gut microbiota, arsenic biotransformation was significantly perturbed. Of note, the urinary monomethylarsonic acid (MMA)/ dimethylarsinic acid (DMA) ratio, a biomarker of arsenic metabolism and toxicity, was markedly increased. Meanwhile, the expression of genes of one-carbon metabolism, including forl2, bhmt, and mthfr, was downregulated, and the liver S-adenosylmethionine (SAM) levels were significantly decreased in the As-treated GM-disrupted mice only. Moreover, As exposure altered the expression of genes of the p53 signaling pathway, and the expression of multiple genes associated with hepatocellular carcinoma (HCC) was also changed in the As-treated GM-disrupted mice only. Collectively, disruption of the GM enhances the effect of As on one-carbon metabolism, which could in turn affect As biotransformation. GM disruption also increases the toxic effects of As and may increase the risk of As-induced HCC in mice.

A few epidemiologic studies suggest that exposure to bisphenol A (BPA) is associated with type 2 diabetes mellitus (T2DM). However, little is known about association between other phenolic endocrine disrupting chemicals (EDCs) and T2DM. In this case-control study, we measured urinary concentrations of 23 phenolic EDCs in 101 individuals from Jeddah, Saudi Arabia, to examine the association of parabens, antimicrobials, bisphenols, benzophenones and bisphenol A diglycidyl ethers with T2DM. Urine samples were collected from 54 T2DM cases and 47 non-diabetic individuals (controls), aged 28-68 years old, during 2015-2016. Unconditional logistic regression was performed to estimate odd ratios (ORs) for the association between diabetes and EDC exposures after adjusting for confounders including age, gender, nationality, smoking status and occupation. Age from 40 to 59 years (OR 5.56, 95% CI 2.20-14.0) and smoking status (OR 2.92, 95% CI 1.25-6.79) showed significant positive associations with T2DM. After adjusting for potential confounders, we found that T2DM cases had high urinary levels of parabens (i.e., methyl- (MeP), ethyl- (EtP), propyl- (PrP) and 4-hydroxy benzoic acid (4-HB)), bisphenols (i.e., bisphenols A (BPA) and F (BPF)), and benzophenone (i.e., 4-hydroxybenzophenone (4-OH-BP)) relative to the controls. Individuals in the 4th quartile for urinary concentrations of MeP, EtP, PrP, 4-HB and BPF and in the 3rd quartile for BPA and 4-OH-BP showed over a 6-fold increase in the odds of having diabetes compared with those in the first quartile. Overall, our study shows that urinary levels of multiple phenolic EDCs were associated with increased risk for diabetes. Further prospective studies are required to verify these associations.

Despite the high production volume and widespread use of methyl siloxanes, limited studies have been conducted to investigate the bioconcentration, biomagnification, and trophic magnification potentials of these substances. In the present study, bioconcentration factors (BCFs) of methyl siloxanes were determined with common carp exposed at environmental relevant levels for 32 days. BCF of octamethylcyclotetrasiloxane (D4) was estimated as 6197 L/Kg, indicating strong bioconcentration potential in the common carp. To assess the food chain transfer of methyl siloxanes, 12 aquatic invertebrates and vertebrates species were collected from a food web in Shuangtaizi estuary in northeastern China and concentrations of methyl siloxanes in these species were determined with gas chromatography mass spectrometry. Trophic magnification factors (TMFs) of decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6), and linear siloxanes (L7–10) were significantly greater than 1 in one food chain selected, which suggest trophic magnification potentials of these methyl siloxanes. Biomagnification factors of D4–D6 and L7–L10 from planktons to Japanese snapping shrimp were greater than 1, indicating biomagnification potentials of these methyl siloxanes from the prey to predator. This is the first study to investigate the bioaccumulation behaviors of methyl siloxanes by coupling BCF and BMF with TMF.

Enhanced in-source fragmentation annotation combined with single quadrupole multiple reaction monitoring (EISA-MRM) has been designed for quantitative mass spectrometry analysis. EISA contrasts to traditional electrospray as a soft ionization technology and is proving to be advantageous since the resulting fragment ions are identical as those generated in tandem mass spectrometry. Criteria established by the European Union Commission Directive 2002/657/EC for electron ionization single quadrupole quantitative analysis was used for the EISA-MRM quantitative analyses and experiments were performed on multiple types of complex samples that included a mixture of 50 standards, as well as cell and plasma extracts. The dynamic range for quantitative analysis was comparable to QqQ-MRM analyses at up to 5 orders of magnitude and the EISA-MRM and QqQ-MRM of the cell and plasma extracts showed similar matrix effects. Amino acid and fatty acid measurements performed from certified NIST 1950 plasma with isotopically labelled standards demonstrated EISA-MRM accuracy in the range of 91-110% for the amino acids, 76-129% for the fatty acids, and precision with a CV < 10%. In order to enhance specificity and sensitivity, a newly developed Correlated SIM Chromatogram (CSC) algorithm was designed to facilitate MRM quality analyses. The EISA-MRM quantitative analysis with CSC informatics enables both precursor and in-source fragment ions to be correlated within a single quadrupole mass spectrometer.

Hypertension and kidney disease have been repeatedly associated with genomic variants and alterations of lysine metabolism. Here, we combined stable isotope labeling with untargeted metabolomics to investigate lysine’s metabolic fate in vivo. Dietary 13C6 labeled lysine was tracked to lysine metabolites across various organs. Globally, lysine reacts rapidly with molecules of the central carbon metabolism, but incorporates slowly into proteins and acylcarnitines. Lysine metabolism is accelerated in a rat model of hypertension and kidney damage, chiefly through N-alpha-mediated degradation. Lysine administration diminished development of hypertension and kidney injury. Protective mechanisms include diuresis, further acceleration of lysine conjugate formation, and inhibition of tubular albumin uptake. Lysine also conjugates with malonyl-CoA to form a novel metabolite Nε-malonyl-lysine to deplete malonyl-CoA from fatty acid synthesis. Through conjugate formation and excretion as fructoselysine, saccharopine, and Nε-acetyllysine, lysine lead to depletion of central carbon metabolites from the organism and kidney. Consistently, lysine administration to patients at risk for hypertension and kidney disease inhibited tubular albumin uptake, increased lysine conjugate formation, and reduced tricarboxylic acid (TCA) cycle metabolites, compared to kidney-healthy volunteers. In conclusion, lysine isotope tracing mapped an accelerated metabolism in hypertension, and lysine administration could protect kidneys in hypertensive kidney disease.

Archived metabolomics data represent a broad resource for the scientific community. However, the absence of tools for the meta-analysis of heterogeneous data types makes it challenging to perform direct comparisons in a single and cohesive workflow. Here we present a framework for the meta-analysis of metabolic pathways and interpretation with proteomic and transcriptomic data. This framework facilitates the comparison of heterogeneous types of metabolomics data from online repositories (e.g., XCMS Online, Metabolomics Workbench, GNPS, and MetaboLights) representing tens of thousands of studies, as well as locally acquired data. As a proof of concept, we apply the workflow for the meta-analysis of i) independent colon cancer studies, further interpreted with proteomics and transcriptomics data, ii) multimodal data from Alzheimer’s disease and mild cognitive impairment studies, demonstrating its high-throughput capability for the systems level interpretation of metabolic pathways. Moreover, the platform has been modified for improved knowledge dissemination through a collaboration with Metabolomics Workbench and LIPID MAPS. We envision that this meta-analysis tool will help overcome the primary bottleneck in analyzing diverse datasets and facilitate the full exploitation of archival metabolomics data for addressing a broad array of questions in metabolism research and systems biology.

Electrospray ionization (ESI) in-source fragmentation (ISF) has traditionally been minimized to promote precursor molecular ion formation, and therefore its value in molecular identification underappreciated. Recently a METLIN-guided in-source annotation (MISA) algorithm was introduced to increase confidence in putative identifications by using ubiquitous in-source fragments. However, MISA is limited by ESI sources that are generally designed to minimize ISF. In this study, enhanced ISF with MISA (eMISA) was created by tuning the ISF conditions to generate in-source fragmentation patterns comparable with higher energy fragments generated at higher collision energies as deposited in the METLIN MS/MS library, without compromising the intensity of precursor ions (median loss ≤ 10% in both positive and negative ionization modes). The analysis of 50 molecules was used to validate the approach in comparison to MS/MS spectra produced via data dependent acquisition (DDA) and data independent acquisition mode (DIA) with quadrupole time-of-flight mass spectrometry (QTOF-MS). Enhanced ISF as compared to QTOF DDA, enables for higher peak intensities for the precursor ions (median: 18 times at negative mode and 210 times at positive mode), with the eMISA fragmentation patterns consistent with METLIN for over 90% of the molecules with respect to fragment relative intensity and m/z. eMISA also provides higher peak intensity as opposed to QTOF DIA with a median increase of 20% at negative mode and 80% at positive mode for all precursor ions. Metabolite identification with eMISA was also successfully validated from the analysis of a metabolic extract from macrophages. An interesting side benefit of enhanced ISF is that it significantly improved the compound identification confidence with low resolution single quadrupole mass spectrometry-based untargeted LC/MS experiments. Overall, enhanced ISF allowed for eMISA to be used as a more sensitive alternative to other QTOF DIA and DDA approaches, and further, it enables the acquisition of ESI TOF and ESI single quadrupole mass spectrometry instrumentation spectra with higher sensitivity and improved molecular identification confidence.

Electrospray ionization (ESI) in-source fragmentation (ISF) has traditionally been minimized to promote precursor molecular ion formation, and therefore its value in molecular identification underappreciated. Recently a METLIN-guided in-source annotation (MISA) algorithm was introduced to increase confidence in putative identifications by using ubiquitous in-source fragments. However, MISA is limited by ESI sources that are generally designed to minimize ISF. In this study, enhanced ISF with MISA (eMISA) was created by tuning the ISF conditions to generate in-source fragmentation patterns comparable with higher energy fragments generated at higher collision energies as deposited in the METLIN MS/MS library, without compromising the intensity of precursor ions (median loss ≤ 10% in both positive and negative ionization modes). The analysis of 50 molecules was used to validate the approach in comparison to MS/MS spectra produced via data dependent acquisition (DDA) and data independent acquisition mode (DIA) with quadrupole time-of-flight mass spectrometry (QTOF-MS). Enhanced ISF as compared to QTOF DDA, enables for higher peak intensities for the precursor ions (median: 18 times at negative mode and 210 times at positive mode), with the eMISA fragmentation patterns consistent with METLIN for over 90% of the molecules with respect to fragment relative intensity and m/z. eMISA also provides higher peak intensity as opposed to QTOF DIA with a median increase of 20% at negative mode and 80% at positive mode for all precursor ions. Metabolite identification with eMISA was also successfully validated from the analysis of a metabolic extract from macrophages. An interesting side benefit of enhanced ISF is that it significantly improved the compound identification confidence with low resolution single quadrupole mass spectrometry-based untargeted LC/MS experiments. Overall, enhanced ISF allowed for eMISA to be used as a more sensitive alternative to other QTOF DIA and DDA approaches, and further, it enables the acquisition of ESI TOF and ESI single quadrupole mass spectrometry instrumentation spectra with higher sensitivity and improved molecular identification confidence.

Background: Arsenic-induced liver X receptor/retinoid X receptor (LXR/RXR) signaling inhibition is a potential mechanism underlying the cardiovascular effects caused by arsenic. The gut microbiota can influence arsenic toxic effects. Objective: We aimed to explore whether gut microbiota play a role in arsenic-induced LXR/RXR signaling inhibition and the subsequent lipid and cholesterol dysbiosis. Methods: Conventional and antibiotic-treated mice (AB-treated mice) were exposed to 0.25 ppm and 1 ppm arsenic for 2 wk. Hepatic mRNAs were extracted and sequenced. The expression levels of genes associated with LXR/RXR signaling were quantified by quantitative real-time polymerase chain reaction (qPCR), and serum and hepatic cholesterol levels were measured. Liquid chromatography–mass spectrometry (LC-MS)–based lipidomics were used to examine serum and hepatic lipids. Results: Pathway analysis indicated that arsenic exposure differentially influenced the hepatic signaling pathways in conventional and AB-treated mice. The expression of sterol regulatory element-binding protein 1 (Srebp1c), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), and cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), as well as cholesterol efflux genes, including ATP binding cassette subfamily G member 5/8 (Abcg5/8) and cluster of differentiation 36 (Cd36), was lower in arsenic-exposed conventional mice but not in AB-treated mice. Similarly, under arsenic exposure, the hepatic expression of scavenger receptor class B member 1 (Scarb1), which is involved in reverse cholesterol transport (RCT), was lower in conventional mice, but was higher in AB-treated animals compared with controls. Correspondingly, arsenic exposure exerted opposite effects on the serum cholesterol levels in conventional and AB-treated mice, i.e., higher serum cholesterol levels in conventional mice but lower levels in AB-treated mice than in respective controls. Serum lipid levels, especially triglyceride (TG) levels, were higher in conventional mice exposed to 1 ppm arsenic, while arsenic exposure did not significantly affect the serum lipids in AB-treated mice. Liver lipid patterns were also differentially perturbed in a microbiota-dependent manner. Conclusions: Our results suggest that in mice, the gut microbiota may be a critical factor regulating arsenic-induced LXR/RXR signaling perturbation, suggesting that modulation of the gut microbiota might be an intervention strategy to reduce the toxic effects of arsenic on lipid and cholesterol homeostasis. https://doi.org/10.1289/EHP4415

Arsenic (As) contamination in water or food is a global issue affecting hundreds of millions of people. Although As is classified as a group 1 carcinogen and is associated with multiple diseases, the individual susceptibility to As-related diseases is highly variable, such that a proportion of people exposed to As have higher risks of developing related disorders. Many factors have been found to be associated with As susceptibility. One of the main sources of the variability found in As susceptibility is the variation in the host genome, namely, polymorphisms of many genes involved in As transportation, biotransformation, oxidative stress response and DNA repair affect the susceptibility of an individual to As toxicity and then influence the disease outcomes. In addition, lifestyles and many nutritional factors, such as folate, vitamin C, and fruit, have been found to be associated with individual susceptibility to As-related diseases. Recently, the interactions between As exposure and the gut microbiome have been of particular concern. As exposure has been shown to perturb gut microbiome composition, and the gut microbiota has been shown to also influence As metabolism, which raises the question of whether the highly diverse gut microbiota contributes to As susceptibility. Here, we review the literature and summarize the factors, such as host genetics and nutritional status, that influence As susceptibility, and we also present potential mechanisms of how the gut microbiome may influence As metabolism and its toxic effects on the host to induce variations in As susceptibility. Challenges and future directions are also discussed to emphasize the importance of characterizing the specific role of these factors in inter-individual susceptibility to As-related diseases.

Bisphenol A (BPA) is a widely present endocrine disruptor chemical found in many household items. Moreover, this chemical can bioaccumulate in various terrestrial and aquatic sources; thereby ensuring continual exposure of animals and humans. For most species, including humans, diet is considered the primary route of exposure. However, there has been little investigation whether commercial-brands of dog foods contain BPA and potential health ramifications of BPA-dietary exposure in dogs. We sought to determine BPA content within dog food, whether short-term consumption of these diets increases serum concentrations of BPA, and potential health consequences, as assessed by potential hematological, serum chemistry, cortisol, DNA methylation, and gut microbiome changes, in dogs associated with short-term dietary exposure to BPA. Fourteen healthy privately-owned dogs were used in this study. Blood and fecal samples were collected prior to dogs being placed for two-weeks on one of two diets (with one considered to be BPA-free), and blood and fecal samples were collected again. Serum/plasma samples were analyzed for chemistry and hematology profiles, cortisol concentrations, 5-methylcytosine in lymphocytes, and total BPA concentrations. Fecal samples were used for microbiome assessments. Both diets contained BPA, and after two-weeks of being on either diet, dogs had a significant increase in circulating BPA concentrations (pre-samples=0.7±0.15ng/mL, post-samples=2.2±0.15ng/mL, p

Despite the widespread use of parabens in a range of consumer products, little is known about bioaccumulation of these chemicals in aquatic environments. In this study, six parabens and four of their common metabolites were measured in abiotic (water, sediment) and biotic (fish including sharks, invertebrates, plants) samples collected from a subtropical marine food web in coastal Florida. Methyl paraben (MeP) was found in all abiotic (100%) and a majority of biotic (87%) samples. 4-Hydroxy benzoic acid (4-HB) was the most abundant metabolite, found in 97% of biotic and all abiotic samples analyzed. The food chain accumulation of MeP and 4-HB was investigated for this food web. The trophic magnification factor (TMF) of MeP was estimated to be 1.83, which suggests considerable bioaccumulation and biomagnification of this compound in the marine food web. In contrast, a low TMF value was found for 4-HB (0.30), indicating that this compound is metabolized and excreted along the food web. This is the first study to document the widespread occurrence of parabens and their metabolites in fish, invertebrates, seagrasses, marine macroalgae, mangroves, seawater, and ocean sediments and to elucidate biomagnification potential of MeP in a marine food web.

The health effects of bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) have been studied extensively in children. The impact of other chemicals in these two classes has not been investigated as fully. We conducted a cross-sectional pilot study of 10–13 y old healthy children. We assessed descriptive, univariable, and multivariable associations of urinary metabolites of bisphenols and phthalates with oxidant stress, insulin resistance, body mass, and endothelial dysfunction. Possible associations with brachial artery distensibility, pulse wave velocity (markers of vascular stiffness), and serum endothelial cell-derived microparticle levels were also assessed. We enrolled 41 participants, 12.1 ± 1.0 y, most of whom were Mexican Americans (42%) or other Hispanics (34%). Increased BPA levels were associated with increased levels of F2-isoprostane (ng/ml) (P = 0.02), with a similar trend for DEHP metabolites. Each log unit increase of high molecular weight (HMW) phthalate metabolites was associated with a 0.550 increase in Homeostatic Model Assessment of insulin resistance (HOMA-IR) units (P = 0.019) and altered circulating levels of activated endothelial cell-derived microparticles (% per ml) (P = 0.026). Bisphenol S (BPS), a replacement for BPA, was associated with increased albumin (mg):creatinine (g) ratio (P = 0.04). Metabolites of HMW phthalates were also associated with decreased brachial artery distensibility (P = 0.047). Exposure to bisphenols and phthalates, including a BPA replacement, is associated with increased oxidant stress, insulin resistance, albuminuria, as well as disturbances in vascular function in healthy children.

Chronic arsenic exposure from drinking water is a global public health issue, which is associated with numerous human diseases and influences millions of people worldwide. The effects of arsenic exposure to the metabolic networks remain elusive. Here, we exposed female C57BL/6J mice to 1 ppm inorganic arsenic in drinking water for 3 months to investigate how arsenic exposure perturbs serum and fecal metabolic profiles. We found decreased levels of serum compounds with antioxidative activities in arsenic-treated mice, in accordance with elevated oxidative stress indicated by higher urinary 8-oxo-2'-deoxyguanosine (8-oxo-dG) levels. Moreover, the levels of multiple lysophosphatidylcholines (lysoPCs) were significantly increased in the sera of arsenic-exposed mice, including lysoPC (O-18:0), lysoPC (20:3), lysoPC (18:1), and lysoPC (22:6). Arsenic exposure perturbed the levels of several key polyunsaturated fatty acids (PUFAs) in the fecal samples in concert with alterations in related microbial pathways. Additionally, changes in the abundances of many functional metabolites, together with decreased levels of amino acids, were found in the fecal samples of arsenic-treated mice. By delineating the impact of arsenic exposure on the metabolic profiles, the findings may provide new biomarkers and mechanistic insights into arsenic-associated diseases.

Arsenic contamination in drinking water has been a worldwide health concern for decades. In addition to being a well-recognized carcinogen, arsenic exposure has also been linked to diabetes, neurological effects, and cardiovascular diseases. Recently, increasing evidence has indicated that gut microbiome is an important risk factor in modulating the development of diseases. We aim to investigate the role of gut microbiome perturbation in arsenic-induced diseases by coupling a mass-spectrometry-based metabolomics approach and an animal model with altered gut microbiome induced by bacterial infection. Serum metabolic profiling has revealed that gut microbiome perturbation and arsenic exposure induced the dramatic changes of numerous metabolite pathways, including fatty acid metabolism, phospholipids, sphingolipids, cholesterols, and tryptophan metabolism, which were not or were less disrupted when the gut microbiome stayed normal. In summary, this study suggests that gut microbiome perturbation can exacerbate or cause metabolic disorders induced by arsenic exposure.