Prenatal exposure to paraquat and nanoscaled TiO2 aerosols alters the gene expression of the developing brain.

Nanopesticides are innovative pesticides involving engineered nanomaterials in their formulation to increase the efficiency of plant protection products, while mitigating their environmental impact. Despite the predicted growth of the nanopesticide use, no data is available on their inhalation toxicity and the potential cocktail effects between their components. In particular, the neurodevelopmental toxicity caused by prenatal exposures might have long lasting consequences. In the present study, we repeatedly exposed gestating mice in a whole-body exposure chamber to three aerosols, involving the paraquat herbicide, nanoscaled titanium dioxide particles (nTiO2), or a mixture of both. Particle number concentrations and total mass concentrations were followed to enable a metrological follow-up of the exposure sessions. Based on the aerosols characteristics, the alveolar deposited dose in mice was then estimated. RNA-seq was used to highlight dysregulations in the striatum of pups in response to the in utero exposure. Modifications in gene expression were identified at post-natal day 14, which might reflect neurodevelopmental alterations in this key brain area. The data suggest an alteration in the mitochondrial function following paraquat exposure, which is reminiscent of the pathological process leading to Parkinson disease. Markers of different cell lineages were dysregulated, showing effects, which were not limited to dopaminergic neurons. Exposure to the nTiO2 aerosol modulated the regulation of cytokines and neurotransmitters pathways, perhaps reflecting a minor neuroinflammation. No synergy was found between paraquat and nTiO2. Instead, the neurodevelopmental effects were surprisingly lower than the one measured for each substance separately.

Comparability of Lipoprotein Particle Number Concentrations Across ES-DMA, NMR, LC-MS/MS, Immunonephelometry, and VAP: In Search of a Candidate Reference Measurement Procedure for apoB and non-HDL-P Standardization.

BACKGROUND: Despite the usefulness of standard lipid parameters for cardiovascular disease risk assessment, undiagnosed residual risk remains high. Advanced lipoprotein testing (ALT) was developed to provide physicians with more predictive diagnostic tools. ALT methods separate and/or measure lipoproteins according to different parameters such as size, density, charge, or content, and equivalence of results across methods has not been demonstrated. METHODS: Through a split-sample study, 25 clinical specimens (CSs) were assayed in 10 laboratories before and after freezing using the major ALT methods for non-HDL particles (non-HDL-P) or apolipoprotein B-100 (apoB-100) measurements with the intent to assess their comparability in the current state of the art. RESULTS: The overall relative standard deviation (CV) of non-HDL-P and apoB-100 concentrations measured by electrospray differential mobility analysis, nuclear magnetic resonance, immunonephelometry, LC-MS/MS, and vertical autoprofile in the 25 frozen CSs was 14.1%. Within-method comparability was heterogeneous, and CV among 4 different LC-MS/MS methods was 11.4% for apoB-100. No significant effect of freezing and thawing was observed. CONCLUSIONS: This study demonstrates that ALT methods do not yet provide equivalent results for the measurement of non-HDL-P and apoB-100. The better agreement between methods harmonized to the WHO/IFCC reference material suggests that standardizing ALT methods by use of a common commutable calibrator will improve cross-platform comparability. This study provides further evidence that LC-MS/MS is the most suitable candidate reference measurement procedure to standardize apoB-100 measurement, as it would provide results with SI traceability. The absence of freezing and thawing effect suggests that frozen serum pools could be used as secondary reference materials.

Advanced lipoprotein testing for cardiovascular diseases risk assessment: a review of the novel approaches in lipoprotein profiling.

With the increasing prevalence of cardiovascular diseases (CVD) worldwide, finding reliable and clinically relevant biomarkers to predict acute cardiovascular events has been a major aim of the scientific and medical community. Improvements of the understanding of the pathophysiological pathways of the disease highlighted the major role of lipoprotein particles, and these past decades have seen the emergence of a number of new methodologies to separate, measure and quantitate lipoproteins. Those methods, also known as advanced lipoprotein testing methods (ALT), have gained acceptance in the field of CVD risk assessment and have proven their clinical relevance. In the context of worldwide standardization and harmonization of biological assays, efforts have been initiated toward standardization of ALT methods. However, the complexity of lipoprotein particles and the multiple approaches and methodologies reported to quantify them have rendered these initiatives a critical issue. In this context and to better understand these challenges, this review presents a summary of the major methods available for ALT with the aim to point out the major differences in terms of procedures and quantities actually measured and to discuss the resulting comparability issues.

Absolute Quantification of Bionanoparticles by Electrospray Differential Mobility Analysis: An Application to Lipoprotein Particle Concentration Measurements.

This study presents an upgraded electrospray differential mobility analysis (ES-DMA) setup for the absolute quantification of bionanoparticle concentrations in biological samples, with a special focus on non-high-density-lipoprotein particle concentrations (non-HDL-P). Metrological characterization of the system's analytical performances for concentration measurements shows that the mean intermediate precision relative standard deviation is 14% for biological samples, 6% for silica nanoparticles, and less than 1% for diameter measurements. This study also demonstrates that the most accurate method for non-HDL-P quantification in native serum samples implies daily calculation of the electrospray transmission efficiency (E) of the system with the WHO SP3-08 reference material. The establishment of the uncertainty budget reveals that the main contribution to particle concentration measurement uncertainties is the electrospray transmission efficiency. This data additionally shows that E is not only low (approximately 15-20%) but also highly variable over time and strongly affected by sample composition. This work suggests that absolute enumeration of bionanoparticles is achievable with ES-DMA but provided that a special care is taken to quantifying E with a calibrator of nature and matrix highly similar to the samples ones.

In vitro monitoring of amyloid ß-peptide oligomerization by Electrospray differential mobility analysis: An alternative tool to evaluate Alzheimer's disease drug candidates.

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein aggregation, like more than twenty other human pathologies. One major protein incriminated in AD is the 42-residue amyloid-ß peptide (Aß1-42) which aggregates to form neurotoxic oligomers and fibrils. While, low molecular weight oligomers have been evidenced as neurotoxic species, only scarce methods raise the challenge to monitor the beginning of the aggregation process, called oligomerization. We propose here an innovative and fast monitoring of the time-dependent Aß1-42 oligomerization pattern by electrospray differential mobility analysis (ES-DMA). We developed a non-denaturing method based on ES-DMA to afford a real-time and direct characterization of the early, metastable and neurotoxic species. This technique provided their size distribution over time. At the beginning of the in vitro oligomerization process of Aß1-42, the size distribution is characterized by two populations with modal diameters around 3.5 and 4nm, corresponding to Monomer and Small oligomers. After few hours, larger species around 10nm are observed. The results were correlated to those obtained by capillary electrophoresis. We also demonstrated the ability of our method to evaluate Aß1-42 kinetics modulators. Thereby, ES-DMA provides new insights on Aß1-42 oligomerization in the presence of sugar-based peptidomimetic analogs which were recently described as modulators of Aß1-42 self-assembly and neurotoxicity inhibitors.

Molecular Isomer Identification of Titan's Tholins Organic Aerosols by Photoelectron/Photoion Coincidence Spectroscopy Coupled to VUV Synchrotron Radiation.

The chemical composition of Titan organic haze is poorly known. To address this issue, laboratory analogues named tholins are synthesized and analyzed by methods often requiring an extraction process in a carrier solvent. These methods exclude the analysis of the insoluble tholins' fraction and assume a hypothetical chemical equivalence between soluble and insoluble fractions. In this work, we present a powerful complementary analysis method recently developed on the DESIRS VUV synchrotron beamline at SOLEIL. It involves soft pyrolysis of tholins at ∼230 °C and electron/ion coincidence analysis of the emitted volatile compounds photoionized by tunable synchrotron radiation. By comparison with reference photoelectron spectra (PES), the spectral information collected on the detected molecules yields their isomeric structure. The method is more readily applied to light species (m/z ≤ 69), while for heavier ones, the number of possibilities and the lack of PES reference spectra in the literature limit its analysis. A notable pattern in the analyzed tholins is the presence of species containing adjacent doubly bonded N atoms, which might be a signature of heterogeneous incorporation of N2 in tholins.

Water adsorption on TiO2 surfaces probed by soft X-ray spectroscopies: bulk materials vs. isolated nanoparticles.

We describe an experimental method to probe the adsorption of water at the surface of isolated, substrate-free TiO2 nanoparticles (NPs) based on soft X-ray spectroscopy in the gas phase using synchrotron radiation. To understand the interfacial properties between water and TiO2 surface, a water shell was adsorbed at the surface of TiO2 NPs. We used two different ways to control the hydration level of the NPs: in the first scheme, initially solvated NPs were dried and in the second one, dry NPs generated thanks to a commercial aerosol generator were exposed to water vapor. XPS was used to identify the signature of the water layer shell on the surface of the free TiO2 NPs and made it possible to follow the evolution of their hydration state. The results obtained allow the establishment of a qualitative determination of isolated NPs' surface states, as well as to unravel water adsorption mechanisms. This method appears to be a unique approach to investigate the interface between an isolated nano-object and a solvent over-layer, paving the way towards new investigation methods in heterogeneous catalysis on nanomaterials.

Ionization photophysics and spectroscopy of cyanoacetylene.

Photoionization of cyanoacetylene was studied using synchrotron radiation over the non-dissociative ionization excitation range 11-15.6 eV, with photoelectron-photoion coincidence techniques. The absolute ionization cross-section and spectroscopic aspects of the parent ion were recorded. The adiabatic ionization energy of cyanoacetylene was measured as 11.573 ± 0.010 eV. A detailed analysis of photoelectron spectra of HC3N involves new aspects and new assignments of the vibrational components to excitation of the A(2)Σ(+) and B(2)Π states of the cation. Some of the structured autoionization features observed in the 11.94 to 15.5 eV region of the total ion yield (TIY) spectrum were assigned to two Rydberg series converging to the B(2)Π state of HC3N(+). A number of the measured TIY features are suggested to be vibrational components of Rydberg series converging to the C(2)Σ(+) state of HC3N(+) at ≈17.6 eV and others to valence shell transitions of cyanoacetylene in the 11.6-15 eV region. The results of quantum chemical calculations of the cation electronic state geometries, vibrational frequencies and energies, as well as of the C-H dissociation potential energy profiles of the ground and electronic excited states of the ion, are compared with experimental observations. Ionization quantum yields are evaluated and discussed and the problem of adequate calibration of photoionization cross-sections is raised.

VUV photodynamics and chiral asymmetry in the photoionization of gas phase alanine enantiomers.

The valence shell photoionization of the simplest proteinaceous chiral amino acid, alanine, is investigated over the vacuum ultraviolet region from its ionization threshold up to 18 eV. Tunable and variable polarization synchrotron radiation was coupled to a double imaging photoelectron/photoion coincidence (i(2)PEPICO) spectrometer to produce mass-selected threshold photoelectron spectra and derive the state-selected fragmentation channels. The photoelectron circular dichroism (PECD), an orbital-sensitive, conformer-dependent chiroptical effect, was also recorded at various photon energies and compared to continuum multiple scattering calculations. Two complementary vaporization methods-aerosol thermodesorption and a resistively heated sample oven coupled to an adiabatic expansion-were applied to promote pure enantiomers of alanine into the gas phase, yielding neutral alanine with different internal energy distributions. A comparison of the photoelectron spectroscopy, fragmentation, and dichroism measured for each of the vaporization methods was rationalized in terms of internal energy and conformer populations and supported by theoretical calculations. The analytical potential of the so-called PECD-PICO detection technique-where the electron spectroscopy and circular dichroism can be obtained as a function of mass and ion translational energy-is underlined and applied to characterize the origin of the various species found in the experimental mass spectra. Finally, the PECD findings are discussed within an astrochemical context, and possible implications regarding the origin of biomolecular asymmetry are identified.

Ionization photophysics and spectroscopy of dicyanoacetylene.

Photoionization of dicyanoacetylene was studied using synchrotron radiation over the excitation range 8-25 eV, with photoelectron-photoion coincidence techniques. The absolute ionization cross-section and detailed spectroscopic aspects of the parent ion were recorded. The adiabatic ionization energy of dicyanoacetylene was measured as 11.80 ± 0.01 eV. A detailed analysis of the cation spectroscopy involves new aspects and new assignments of the vibrational components to excitation of the quasi-degenerate A(2)Πg, B(2)Σg(+) states as well as the C(2)Σu(+) and D(2)Πu states of the cation. Some of the structured autoionization features observed in the 12.4-15 eV region of the total ion yield spectrum were assigned to vibrational components of valence shell transitions and to two previously unknown Rydberg series converging to the D(2)Πu state of C4N2(+). The appearance energies of the fragment ions C4N(+), C3N(+), C4(+), C2N(+), and C2(+) were measured and their heats of formation were determined and compared with existing literature values. Thermochemical calculations of the appearance potentials of these and other weaker ions were used to infer aspects of dissociative ionization pathways.

Absolute photoionization cross section of the ethyl radical in the range 8-11.5 eV: synchrotron and vacuum ultraviolet laser measurements.

The absolute photoionization cross section of C(2)H(5) has been measured at 10.54 eV using vacuum ultraviolet (VUV) laser photoionization. The C(2)H(5) radical was produced in situ using the rapid C(2)H(6) + F → C(2)H(5) + HF reaction. Its absolute photoionization cross section has been determined in two different ways: first using the C(2)H(5) + NO(2) → C(2)H(5)O + NO reaction in a fast flow reactor, and the known absolute photoionization cross section of NO. In a second experiment, it has been measured relative to the known absolute photoionization cross section of CH(3) as a reference by using the CH(4) + F → CH(3) + HF and C(2)H(6) + F → C(2)H(5) + HF reactions successively. Both methods gave similar results, the second one being more precise and yielding the value: σ(C(2)H(5))(ion) = (5.6 ± 1.4) Mb at 10.54 eV. This value is used to calibrate on an absolute scale the photoionization curve of C(2)H(5) produced in a pyrolytic source from the C(2)H(5)NO(2) precursor, and ionized by the VUV beam of the DESIRS beamline at SOLEIL synchrotron facility. In this latter experiment, a recently developed ion imaging technique is used to discriminate the direct photoionization process from dissociative ionization contributions to the C(2)H(5)(+) signal. The imaging technique applied on the photoelectron signal also allows a slow photoelectron spectrum with a 40 meV resolution to be extracted, indicating that photoionization around the adiabatic ionization threshold involves a complex vibrational overlap between the neutral and cationic ground states, as was previously observed in the literature. Comparison with earlier photoionization studies, in particular with the photoionization yield recorded by Ruscic et al. is also discussed.

VUV state-selected photoionization of thermally-desorbed biomolecules by coupling an aerosol source to an imaging photoelectron/photoion coincidence spectrometer: case of the amino acids tryptophan and phenylalanine.

Gas phase studies of biological molecules provide structural and dynamical information on isolated systems. The lack of inter- or intra-molecular interactions facilitates the interpretation of the experimental results through theoretical calculations, and constitutes an informative complement to the condensed phase. However advances in the field are partially hindered by the difficulty of vaporising these systems, most of which are thermally unstable. In this work we present a newly developed aerosol mass thermodesorption setup, which has been coupled to a Velocity Map Imaging (VMI) analyzer operated in coincidence with a Wiley-McLaren Time of Flight spectrometer, using synchrotron radiation as a single photon ionization source. Although it has been previously demonstrated that thermolabile molecules such as amino acids can be produced intact by the aerosol vaporisation technique, we show how its non-trivial coupling to a VMI analyzer plus the use of electron/ion coincidences greatly improves the concept in terms of the amount of spectroscopic and dynamic information that can be extracted. In this manner, we report on the valence shell ionization of two amino acids, tryptophan and phenylalanine, for which threshold photoelectron spectra have been recorded within the first 3 eV above the first ionization energy using synchrotron radiation emitted from the DESIRS beamline located at SOLEIL in France. Their adiabatic ionization energies (IEs) have been measured at 7.40 ± 0.05 and 8.65 ± 0.02 eV, respectively, and their spectra analyzed using existing theoretical data from the literature. The IE values agree well with previously published ones, but are given here with a considerably reduced uncertainty by up to a factor of 5. The photostability of both amino acids is also described in detail, through the measurement of the state-selected fragmentation pathways via the use of threshold electron/ion coincidences (TPEPICO), with appearance energies for the different photofragments given for the vaporization temperatures studied, in correlation with the different molecular orbitals involved as identified from the Threshold Photoelectron Spectra (TPES).

Photoionization of atmospheric aerosol constituents and precursors in the 7-15 eV energy region: experimental and theoretical study.

Photoionization mass spectrometry (PIMS) has been used to study the dissociative ionization of three anthropogenic atmospheric aerosol precursors (o-xylene, 2-methylstyrene, indene) and five of their main atmospheric degradation products (o-tolualdehyde, 2-methylphenol, o-toluic acid, phthalic acid, and phthaldialdehyde). Ionization and fragment appearance energies have been experimentally determined in the 7-15 eV photon energy regime. Moreover, intensive ab inito quantum chemical calculations have been performed to compute the first ionization energies and heats of formation of these compounds (including also phthalic anhydride). Several methods have been used, and the theoretical results are compared to the experimental values with the aim to find the best method to predict thermochemical data for similar molecules. The vacuum-UV fragmentation pathways following photoionization are discussed. The results of this work are important with respect to the analytical chemistry of these compounds since their basic gas phase ion energetics data are mostly unknown. They will help in interpreting real-time mass spectrometric measurements used for the study of organic aerosol formation in smog chambers and in the real atmosphere.