6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding.

The emerging toxicant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is of wide concern due to its ubiquitous occurrence and high toxicity. Despite regular human exposure, limited evidence exists about its presence in the body and potential health risks. Herein, we analyzed cerebrospinal fluid (CSF) samples from Parkinson's disease (PD) patients and controls. The CSF levels of 6PPD-Q were twice as high in PD patients compared to controls. Immunostaining assays performed with primary dopaminergic neurons confirm that 6PPD-Q at environmentally relevant concentrations can exacerbate the formation of Lewy neurites induced by α-synuclein preformed fibrils (α-syn PFF). Assessment of cellular respiration reveals a considerable decrease in neuronal spare respiratory and ATP-linked respiration, potentially due to changes in mitochondrial membrane potential. Moreover, 6PPD-Q-induced mitochondrial impairment correlates with an upsurge in mitochondrial reactive oxygen species (mROS), and Mito-TEMPO-driven scavenging of mROS can lessen the amount of pathologic phospho-serine 129 α-synuclein. Untargeted metabolomics provides supporting evidence for the connection between 6PPD-Q exposure and changes in neuronal metabolite profiles. In-depth targeted metabolomics further unveils an overall reduction in glycolysis metabolite pool and fluctuations in the quantity of TCA cycle intermediates. Given its potentially harmful attributes, the presence of 6PPD-Q in human brain could potentially be a risk factor for PD.

Stable isotope-assisted mass spectrometry reveals in vivo distribution, metabolism, and excretion of tire rubber-derived 6PPD-quinone in mice.

6PPD-quinone (6PPD-Q) has been identified as a ubiquitous contaminant in the surrounding locality, including air particles, roadside soils, dust, and water. Recently, the prevalence of 6PPD-Q in human urine has accentuated the urgency for investigating its biological fate. To address this, we conducted a stable isotope-assisted high-resolution mass spectrometry (HRMS) assay to unveil the distribution, metabolism, excretion, and toxicokinetic properties of this contaminant in a mouse model. Mice were fed with a single dose of deuterated 6PPD-Q-d5 at human-relevant exposure levels. Results indicated that 6PPD-Q was quickly assimilated and distributed into bloodstream and main organs of mice, with the concentrations reaching peaks under 1 h following administration. Notably, 6PPD-Q was primarily distributed in the adipose tissue, marked by a significant Cmax (p < 0.05), followed by the kidney, lung, testis, liver, spleen, heart, and muscle. In addition, our measurement demonstrated that 6PPD-Q can penetrate the blood-brain barrier of mice within 0.5 h after exposure. The half-lives (t1/2) of 6PPD-Q in serum, lung, kidney, and spleen of mice were measured at 12.7 ± 0.3 h, 20.7 ± 1.4 h, 21.6 ± 5.3 h, and 20.6 ± 2.8 h, respectively. Using HRMS combined with isotope tracing techniques, two novel hydroxylated metabolites of 6PPD-Q in the mice liver were identified for the first time, which provides new insights into its rapid elimination in-vivo. Meanwhile, fecal excretion was identified as the main excretory pathway for 6PPD-Q and its hydroxylated metabolites. Collectively, our findings extend the current knowledge on the biological fate and exposure status of 6PPD-Q in a mouse model, which has the potential to be extrapolated to humans.

Recent applications of mass spectrometry in the analysis of transformation products of emerging contaminants in PM2.5.

Ambient pollution correlated to fine particulate matter (PM2.5) is a worldwide environmental issue as it is highly associated with human health and eco-environmental safety. A significant part regarding the toxicity of PM2.5 is attributed to its bonded contaminants. Appreciable efforts have been performed to study the occurrence, exposure, and toxicological properties of chemicals of emerging concerns in PM2.5. Recent works indicated a broad environmental transformation of emerging contaminants in the atmospheric environment and highlighted the significance of PM2.5 bonded transformation products, which may exhibit higher environmental concentrations and toxicities compared to their parent compounds. Among these studies, mass spectrometry has been widely applied for the analysis of transformation products of emerging contaminants in PM2.5 on the aspects of suspect/non-target screening, structure elucidation, concentration profiling, and toxicity determination. This review describes key mass spectrometry-based analytical strategies and applications for determining transformation products in PM2.5 and presents outlooks for their analysis.

Mass spectrometric determination of N7-HPTE-dG and N7-HPTE-Gua in mammalian cells and mice exposed to methoxychlor, an emergent persistent organic pollutant.

Methoxychlor (MXC) is an organopesticide classified as a "Proposed Persistent Organic Pollutant" in the Stockholm Convention, and recent studies revealed that MXC could induce DNA strand breaks, whereas its underlying mechanisms were underinvestigated. Here, we first reported that hydroxymethoxychlor (HPTE), one of MXC's active metabolites, could be oxidized in vivo to form quinone intermediate, which attacked N7 position of 2'-deoxyguanosine to form N7-HPTE-deoxyguanosine (N7-HPTE-dG), followed by depurination to produce N7-HPTE-guanine (N7-HPTE-Gua) in MXC-treated mammalian cells and tissues from mice fed with MXC, employing an ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method. We observed a positive correlation between the doses of MXC exposure and the levels of N7-HPTE-Gua and N7-HPTE-dG in cytoplasm and genomic DNA, respectively. Furthermore, after removal of exogenous MXC, the amount of genomic N7-HPTE-dG was significantly decreased during 24 h, while the level of cytoplasmic N7-HPTE-Gua was elevated during first 12 h, indicating the accumulation of the N7-HPTE-Gua in cells. Additionally, for animal experiment, genomic N7-HPTE-dG was observed in livers and cortexes from female C57BL/6 mice fed with MXC, suggesting a potential mechanism of its hepatoxicity and neurotoxicity. Overall, our study provides new understanding about the formation of MXC-induced DNA adducts in mammalian cells and animal models.

Metabolic and Lipid Alterations in Mice Brain Cortex after PM2.5 Exposure.

Fine particulate matter (PM2.5) has been reported to be associated with neurological disorders. However, the effects of PM2.5 on changes in metabolic and lipid profile of the brain are unclear. In this study, global metabolomics and lipidomics in mice cortex were investigated from the analyses by ultraperformance liquid chromatography-Orbitrap mass spectrometry. The partial least-squares discriminant analysis showed that the metabolite and lipid profiles were significantly altered by PM2.5 exposure. The changed metabolic pathways including alanine, aspartate, and glutamate metabolism, carnitine metabolism, and glycerophospholipid remodeling pathway were found to be associated with a neurodegenerative process according to their corresponding molecular mechanisms. Our results indicated that PM2.5 exposure could induce neurological damage.

Correction: Wang, F., et al. Effect of Low-Frequency Electromagnetic Casting on Micro-Structure and Macro-Segregation of 5A90 Alloy Ingots. Materials 2020, 13, 2720.

In the original article [...].

Effect of Low-Frequency Electromagnetic Casting on Micro-Structure and Macro-Segregation of 5A90 Alloy Ingots.

The effect of low-frequency electromagnetic fields on the micro-structure and macro-segregation of 5A90 alloy ingots during the semi-continuous casting process were quantitatively investigated. The ingots of a 5A90 alloy with a diameter 170 mm were produced by the conventional direct chill casting (DCC) process and low-frequency electromagnetic casting (LFEC) with 10 Hz/100 A. The results showed that LFEC can substantially refine the micro-structure and shorten the width of the columnar grain area of an ingot. The refinement effect came with the relieving of grain boundary segregation and an improvement in the macro-segregation of the ingot. Compared with the traditional DCC process, the tensile properties of the aged alloy prepared by the LFEC process were improved due to the effects of the increase in solid solubility and the strengthening of the grain refinement, so that the stability of the tensile properties was also improved. Meanwhile, the rate of yield increased by 2.3% with a decrease in the peeling thickness of the ingot.

Deep learning applications in automatic needle segmentation in ultrasound-guided prostate brachytherapy.

PURPOSE: High-Dose-Rate (HDR) brachytherapy is one of the most effective ways to treat the prostate cancer, which is the second most common cancer in men worldwide. This treatment delivers highly conformal dose through the transperineal needle implants and is guided by a real time ultrasound (US) imaging system. Currently, the brachytherapy needles in the US images are manually segmented by physicists during the treatment, which is time consuming and error prone. In this study, we propose a set of deep learning-based algorithms to accurately segment the brachytherapy needles and locate the needle tips from the US images. METHODS: Two deep neural networks are developed to address this problem. First, a modified deep U-Net is used to segment the pixels belonging to the brachytherapy needles from the US images. Second, an additional VGG-16-based deep convolutional network is combined with the segmentation network to predict the locations of the needle tips. The networks are trained and evaluated on a clinical US images dataset with labeled needle trajectories collected in our hospital (Institutional Review Board approval (IRB 41755)). RESULTS: The evaluation results show that our method can accurately extract the trajectories of the needles with a resolution of 0.668 mm and 0.319 mm in x and y direction, respectively. 95.4% of the x direction and 99.2% of the y direction have error ≤ 2 mm. Moreover, the position resolutions of the tips are 0.721, 0.369, and 1.877 mm in x, y, and z directions, respectively, while 94.2%, 98.3%, and 67.5% of the data have error ≤ 2 mm. CONCLUSIONS: This paper proposed a neural network-based algorithm to segment the brachytherapy needles from the US images and locate the needle tip. It can be used in the HDR brachytherapy to help improve the efficiency and quality of the treatments.