PM2.5 exposure contributes to anxiety and depression-like behaviors via phenyl-containing compounds interfering with dopamine receptor.

As a global problem, fine particulate matter (PM2.5) really needs local fixes. Considering the increasing epidemiological relevance to anxiety and depression but inconsistent toxicological results, the most important question is to clarify whether and how PM2.5 causally contributes to these mental disorders and which components are the most dangerous for crucial mitigation in a particular place. In the present study, we chronically subjected male mice to a real-world PM2.5 exposure system throughout the winter heating period in a coal combustion area and revealed that PM2.5 caused anxiety and depression-like behaviors in adults such as restricted activity, diminished exploratory interest, enhanced repetitive stereotypy, and elevated acquired immobility, through behavioral tests including open field, elevated plus maze, marble-burying, and forced swimming tests. Importantly, we found that dopamine signaling was perturbed using mRNA transcriptional profile and bioinformatics analysis, with Drd1 as a potential target. Subsequently, we developed the Drd1 expression-directed multifraction isolating and nontarget identifying framework and identified a total of 209 compounds in PM2.5 organic extracts capable of reducing Drd1 expression. Furthermore, by applying hierarchical characteristic fragment analysis and molecular docking and dynamics simulation, we clarified that phenyl-containing compounds competitively bound to DRD1 and interfered with dopamine signaling, thereby contributing to mental disorders. Taken together, this work provides experimental evidence for researchers and clinicians to identify hazardous factors in PM2.5 and prevent adverse health outcomes and for local governments and municipalities to control source emissions for diminishing specific disease burdens.

Selective Mono-Defluorinative Cross-Coupling of Trifluoromethyl arenes via Multiphoton Photoredox Catalysis.

A new cross-coupling of trifluoromethyl arenes has been realized via multiphoton photoredox catalysis. Trifluoromethyl arenes were demonstrated to undergo selective mono-defluorinative alkylation under mild reaction conditions providing access to a series of valuable α,α-difluorobenzylic compounds. The reaction shows broad substrate scope and general functional group tolerance. In addition to the electron-deficient trifluoromethyl arenes that are easily reduced to the corresponding radical anion, more challenging electron-rich substrates were also successfully applied. Steady-State Stern-Volmer quenching studies indicated that the trifluoromethyl arenes were reduced by the multiphoton excited Ir-based photocatalyst.

Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

Mixed Metal Components in PM2.5 Contribute to Chemokine Receptor CCR5-Mediated Neuroinflammation and Neuropathological Changes in the Mouse Olfactory Bulb.

Particulate matter, especially PM2.5, can invade the central nervous system (CNS) via the olfactory pathway to induce neurotoxicity. The olfactory bulb (OB) is the key component integrating immunoprotection and olfaction processing and is necessarily involved in the relevant CNS health outcomes. Here we show that a microglial chemokine receptor, CCR5, is the target of environmentally relevant PM2.5 in the OB to trigger neuroinflammation and then neuropathological injuries. Mechanistically, PM2.5-induced CCR5 upregulation results in the pro-inflammatory paradigm of microglial activation, which subsequently activates TLR4-NF-κB neuroinflammation signaling and induces neuropathological changes that are closely related to neurodegenerative disorders (e.g., Aß deposition and disruption of the blood-brain barrier). We specifically highlight that manganese and lead in PM2.5 are the main contributors to CCR5-mediated microglial activation and neuroinflammation in synergy with aluminum. Our results uncover a possible pathway of PM2.5-induced neuroinflammation and identify the principal neurotoxic components, which can provide new insight into efficiently diminishing the adverse health effects of PM2.5.

Nontargeted Identification of Organic Components in Fine Particulate Matter Related to Lung Tumor Metastasis Based on an Adverse Outcome Pathway Strategy.

Emerging studies implicate fine particulate matter (PM2.5) and its organic components (OCs) as urgent hazard factors for lung cancer progression in nonsmokers. Establishing the adverse outcome pathway (AOP)-directed nontargeted identification method, this study aimed to explore whether PM2.5 exposure in coal-burning areas promoted lung tumor metastasis and how we identify its effective OCs to support traceability and control of regional PM2.5 pollution. First, we used a nude mouse model of lung cancer for PM2.5 exposure and found that the exposure significantly promoted the hematogenous metastases of A549-Luc cells in lung tissues and the adverse outcomes (AOs), with key events (KEs) including the changed expression of epithelial-mesenchymal transition (EMT) markers, such as suppression of E-cad and increased expression of Fib. Subsequently, using AOs and KEs as adverse outcome directors, we identified a total of 35 candidate chemicals based on the in vitro model and nontargeted analysis. Among them, tributyl phosphate (C12H27O4P), 2-bromotetradecane (C14H29Br), and methyl decanoate (C11H22O2) made greater contributions to the AOs. Finally, we clarified the interactions between these OCs and EMT-activating transcription factors (EMT-ATFs) as the molecular initiation event (MIE) to support the feasibility of the above identification strategy. The present study updates a new framework for identifying tumor metastasis-promoting OCs in PM2.5 and provides solid data for screening out chemicals that need priority control in polluted areas posing higher lung cancer risk.

Group†14 Elements Hetero-Difunctionalizations via Nickel-Catalyzed Electroreductive Cross-Coupling.

The difunctionalization of unsaturated bonds plays a vital role in the enrichment of molecular complexity. While various catalytic methods for alkene and alkyne difunctionalization have been developed in recent years, hetero-functionalization the introduction of two different atoms has been less explored. This is mainly due to the challenges associated with achieving high chemo-, regio-, and stereoselectivity, especially when adding two similar atoms from the same group across unsaturated bonds. In this study, we describe a nickel-catalyzed, three-component reductive protocol for group 14 element hetero-difunctionalization of 1,3-enynes using electrochemistry. This new method is mild, selective, and general, allowing for the silyl-, germanyl-, and stannyl-alkylation of enynes. Various chlorosilanes as well as chlorogermans, and chlorostannanes can be successfully used in combination with aryl/alkyl-substituted 1,3-enynes and primary, secondary, and tertiary alkyl bromides in the electroreductive coupling.

New Insights into Prenatal NO2 Exposure and Behavioral Abnormalities in Male Offspring: Disturbed Serotonin Metabolism and Delayed Oligodendrocyte Development.

Epidemiological studies show that prenatal exposure to nitrogen dioxide (NO2) might cause behavioral abnormalities in childhood. However, toxicological mechanisms for such effects remain unclear, and it is still difficult to define adverse outcome pathways linking exposures to behavioral phenotypes. In this study, by exposing pregnant mice to NO2 (2.5 ppm, 5 h/day) throughout gestation, we provided the first experimental evidence that prenatal NO2 exposure did cause anxiety- and depression-like behaviors in weaning male offspring but not females. Specifically, the behavioral abnormalities were associated with abnormal myelination and the alterations attributed to the delayed oligodendrocyte (OL) development in the fetus and the early stage after birth. The expression of platelet-derived growth factor receptor α (Pdgfr-α) and Olig2 significantly decreased in the NO2 group at E13.5 and E15.5, and the expression of Olig2, adenomatous polyposis coli colon (Cc1), and myelin basic protein (Mbp) was reduced in offspring at PNDs 1, 7, and 21. We performed the targeted metabolomic analysis of neurotransmitters in the placenta and found that prenatal exposure to NO2 disturbed the metabolism of placental neurotransmitters. Serotonin (5-HT) was transferred from the placenta to the fetus at E10.5, and its accumulation in the fetal forebrain might affect oligodendrocyte progenitor cell (OPC) differentiation and OL maturation and eventually be involved in behavioral abnormalities. Our findings provide new insights into the association between prenatal NO2 exposure with anxiety- and depression-like behaviors in male offspring.

Bisphenol A Analogs Induce Cellular Dysfunction in Human Trophoblast Cells in a Thyroid Hormone Receptor-Dependent Manner: In Silico and In Vitro Analyses.

Bisphenol A (BPA) and its analogs are frequently detected in human daily necessities and environmental media. Placental thyroid hormone plays an important role in fetal development. Herein, we followed the adverse outcome pathway (AOP) to explore the toxic mechanisms of BPA and its analogs toward placental thyroid hormone receptor (TR). First, the TOX21 database was used, and the interactions between BPA analogs and the ligand-binding domains (LBDs) of two subtypes of TR (TRα and TRß) were subjected to in silico screening using molecular docking (MD) and molecular dynamics simulation (MDS). Fluorescence spectra and circular dichroism (CD) showed that BPA and its analogs interfere with TRs as a molecular initiation event (MIE), including static fluorescence quenching and secondary structural content changes in TR-LBDs. Key events (KEs) of the AOP, including the toxicity induced in placental chorionic trophoblast cells (HTR-8/SVneo) by an inverted U-shaped dose effect and changes in ROS levels, were tested in vitro. BPA, BPB, and BPAF significantly changed the expression level of TRß, and only BPAF significantly downregulated the expression level of TRα. In conclusion, our study contributes to the health risk assessment of BPA and its analogs regarding placental adverse outcomes (AOs).

Gestational exposure to NO2 aggravates placental senescence.

Placental senescence is a normal physiological process of placenta, while premature placental senescence has been confirmed to be associated with some adverse pregnancy complications. Epidemiological studies indicate that NO2 exposure can aggravate placental senescence which is represented by fibrosis and abnormal telomere homeostasis, etc. In this study, pregnant C57BL/6 mice were exposed to NO2 (2.5 ppm, 5 h/day) daily in a dynamic exposure chamber throughout the gestation period, and were sacrificed at embryonic day 13.5 (E13.5), E15.5 and E18.5. Placenta were harvested and conducted for histopathological examination and telomere evaluation. Our results showed that gestational NO2 exposure significantly aggravated placental fibrosis and calcification, and up-regulated the related bio-markers (connective tissue growth factor (Ctgf) and transforming growth factor-ß1 (Tgf-ß1)) at E18.5. In addition, gestational exposure to NO2 also activated senescence related pathway (p53/p21) at E18.5. Furthermore, gestational NO2 exposure significantly shortened telomere length at E18.5, and the expression of telomere homeostasis regulation genes telomeric repeat binding factor 1 (Trf1), protection of telomeres 1a (Pot1a) and Pot1b were significantly increased while telomerase reverse transcriptase (Tert) was suppressed after NO2 exposure at E13.5 or E18.5, respectively. Importantly, DNA methylation status of the 22nd at E13.5 and 32nd at E18.5 site in sub-telomeric region of chromosome 1 was significantly altered. Based on the above results, our present study indicated that gestational NO2 exposure could lead to premature placental senescence during the late trimester of pregnancy via aggravation of fibrosis and telomere length shortening regulated by telomere regulatory enzyme and DNA methylation.

Maternal NO2 exposure disturbs the long noncoding RNA expression profile in the lungs of offspring in time-series patterns.

Gestation is a sensitive window to nitrogen dioxide (NO2) exposure, which may disturb fetal lung development and lung function later in life. Animal and epidemiological studies indicated that long noncoding RNAs (lncRNAs) participate in abnormal lung development induced by environmental pollutant exposure. In the present study, pregnant C57BL/6J mice were exposed to 2.5 ppm NO2 (mimicking indoor occupational exposure) or clean air, and lncRNAs expression profiles in the lungs of offspring mice were determined by lncRNA-seq on embryonic day 13.5 (E13.5), E18.5, postnatal day 1 (P1), and P14. The lung histopathology examination of offspring was performed, followed by weighted gene coexpression network analysis (WGCNA), prediction of lncRNAs-target genes, and the biological processes enrichment analysis of lncRNAs. Our results indicated that maternal NO2 exposure induced hypoalveolarization on P14 and differentially expressed lncRNAs showed a time-series pattern. Following WGCNA and enrichment analysis, 2 modules participated in development-related pathways. Importantly, the expressions of related genes were altered, some of which were confirmed to be related to abnormal vascular development and even lung diseases. The research points out that the maternal NO2 exposure leads to abnormal lung development in offspring that might be related to altered lncRNAs expression profiles with time-series-pattern.

Reactivity in Nickel-Catalyzed Multi-component Sequential Reductive Cross-Coupling Reactions.

The nickel-catalyzed three-component reductive carbonylation of alkyl halides, aryl halides, and ethyl chloroformate is described. Ethyl chloroformate is utilized as a safe and readily available source of CO in this multi-component protocol, providing an efficient and practical alternative for the synthesis of aryl-alkyl ketones. The reaction exhibits a wide substrate scope and good functional group compatibility. Experimental and DFT mechanistic studies highlight the complexity of the cross-electrophile coupling and provide insight into the sequence of the three consecutive oxidative additions of aryl halide, chloroformate, and alkyl halide.

Reductive Cross-Coupling of α-Oxy Halides Enabled by Thermal Catalysis, Photocatalysis, Electrocatalysis, or Mechanochemistry.

Herein, we report a reductive cross-coupling reaction of α-oxy halides, simply generated from aldehydes, with a series of C(sp2 )- and C(sp)-electrophiles. A wide range of aryl and heteroatom aryl halides, vinyl bromides, alkynyl bromides, and acyl chlorides react with unhindered and hindered aldehyde-derived α-oxy halides by providing protected alcohols as well as α-hydroxy ketones. Noteworthy, the reductive couplings are achieved not only through thermal catalysis with the use of metal reductants but also by photocatalysis, electrochemistry, and mechanochemistry. The unrestricted interchange of the four strategies indicates their underlying mechanistic similarities. The generation of NiI intermediate is proposed to be the key point for ketyl radical formation via a single-electron transfer (SET) event, which was rationalized by an array of control experiments and density functional theory (DFT) calculations.

Maternal PM2.5 exposure and abnormal placental nutrient transport.

Epidemiological studies of human and animal experiments indicated that gestational exposure to atmospheric pollutants could be followed by the abnormal placental development. However, the effects of this exposure on the placental transportation for nutrients have not been systematically investigated. In this study, fine particulate matters (PM2.5) samples were collected in Taiyuan and pregnant rodent models were administered with 3 mg/kg b.w. PM2.5 by oropharyngeal aspiration every other day starting on embryonic day 0.5 (E0.5). Then the pregnant mice were sacrificed and their placentas were collected at different time points. The results showed that maternal PM2.5 exposure (MPE) disrupted the expression of proliferating cell nuclear antigen (PCNA) at all time points and inhibited the cell proliferation in placenta. Following that, the capacity for placental nutrient transport was impaired. The changes at E18.5 were observed most significantly, showing the altered mRNA expression of amino acid, long-chain polyunsaturated fatty acid (LCPUFA), glucose and folate transporters. In addition, the glycogen content was elevated at E18.5, and the triglyceride content was increased at E13.5 and E15.5 and decreased at E18.5 in the placenta after MPE. In a word, the adverse effect induced by MPE revealed that MPE led tothe disruption on the nutrient supply to the developing fetus via modulating the abundance of placental nutrient transporters (PNT).

Nickel-Catalyzed C-Heteroatom Cross-Coupling Reactions under Mild Conditions via Facilitated Reductive Elimination.

The formation of C-heteroatom bonds represents an important type of bond-forming reaction in organic synthesis and often provides a fast and efficient access to privileged structures found in pharmaceuticals, agrochemical and materials. In contrast to conventional Pd- or Cu-catalyzed C-heteroatom cross-couplings under high-temperature conditions, recent advances in homo- and heterogeneous Ni-catalyzed C-heteroatom formations under mild conditions are particularly attractive from the standpoint of sustainability and practicability. The generation of NiIII and excited NiII intermediates facilitate the reductive elimination step to achieve mild cross-couplings. This review provides an overview of the state-of-the-art approaches for mild C-heteroatom bond formations and highlights the developments in photoredox and nickel dual catalysis involving SET and energy transfer processes; photoexcited nickel catalysis; electro and nickel dual catalysis; heterogeneous photoredox and nickel dual catalysis involving graphitic carbon nitride (mpg-CN), metal organic frameworks (MOFs) or semiconductor quantum dots (QDs); as well as more conventional zinc and nickel dual catalyzed reactions.

Mechanistic Insight into the Photoredox-Nickel-HAT Triple Catalyzed Arylation and Alkylation of α-Amino Csp3-H Bonds.

We report here a comprehensive computational analysis of the mechanisms of the photoredox-nickel-HAT (HAT: hydrogen atom transfer) catalyzed arylation and alkylation of α-amino Csp3-H bonds developed by MacMillan and co-workers. Different alternatives for the three catalytic cycles were tested to identify unambiguously the operative reaction mechanism. Our analysis indicated that the IrIII photoredox catalyst, upon irradiation with visible light, can be either reduced or oxidized by the HAT and nickel catalysts, respectively, indicating that both reductive and oxidative quenching catalytic cycles can be operative, although the reductive cycle is favored. Our analysis of the HAT cycle indicated that activation of a α-amino Csp3-H bond of the substrate is facile and selective relative to activation of a ß-amino Csp3-H bond. Finally, our analysis of the nickel cycle indicated that both arylation and alkylation of α-amino Csp3-H bonds occurs via the sequence of nickel oxidation states NiI-NiII-NiI-NiIII and of elementary steps: radical addition-SET-oxidative addition-reductive elimination.

Maternal Exposure to PM2.5 Affects Fetal Lung Development at Sensitive Windows.

Lung development continues from the embryonic period to adulthood. Previous epidemiological studies have noted that maternal exposure of atmospheric pollutants during the sensitive windows disturbed the lung development and increased the risk of lung diseases after birth, but the experimental evidence was insufficient. In the present study, we exposed plug-positive mice to PM2.5 (3 mg/kg b.w.) by oropharyngeal aspiration every other day, and intended to test whether maternal PM2.5 exposure affected prenatal lung development in the offspring. First, maternal PM2.5 exposure decreased embryo weight and crown-rump length at E18.5 but not in earlier developmental stages (E0-E16.5). Second, maternal PM2.5 exposure did not prevent lung-bud and tracheal specification, and did not cause abnormalities in branching morphogenesis, distal lung epithelium, and mesenchyme differentiation in earlier stages of lung development (E0-E16.5). However, the exposure significantly disturbed the distal lung epithelium and mesenchyme differentiation of lung, led to reduced intact rings of trachea, and suppressed the expression of lung development-related genes (Nkx2.1, Tbx4, Tbx5, and Sox9) at E18.5. Finally, we found that the exposure not only increased PM2.5-bound metal content (Pb and Cu) but also caused inflammatory response in the placenta, which transmitted from the mother to the fetus and contributed to the developmental abnormalities.

PM2.5 exposure induces age-dependent hepatic lipid metabolism disorder in female mice.

Particulate matter exposure has been described to elevate the risk of lung and cardiovascular diseases. An increasing number of recent studies have indicated positive correlations between PM2.5 (the fraction of airborne particles with an aerodynamic diameter less than 2.5 µm) exposure and the risk of liver diseases. However, research on the effects of PM2.5 exposure on liver fat synthesis, secretion, and clearance mechanisms under normal diet conditions is limited, and whether these effects are age-dependent is largely unknown. Female C57BL/6 mice at different ages (4 weeks (4 w), 4 months (4 m), and 10 months (10 m)) were treated with 3 mg/kg body weight of PM2.5 every other day for 4 weeks. Subsequently, the ultrastructural changes of liver, the expression of genes involved in oxidative damage and lipid metabolism in the liver were examined. Observation of hepatic ultrastructure showed more and larger lipid droplets in the livers of 4-week-old and 10-month-old mice exposed to PM2.5. Further analysis showed that PM2.5 exposure increased the expression of genes related to lipid synthesis, but decreased the expression of genes involved in lipid transport and catabolism in the livers of 10-month-old mice. Our findings suggest that exposure to PM2.5 disrupts the normal metabolism of liver lipids and induces lipid accumulation in the liver of female mice in an age-dependent manner, with older mice being more susceptible to PM2.5.

Regioselective Hydroalkylation and Arylalkylation of Alkynes by Photoredox/Nickel Dual Catalysis: Application and Mechanism.

Alkynes are an important class of organic molecules due to their utility as versatile building blocks in synthesis. Although efforts have been devoted to the difunctionalization of alkynes, general and practical strategies for the direct hydroalkylation and alkylarylation of terminal alkynes under mild reaction conditions are less explored. Herein, we report a photoredox/nickel dual-catalyzed anti-Markovnikov-type hydroalkylation of terminal alkynes as well as a one-pot arylalkylation of alkynes with alkyl carboxylic acids and aryl bromides via a three-component cross-coupling. The results indicate that the transformations proceed via a new mechanism involving a single-electron transfer with subsequent energy-transfer activation pathways. Moreover, steady-state and time-resolved fluorescence-spectroscopy measurements, density functional theory (DFT) calculations, and wavefunction analysis have been performed to give an insight into the catalytic cycle.

Cascade Cross-Coupling of Dienes: Photoredox and Nickel Dual Catalysis.

Chemical transformations based on cascade reactions have the potential to simplify the preparation of diverse and architecturally complex molecules dramatically. Herein, we disclose an unprecedented and efficient method for the cross-coupling of radical precursors, dienes, and electrophilic coupling partners via a photoredox- and nickel-enabled cascade cross-coupling process. The cascade reaction furnishes a diverse array of saturated carbo- and heterocyclic scaffolds, thus providing access to a quick gain in C-C bond saturation.

Maternal NO2 exposure induces cardiac hypertrophy in male offspring via ROS-HIF-1α transcriptional regulation and aberrant DNA methylation modification of Csx/Nkx2.5.

Maternal exposure to nitrogen dioxide (NO2) poses a risk for morbidity and mortality in infantile congenital heart diseases and even adult cardiovascular diseases. However, the experimental evidence supporting these effects is insufficient, and the related regulatory mechanisms are unknown. In the present study, we aimed to determine whether maternal NO2 exposure causes cardiac hypertrophy-related consequences in offspring, and if so, how these adverse effects occur in the postnatal heart. The results indicate that in mice, maternal NO2 exposure causes cardiac hypertrophy in male offspring. This altered phenotype was accompanied by increased expression of atrial natriuretic peptide, B-type natriuretic peptide, bone morphogenetic protein 10 and ß-myosin heavy chain and elevated activities of cardiomyocyte injury markers, including serum glutamate-oxaloacetate transaminase, lactate dehydrogenase and kinases creatine phosphokinase (CK-MB) in serum. The cardiac-specific transcription factor Csx/Nkx2.5 played an important role in the induction of cardiac hypertrophy and cardiomyocyte injury, and the action was associated with ROS-HIF-1α transcriptional regulation and DNA hypomethylation modification.