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PM 2.5 is a complex mixture, with water-soluble inorganic ions (WSII), mainly NH 4 +, SO 4 2−, and NO 3 −, constituting major components. Early-life PM 2.5 exposure has been shown to induce adverse health consequence but it is difficult to determine whether such an effect occurs prenatally (preconception, gestational) or postnatally in human studies. Four groups of C57BL/6 J mice were assigned to four exposure conditions: PM 2.5 NO 3 −, PM 2.5 SO 4 2−, PM 2.5 NH 4 + and clean air, and exposure started at 4 weeks old. At 8 weeks old, mice bred within group. The exposure continued during gestation. After delivery, both the maternal and F 1 mice (offspring) were kept in clean air without exposure to PM 2.5. Respiratory function and pulmonary pathology were assessed in offspring mice at 8 weeks of age. In parallel, placenta tissue was collected for transcriptome profiling and mechanistic investigation. F 1 mice in PM 2.5 NH 4 +, SO 4 2- and NO 3 − groups had 32.2 % (p=6.0e-10), 30.3 % (p=3.8e-10) and 16.9 % (p=5.7e-8) lower peak expiratory flow (PEF) than the clean air group. Importantly, the exposure-induced lung function decline was greater in male than female offspring. Moreover, exposure to PM 2.5 WSII before conception and during gestation was linked to increased airway wall thickness and elevated pulmonary neutrophil and macrophage counts in the offspring mice. At the molecular level, the exposure significantly disrupted gene expression in the placenta, affecting crucial functional pathways related to sex hormone response and inflammation. PM 2.5 WSII exposure during preconception and gestational period alone without post-natal exposure substantially impacted offspring's respiratory function as measured at adolescent age. Our results support the paradigm of fetal origin of environmentally associated chronic lung disease and highlight sex differences in susceptibility to air pollution exposure. • Prenatal PM 2.5 exposure impaired lung function in offspring mice even without postnatal pollution exposure. • Prenatal PM 2.5 exposure also led to airway remodeling in offspring mice when reached adulthood. • Dysregulation of the reproductive organs and placenta may mechanistically explain the air pollution induced developmental origins of respiratory functions impairment. [ABSTRACT FROM AUTHOR]

Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co‐expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short‐chain acylcarnitines/amino acids and medium/long‐chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP‐AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co‐expression network analysis of the AMP‐AD brain RNA‐seq data suggests the CPT1A‐ and ABCA1‐centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short‐chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large‐scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background Air pollution is a leading cause of global disease burden. Lack of suitable methods for long term measuring exposure level at individual level is crippling environmental epidemiology research of air pollution. Methods We report an integrative system, Bio3Air, for long term measurement of individual level air pollution exposure, currently focusing on ambient particulate matter (PM). The novel system in real-time quantifies individual's outdoor/indoor status, geological location, lung ventilation rate and PM concentration of individual's surrounding environment, and these metrics are subsequently incorporated in calculating PM exposure. Results The system is fully developed and tested in China, USA and Canada, and has been successfully applied in epidemiology study. Bio3Air offers high reliability, sensitivity, reproducibility (>99%) and accuracy. It has high time- and spatial- resolution (≤ 2 min and ≤ 20 m, respectively). Bio3Air achieved 91.89% consistency with "gold-standard" method (membrane collection and off-line analysis). Conclusions Bio3Air represents a substantial methodological advance in environmental health research of air pollution. It captures information relevant in measuring individual's PM exposure (e.g. real-time outdoor/indoor status, location and lung ventilation rate). Such information is typically missed by conventional approaches. Additional features of Bio3Air include easy-to-use, cost-effectiveness and automated data collection, making it a powerful tool facilitating studies of air pollution exposure and health consequences. Highlights • We developed a novel system, Bio3Air, for long-term measure of particulate matter (PM) exposure at individual level. • The system demonstrated high time- and spatial-resolution, data reproducibility and accuracy in quantifying PM exposure. • Bio3Air is potentially useful tool facilitating studies on air pollutant exposure and health consequences. [ABSTRACT FROM AUTHOR]

Abstract Background Ambient particulate matter (PM) exposure has been associated with respiratory function decline in epidemiological studies. We hypothesize that a possible underlying mechanism is the perturbation of airway microbiome by PM exposure. Methods During October 2016–October 2017, on two human cohorts (n = 115 in total) in Shanghai China, we systematically collected three categories of data: (1) respiratory functions, (2) airway microbiome from sputum, and (3) PM 2.5 (PM of ≤ 2.5 µm in diameter) level in ambient air. We investigated the impact of PM 2.5 on airway microbiome as well as the link between airway microbiome and respiratory functions using linear mixed regression models. Results The respiratory function of our primary interest includes forced vital capacity (FVC) and forced expiratory volume in 1st second (FEV 1). FEV 1 /FVC, an important respiratory function trait and key diagnosis criterion of COPD, was significantly associated with airway bacteria load (p = 0.0038); and FEV 1 was associated with airway microbiome profile (p = 0.013). Further, airway microbiome was significantly influenced by PM 2.5 exposure (p = 4.48E-11). Conclusions To our knowledge, for the first time, we demonstrated the impact of PM 2.5 on airway microbiome, and reported the link between airway microbiome and respiratory functions. The results expand our understanding on the scope of PM 2.5 exposure's influence on human respiratory system, and point to novel etiological mechanism of PM 2.5 exposure induced diseases. Highlights • On human cohorts, we demonstrate the impact of PM 2.5 exposure on respiratory tract microbiome. • The strongest impact is attributed to exposure occurred ≥6 days prior to microbiome collection. • This study reports the link between airway microbiome and human respiratory functions. [ABSTRACT FROM AUTHOR]

Electronic cigarette (e-cig) use is increasing worldwide, especially among young individuals. Spirometry measures airflow obstruction and is the primary tool for diagnosing/monitoring respiratory diseases in clinical settings. This study aims to assess the effects of chronic e-cig exposure on spirometric traits, and directly compare to conventional combustible-cigarette (c-cig). We employed an e- and c-cig aerosol generation system that resembled human smoking/vaping scenario. Fifty 6-week old C57BL/6 mice were equally divided into five groups and exposed to clean air (control), e-cig aerosol (low- and high-dose), and c-cig aerosol (low- and high-dose), respectively, for 10 weeks. Afterwards, growth trajectory, spirometry and pulmonary pathology were analyzed. Both e- and c-cig exposure slowed down growth and weight gain. Low dose e-cig exposure (1 h exposure per day) resulted in minimal respiratory function damage. At high dose (2 h exposure per day), e-cig exposure deteriorated 7 spirometry traits but by a smaller magnitude than c-cig exposure. For example, comparing to clean air controls, high dose e- and c-cig exposure increased inspiratory resistance by 24.3% (p = 0.026) and 66.7% (p = 2.6e-5), respectively. Low-dose e-cig exposure increased alveolar macrophage count but did not lead to airway remodeling. In contrast, even low-dose c-cig caused alveoli break down and thickening of the small airway, hallmarks of airway obstructive disease. We conducted well-controlled animal exposure experiments assessing chronic e-cig exposure's effects on spirometry traits. Further, mechanistic study characterized airway remodeling, alveolar tissue lesion and inflammation induced by e- and c-cig exposure. Our findings provided scientific and public health insights on e-cig's health consequences, especially in adolescent users. • Health impacts of electronic and combustible cigarette (e-cig and c-cig) were studied. • Low dose e-cig exposure resulted in minimal respiratory function decline in mice. • High dose e-cig exposure induced airflow obstruction, but less severe than c-cig. • E-cig induced COPD-like airway remodeling, but less severe than c-cig. • C-cig caused alveolar oxidative lesion, while e-cig had no effect. [ABSTRACT FROM AUTHOR]

Nitrate is a major pollutant component in ambient PM 2.5. It is known that chronic exposure to PM 2.5 NO 3 − damages respiratory functions. We aim to explore the underlying toxicological mechanism at single cell resolution. We systematically conducted exposure experiments on forty C57BL/6 mice, assessed respiratory functions, and profiled lung transcriptome.. Afterward, we estimated the cell type compositions from RNA-seq data using deconvolution analysis. The genes and pathways associated with respiratory function and dysregulated by to PM 2.5 NO 3 − exposure were characterized at bulk-tissue and single-cell resolution. PM 2.5 NO 3 − exposure did not significantly modify the cell type composition in lung, but profoundly altered the gene expression within each cell type. At ambient concentration (22 μg/m3), exposure significantly (FDR<10%) altered 95 genes' expression. Among the genes associated with respiratory functions, a large fraction (74.6–91.7%) were significantly perturbed by PM 2.5 NO 3 − exposure. For example, among the 764 genes associated with peak expiratory flow (PEF), 608 (79.6%) were affected by exposure (p = 1.92e-345). Pathways known to play role in lung disease pathogenesis, including circadian rhythms, sphingolipid metabolism, immune response and lysosome, were found significantly associated with respiratory functions and disrupted by PM 2.5 NO 3 − exposure. This study extended our knowledge of PM 2.5 NO 3 − exposure's effect to the levels of lung gene expression, pathways, lung cell type composition and cell specific transcriptome. At single cell resolution, we provided insights in toxicological mechanism of PM 2.5 NO 3 − exposure and subsequent pulmonary disease risks. [Display omitted] • We conducted the first single cell RNA-sequencing study on PM 2.5 exposure's health effect. • PM 2.5 NO 3 − exposure did not modify the cell type composition in lung, but dysregulated within-cell gene expression. • Even at ambient concentration (22mg/m3), PM 2.5 NO 3 − exposure produced profound consequences. • Circadian rhythms, lysosome and response to stimulus were associated with respiratory functions and disrupted by exposure. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Method: We used an integrative genomic approach to determine the epigenomic annotations enriched for AD risk variants and applied a summary‐data based Mendelian Randomization to link myeloid enhancer activity to target gene expression regulation and AD risk modification. Result: We show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia, nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the MS4A locus we identified a single candidate functional variant within an CTCF binding site, that is predicted to alter chromatin looping and MS4A gene expression. We used human induced pluripotent stem cells (hiPSC)‐derived microglia to provide experimental validation of this putative causal variant. Conclusion: Combined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Earlier pathway analyses have implicated lipid metabolism, immune response and endocytosis. Method: We used LDscore regression to determine the epigenomic annotations enriched for AD risk variants. We then integrated AD GWAS signals with epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. Result: We show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia. Using summary‐data based Mendelian Randomization nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the APOE locus we used genome editing to generate isogenic human induced pluripotent stem cells (hiPSC) combined with transcriptomics to demonstrate dyshomeostasis of lipid metabolism in APOE44 glial cells from. Conclusion: Combined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD. [ABSTRACT FROM AUTHOR]

Impaired in utero fetal growth trajectory may have long term health consequences of the newborns and increase risk of adulthood metabolic diseases. Prenatal exposure to air pollution has been linked to fetal development restriction; however, the impact of exposure to ambient air pollutants on the entire course of intrauterine fetal development has not been comprehensively investigated. During 2015–2018, two cohorts of mother-infant dyads (N = 678 and 227) were recruited in Shanghai China, from which three categories of data were systematically collected: (1) daily exposure to six air pollutants during pregnancy, (2) fetal biometry in the 2nd (gestational week 24, [GW24]) and 3rd trimester (GW36), and (3) neonatal outcomes at birth. We investigated the impact of prenatal exposure to air pollutant mixture on the trajectory of fetal development during the course of gestation, adjusting for a broad set of potential confounds. Prenatal exposure to PM 2.5 , PM 10 , SO 2 and O 3 significantly reduced fetal biometry at GW24, where SO 2 had the most potent effect. For every 10 μg/m3 increment increase of daily SO 2 exposure during the 1st trimester shortened femur length by 2.20 mm (p = 6.7E-21) translating to 5.3% reduction from the average of the study cohort. Prenatal air pollution exposure also decreased fetal biometry at GW36 with attenuated effect size. Comparing to the lowest exposed quartile, fetus in the highest exposed quartile had 6.3% (p = 3.5E-5) and 2.1% (p = 2.4E-3) lower estimated intrauterine weight in GW24 and GW36, respectively; however, no difference in birth weight was observed, indicating a rapid catch-up growth in the 3rd trimester. To our knowledge, for the first time, we demonstrated the impact of prenatal exposure to ambient air pollutants on the course of intrauterine fetal development. The altered growth trajectory and rapid catch-up growth in associated with high prenatal exposure may lead to long-term predisposition for adulthood metabolic disorders. Image 1 • Impaired in utero fetal growth trajectory may have long term health consequences. • Two cohorts were recruited to study prenatal exposure to air pollution on the course of intrauterine fetal development. • Prenatal exposure to PM 2.5 , PM 10 , SO 2 and O 3 significantly reduced fetal biometry at gestational week 24. • Prenatal exposure causes growth restriction in the 2nd gestational trimester, and rapid catch-up grow in the 3rd trimester. • The air pollution induced growth restriction is asymmetric, disproportionally affecting the trunk development. [ABSTRACT FROM AUTHOR]