PAH
Phenylalanine-4-hydroxylase (EC 1.14.16.1) (PAH) (Phe-4-monooxygenase)
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Further knowledge on modifiable aging risk factors is required to mitigate the increasing burden of age-related diseases in a rapidly growing global demographic of elderly individuals. We explored the effect of everyday exposure to polycyclic aromatic hydrocarbons (PAHs), which are fundamental constituents of air pollution, on cellular biological aging. This was determined via the analysis of leukocyte telomere length (LTL), mitochondrial DNA copy number (LmtDNAcn), and by the formation of anti-benzo[a]pyrene diolepoxide (B[a]PDE-DNA) adducts. The study population consisted of 585 individuals living in North-East Italy. PAH exposure (diet, indoor activities, outdoor activities, traffic, and residential exposure) and smoking behavior were assessed by questionnaire and anti-B[a]PDE-DNA by high-performance-liquid-chromatography. LTL, LmtDNAcn and genetic polymorphisms [glutathione S-transferase M1 and T1 (GSTM1; GSTT1)] were measured by polymerase chain reaction. Structural equation modelling analysis evaluated these complex relationships. Anti-B[a]PDE-DNA enhanced with PAH exposure (p = 0.005) and active smoking (p = 0.0001), whereas decreased with detoxifying GSTM1 (p = 0.021) and in females (p = 0.0001). Subsequently, LTL and LmtDNAcn reduced with anti-B[a]PDE-DNA (p = 0.028 and p = 0.018), particularly in males (p = 0.006 and p = 0.0001). Only LTL shortened with age (p = 0.001) while elongated with active smoking (p = 0.0001). Besides this, the most significant determinants of PAH exposure that raised anti-B[a]PDE-DNA were indoor and diet (p = 0.0001), the least was outdoor (p = 0.003). New findings stemming from our study suggest that certain preventable everyday life exposures to PAHs reduce LTL and LmtDNAcn. In particular, the clear association with indoor activities, diet, and gender opens new perspectives for tailored preventive measures in age-related diseases. Everyday life exposure to polycyclic aromatic hydrocarbons reduces leukocyte telomere length and mitochondrial DNA copy number through anti-B[a]PDE-DNA adduct formation.
Keywords
- Biological aging
- DNA adduct
- Mitochondrial DNA copy number
- Polycyclic aromatic hydrocarbon
- Structural equation modelling
- Telomere length
Light absorption by brown carbon (BrC) is dynamic due to atmospheric aging processes, leading to complex and poorly constrained effects on photochemistry and climate. In this study, a smog chamber was used to simulate the heterogeneous ozone (O ) aging of soot particles. Twelve aging times and seven O concentrations were set to investigate the effects of aging degree on BrC light absorption. The results showed that light absorption by BrC was enhanced after O aging, but followed a non-monotonic trend with an initial increase and subsequent decrease. An aging time of 60 min and O concentration of 1.2 ppm were optimal for enhancing BrC absorption, where the contribution of BrC to total absorption and the contribution of BrC relative to black carbon absorption at 370 nm of ozonized soot were 23.0 ± 1.8% and 30.0 ± 3.0%, respectively, much greater than those of fresh soot (8.1 ± 1.1% and 8.8 ± 1.3%, respectively). The absorption Ångström exponent (AAE) and delta C (ΔC) of ozonized soot at 60 min ranged from 1.18 ± 0.01 to 1.31 ± 0.03 and from 13.5 ± 7.0 to 24.3 ± 13.5 μg m , respectively, and were greater than those of fresh soot (1.12 ± 0.02 and 8.0 ± 0.8 μg m ), but also showed non-monotonic trends, suggesting the formation of BrC during O aging. Comparative results indicated that AAE might be a better BrC indicator for soot than ΔC. The non-monotonic trend was tentatively explained by changes in organic carbon, oxygenated functional groups and conjugated structures, as well as polycyclic aromatic hydrocarbon (PAH) degradation and oxygenated PAH formation. The relative intensities of oxidative formation and degradation of chromophores may determine BrC evolution during O aging. This study will be useful for clarifying BrC evolution in the atmosphere and estimating its radiative forcing.
MeSH Terms
- Aerosols
- Biomass
- Carbon
- Ozone
- Smog
- Soot
Keywords
- Absorption Ångström exponent
- Brown carbon
- Light absorption
- Ozone aging
- Soot particles
Pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is a lethal complication affecting 8-15% of patients. Screening tests such as echocardiography and pulmonary function tests allow for triaging patients for diagnosis by right heart catheterization. Understanding risk factors of SSc-PAH could help differentiate high-risk patients. A systematic review was conducted to determine associations with SSc-PAH, including clinical/disease characteristics, antibodies, labs and biomarkers. The frequencies of publications featuring each risk/association were reported. Among 2654 articles, 984 duplicates and 1578 irrelevant articles were removed, leaving 92 articles for manual screening. After excluding 55 papers with small sample sizes, publications from identical cohorts, not English language, or PAH not ascertained by RHC, 37 articles were eligible. A total of 43 factors for SSc-PAH were identified within seven categories. Several associations were due to PAH and risk factors such as dynpnea, right heart failure, and short 6-minute walk distance. Patient characteristics (14), pulmonary physiology (6), antibody profiles (6) and genetics/epigenetics (6) had the most numerous and diverse factors, while biomarkers (4) and other labs (2) features were infrequent. Low carbon monoxide (DLCO) (6), older age (4), longer disease duration (4), positive anticentromere antibodies (ACA) (4), telangiectasias (4), high brain natriuretic peptide (4) were frequent associations. Risk factors for SSc-PAH such as ACA, older age, longer disease duration limited cutaneous SSc subset and presence of ILD may enrich screening programs. Genes and other antibody profiles are inconsistent and requires further validation.
MeSH Terms
- Aging
- Humans
- Natriuretic Peptide, Brain
- Pulmonary Arterial Hypertension
- Risk Factors
- Scleroderma, Systemic
This study investigated the differences in the risk of potentially avoidable hospitalization (PAH) among eligible long-term care insurance (LTCI) beneficiaries with dementia for LTCI services in Korea. Nested case-control study was conducted using the National Health Insurance Service-Senior claim database. Cases of individuals who had a PAH incident diagnosis and controls were selected by incidence density sampling and matched to cases based on age, sex, and difficulty of daily living among dementia patients. We conducted incidence density sampling three times by PAH type. Our main results were presented by conditional logistic regression analysis for the matched case-control studies. Out of the 7,352 eligible LTCI beneficiary patients, there were 1,231 cases (16.7%) in overall PAH, 132 cases (19.0%) in acute PAH and 1,114 cases (16.7%) in chronic PAH categories. In terms of individual risk of overall and chronic PAH, the odds ratios of those who did not receive any services were 1.336 time higher (95% confidence interval [CI], 1.159-1.540) and 1.280 time higher (95% CI, 1.103-1.485) compared to those who received home care, respectively. For risk of acute PAH, the odds ratios of those who did receive institutional care were 2.046 time higher (95% CI, 1.170-3.578) compared to those who received home care. This study identified the differences in risk of PAH incidents according to the type of LTCI service in the elderly population in Korea. Therefore, it will require substantial effort and strategy from health policy makers to improve care quality.
Keywords
- Aging
- Dementia
- Long-Term Care
Atmospheric polycyclic aromatic hydrocarbons (PAHs) disproportionately affect human health across the globe, and differential exposure is believed to drive the unequal health burden. Therefore, this study assessed and compared the burden of disease, in disability-adjusted life years (DALYs), at the same level (or limit) of exposure to atmospheric PAHs in nine countries. We calculated the DALYs per person-year per ng/m of benzo[a]pyrene from ten cancers and thirty-four non-cancer adverse outcomes using published toxicity information and country-specific disease severity. Exposure duration was averaged over 30 years and we adjusted for early-life vulnerability to cancer. The DALYs per person-year per ng/m of fifteen other individual PAHs was calculated using relative potency factors, and toxicity factors derived from quantitative structure-activity relationships. We found that even at the same level of exposure to PAHs, the incremental burdens of disease varied substantially across countries. For instance, they varied by about 2-3 folds between Nigeria and the USA. Countries having the lowest longevity had the highest DALYs per person-year per ng/m of each PAH. Kruskal-Wallis test (α = 0.05) showed that the variation across countries was significant. The post hoc tests detected a significant difference between two countries when the gap in longevity was >10 years. This suggests that countries having very low average life expectancy require more stringent PAH limit. Linear or exponential function of average longevity gave valid approximation of the DALYs per person-year per ng/m of benzo[a]pyrene or phenanthrene, respectively. Furthermore, we used global gridded surface benzo[a]pyrene concentrations and global population dataset for 2007, with spatial resolution of 0.1° × 0.1°, to calculate the contribution of differential exposures to the estimated DALYs per person-year. We found that in six out of nine countries, differential exposures to PAH contribute less to the estimated health loss than differential severities of the diseases. This indicates that the risk to health from PAHs may be underreported if the severities of the diseases in the countries are not considered.
MeSH Terms
- Air Pollutants
- Benzo(a)pyrene
- Cost of Illness
- Environmental Exposure
- Humans
- Life Expectancy
- Longevity
- Neoplasms
- Nigeria
- Polycyclic Aromatic Hydrocarbons
- Quality-Adjusted Life Years
- Socioeconomic Factors
- United States
Keywords
- Cumulative risk assessment
- Disability-adjusted life years (DALYs)
- Quantitative structure-activity relationships (QSAR)
- Relative toxicity factor (RTF)
- Susceptibility
- Vulnerability
Cellular senescence is recognized as a crucial contributor to the pathobiology of various degenerative and cardiovascular diseases, such as idiopathic pulmonary fibrosis and atherosclerosis. We describe the potential link between cellular senescence and the degenerative character of neointimal pulmonary vascular disease in pulmonary arterial hypertension (PAH). Senescence markers have been described in remodeled pulmonary arteries, and PAH and senescence share common triggers and pathogenic pathways, such as transforming growth factor-β/bone morphogenetic protein and TNF-α. In addition, interventions that target a senescence phenotype also target pulmonary vascular remodeling [i]in vivo[/i]. These data provide a basis for further exploration of the role of senescence in the pathobiology of PAH and for preclinical trials with a senolytic class of drugs.
MeSH Terms
- Aging
- Animals
- Cellular Senescence
- Humans
- Janus Kinases
- Lung
- Pulmonary Arterial Hypertension
- STAT Transcription Factors
- Signal Transduction
Keywords
- cellular senescence
- pulmonary arterial hypertension
- senescence-associated secretory phenotype
- senolysis
- vascular remodeling
Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC of 0.6 µg/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC of 20 nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC of only 4.4 µM, a semisynthetic pyrazole-derivative P5b, has ∼10-fold improved potency (IC , 0.49 μM). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G -G phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents.
MeSH Terms
- Antineoplastic Agents
- Benzopyrans
- Breast Neoplasms
- Cell Cycle
- Cell Proliferation
- Cellular Senescence
- Cytochrome P-450 CYP1A1
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Female
- Flavones
- Flow Cytometry
- Furans
- HEK293 Cells
- Humans
- MCF-7 Cells
- Models, Molecular
- Molecular Structure
- Structure-Activity Relationship
Keywords
- CYP1A1
- Cell cycle
- Furanoflavones
- Lanceolatin B
- Pongapin
- Senescence
Aging is related to an increased risk of morbidity and mortality and is affected by environmental factors. Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health outcomes; but the association of such exposure with DNA methylation aging, a novel aging marker, is unclear. Our aim was to investigate the association of PAH exposure with methylation aging. We trained and validated a methylation age predictor suitable for Chinese populations using whole blood methylation data in 989 Chinese and 160 Caucasians. We defined two aging indicators: δage, as methylation age minus chronological age; and aging rate, the ratio of methylation to chronological age. The association of PAH exposure with aging indicators was evaluated using linear regressions in three panels of healthy Chinese participants ([i]N[/i]=539, among the aforementioned 989 Chinese participants) whose exposure levels were assessed by 10 urinary monohydroxy-PAH metabolites. We developed a methylation age predictor providing accurate predictions in both Chinese individuals and Caucasian persons (R=0.94-0.96, RMSE=3.8-4.3). Among the 10 urinary metabolites that we measured, 1-hydroxypyrene and 9-hydroxyphenanthrene were associated with methylation aging independently of other OH-PAHs and risk factors; 1-unit increase in 1-hydroxypyrene was associated with a 0.53-y increase in Δage [95% confidence interval (CI): 0.18, 0.88; false discovery rate (FDR) [i]FDR[/i]=0.004] and 1.17% increase in aging rate (95% CI: 0.36, 1.98; [i]FDR[/i]=0.02), whereas for 9-hydroxyphenanthrene, the increase was 0.54-y for Δage (95% CI: 0.17, 0.91; [i]FDR[/i]=0.004), and 1.15% for aging rate (95% CI: 0.31, 1.99; [i]FDR[/i]=0.02). The association direction was consistent across the three Chinese panels with the association magnitude correlating with the panels' exposure levels; the association was validated by methylation data of purified leukocytes. Several cytosine-phosphoguanines, including those located on [i]FHL2[/i] and [i]ELOVL2[/i], were found associated with both aging indicators and monohydroxy-PAH levels. We developed a methylation age predictor specific for Chinese populations but also accurate for Caucasian populations. Our findings suggest that exposure to PAHs may be associated with an adverse impact on human aging and epigenetic alterations in Chinese populations. https://doi.org/10.1289/EHP2773.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- China
- DNA Methylation
- Environmental Exposure
- Epigenesis, Genetic
- European Continental Ancestry Group
- Female
- Humans
- Male
- Middle Aged
- Occupational Exposure
- Phenanthrenes
- Polycyclic Aromatic Hydrocarbons
- Pyrenes
Approximately 5%-10% of adults with congenital heart disease (CHD) develop pulmonary arterial hypertension (PAH), which affects life expectancy and quality of life. Arrhythmias are common among these patients, but their incidence and impact on outcome remains uncertain. All adult patients with PAH associated with CHD (PAH-CHD) seen in a tertiary centre between 2007 and 2015 were followed for new-onset atrial or ventricular arrhythmia. Clinical variables associated with arrhythmia and their relation to mortality were assessed using Cox analysis. A total of 310 patients (mean age 34.9±12.3 years, 36.8% male) were enrolled. The majority had Eisenmenger syndrome (58.4%), 15.2% had a prior defect repair and a third had Down syndrome. At baseline, 14.2% had a prior history of arrhythmia, mostly supraventricular arrhythmia (86.4%). During a median follow-up of 6.1 years, 64 patients developed at least one new arrhythmic episode (incidence 3.47% per year), mostly supraventricular tachycardia or atrial fibrillation (78.1% of patients). Arrhythmia was associated with symptoms in 75.0% of cases. The type of PAH-CHD, markers of disease severity and prior arrhythmia were associated with arrhythmia during follow-up. Arrhythmia was a strong predictor of death, even after adjusting for demographic and clinical variables (HR 3.41, 95% CI 2.10 to 5.53, p<0.0001). Arrhythmia is common in PAH-CHD and is associated with an adverse long-term outcome, even when managed in a specialist centre.
MeSH Terms
- Adult
- Arrhythmias, Cardiac
- Female
- Greece
- Heart Defects, Congenital
- Humans
- Hypertension, Pulmonary
- Incidence
- Life Expectancy
- Long Term Adverse Effects
- Male
- Middle Aged
- Patient Care Management
- Quality of Life
- Retrospective Studies
- Risk Assessment
- Risk Factors
- Severity of Illness Index
Keywords congenital heart disease
Biochar has high potential for organic pollutant immobilization due to its powerful sorption capacity. Nevertheless, potential risks may exist when biochar-sorbed organic pollutants are bioavailable. A direct plant exposure assay in combination with an organic solvent extraction experiment was carried out in this study to investigate the bioavailability of polycyclic aromatic hydrocarbons (PAHs) with the application of pine needle biochars pyrolyzed under different temperatures (100, 300, 400, and 700 °C; referred as P100-P700 accordingly). Biochar reduced solvent extractability and plant uptake of PAHs including naphthalene (Naph), acenaphthene (Acen), phenanthrene (Phen), and pyrene (Pyr), especially for three- and four-ring PAHs (Phen and Pyr) with high-temperature biochar. Plant uptake assay validates with organic solvent extraction for bioavailability assessment. Sorption of PAHs to biochars reduced plant uptake of PAHs in roots and shoots by lowering freely dissolved PAHs. Aging process reduced the bioavailability of PAHs that were bound to biochar. High pyrolysis temperature can be recommended for biochar preparation for purpose of effectively immobilizing PAHs, whereas application of moderate-temperature biochar for PAH immobilization should concern the potential risks of desorption and bioavailability of PAHs.
MeSH Terms
- Biological Availability
- Charcoal
- Hot Temperature
- Naphthalenes
- Phenanthrenes
- Polycyclic Aromatic Hydrocarbons
- Pyrenes
- Soil
- Temperature
Keywords
- Aging
- Bioavailability
- Biochar
- Plant uptake
- Polycyclic aromatic hydrocarbons
- Pyrolysis temperature
Epidemiological studies have suggested that elevated levels of air pollution contribute to an increased incidence or severity of asthma. Although late-onset adult asthma seems to be more attributable to environmental risk factors, limited data is available on the impact of early-life exposure to size-fractionated ambient particulate matter (PM) on asthma in adults. We aimed to determine the effect on the development and exacerbation of asthma in the adult after the mice were exposed as juveniles to three size-fractionated ambient particulates collected from Beijing. The three size-fractionated ambient particulates were collected from urban Beijing in winter, heavily affected by traffic and coal-fired emissions. The typical morphological and major chemical components of the PM were characterized first. Oxidative stress and expression of DNA methyltransferases (DNMTs) were then examined in vitro and in the lungs of mouse pups 48 h after exposure to PM by oropharyngeal aspiration. When the exposed and control juvenile mice matured to adulthood, an antigen-induced asthma model was established and relevant bio-indices were assessed. PM with different granularities can induce oxidative stress; in particular, F1, with the smallest size (< 0.49 μm), decreased the mRNA expression of DNMTs in vitro and in vivo the most significantly. In an asthma model of adult mice, previous exposure as juveniles to size-fractionated PM caused increased peribronchiolar inflammation, increased airway mucus secretion, and increased production of Th2 cytokines and chemokines. In general, F1 and F2 (aerodynamic diameter < 0.95 μm) particulates affected murine adult asthma development more seriously than F3 (0.95-1.5 μm). Moreover, F1 led to airway inflammation in the form of both increased neutrophils and eosinophils in BALF. The activation of the TGF-β1/Smad2 and Smad3/Stat3 signaling pathways leading to airway fibrosis was more profoundly induced by F1. This study demonstrated that exposure to ambient PM in juvenile mice enhanced adult asthma development, as shown by increased Th2 responses, which might be associated with the persistent effects resulting from the oxidative stress and decreased gene expression of DNMTs induced by PM exposure. The observed differences between the effects of three size-fractionated particulates were attributed to particle sizes and chemical constituents, including heavy metals and also PAHs, since the amounts of PAH associated with more severe toxicity were enriched equivalently in the F1 and F2 fractions. Relative to the often mentioned PM2.5, PM with an aerodynamic diameter smaller than 0.95 μm had a more aggravating effect on asthma development.
MeSH Terms
- Aging
- Air Pollutants
- Animals
- Asthma
- Beijing
- Bronchoalveolar Lavage Fluid
- Cell Line
- Cytokines
- Female
- Immunoglobulins
- Inhalation Exposure
- Lung
- Mice, Inbred BALB C
- Oxidative Stress
- Particle Size
- Particulate Matter
Keywords
- Adulthood
- Allergic asthma
- Early-life exposure
- Particulate matter
The aim of this study was to determine the effect of biochar aging on the content of polycyclic aromatic hydrocarbons (PAHs) (the total content - C , and the freely dissolved - C ) in biochar and its ecotoxicity. Two biochars (BCS and BCM) with varying properties were aged for 420 days at different temperatures (-20 °C, 4 °C, 20 °C, 70 °C), at a variable temperature (-20/20 °C), in the presence of nutrients, and in the presence of inoculum and nutrients. After the aging process, C and C PAHs were determined in samples obtained and an ecotoxicological analysis was performed, which involved tests with bacteria (Vibrio fischeri), invertebrates (Folsomia candida) and plants (Lepidium sativum). Aging significantly affected all the parameters tested. The range of changes in the studied parameters depended on the type of biochar and ageing conditions. In the case of most of the aging methods, PAH content (C , C ) and toxicity were found to decrease. Aging in the presence of microorganisms and nutrients and in the presence of nutrients alone caused the greatest reduction in C PAH content (a reduction from 30 to 100% relative to non-aged biochar), C PAH content (a reduction from 12 to 100%), root growth inhibition (a reduction from 73 to 90%), and luminescence inhibition (a reduction from 24 to 100%). In the case of C PAHs and toxicity to F. candida, some aging methods caused their increase. The study also found a significant relationship between the changes in C PAH content during aging and inhibition of root growth (BCS, BCM) and inhibition of V. fischerii luminescence (BCM). In no case was a significant correlation (P ≥ 0.05) between C PAHs and the investigated toxicity parameters found.
MeSH Terms
- Aliivibrio fischeri
- Animals
- Arthropods
- Charcoal
- Ecotoxicology
- Lepidium sativum
- Plants
- Polycyclic Aromatic Hydrocarbons
- Soil Pollutants
- Temperature
- Toxicity Tests
Keywords
- Aging
- Bioavailability
- Biochar
- PAHs
- Toxicity
- Weathering
Aging soot in soil under neutral aqueous condition for 30days significantly (p<0.05) reduced the apparent gastrointestinal bioaccessibility (B ) of polycyclic aromatic hydrocarbons (PAHs) and PAH derivatives (d-PAHs) natively present in a composite fuel soot sample. B was determined under fasting conditions by a previously developed in vitro digestive model that includes silicone sheet as a third phase absorptive sink in the small intestinal stage. Redistribution of contaminants from soot to soil, determined in independent experiments, was too small to affect B . Prior uptake by soot of a commercial humic acid representing dissolved soil organic matter had no impact on B . We identified two causes for the reduction in B by soil and found they were approximately additive. One is an aging time-independent "matrix effect" attributable to competitive sorption by the soil of labile contaminant that is desorbed from the soot during the digestion test. The other is the dissolution of soluble substances from the soot during the aging process that increases soot surface area and nanoporosity. The increased surface area and nanoporosity drive contaminants from labile to nonlabile states in the soot and decrease the desorption into the digestive fluid, the former contributing most to the reduction in B . The present study shows that mixing of raw soot with soil has important effects, both aging and non-aging, on the bioaccessibility of soot-borne contaminants.
MeSH Terms
- Biological Availability
- Polycyclic Aromatic Hydrocarbons
- Soil
- Soot
- Water
Keywords
- Aging
- Bioaccessibility
- In vitro digestive models
- PAHs and PAH derivatives
- Soot
Accumulating evidence suggests that polycyclic aromatic hydrocarbons (PAH) which adsorbed on the surface of ambient air particulate matters (PM), are the major toxic compound to cause cardiovascular and respiratory diseases, even cancer. However, its detrimental effects on human skin cell remain unclear. Here, we demonstrated that SRM1649b, a reference urban dust material of PAH, triggers human skin cells aging through cell cycle arrest, cell growth inhibition and apoptosis. Principally, SRM1649b facilitated Aryl hydrocarbon receptor (AhR) translocated into nucleus, subsequently activated ERK/MAPK signaling pathway, and upregulated aging-related genes expression. Most important, we found that AhR antagonist efficiently revert the aging of skin cells. Thus our novel findings firstly revealed the mechanism of skin aging under PAH contamination and provided potential strategy for clinical application.
MeSH Terms
- Apoptosis
- Cell Cycle Checkpoints
- Cell Proliferation
- Cells, Cultured
- Dose-Response Relationship, Drug
- Humans
- Keratinocytes
- Polycyclic Aromatic Hydrocarbons
- Receptors, Aryl Hydrocarbon
- Skin Aging
- Structure-Activity Relationship
Keywords
- Aging-related genes
- Aryl hydrocarbon receptor
- Clinical applications
- MAPK signaling pathway
- Polycyclic aromatic hydrocarbons
- Skin cell aging
The study concerns evaluation of engagement of serotonergic system in the mechanisms of antimutagenic protection and survival under adverse conditions. It is shown that under long-term exposure to oil and industrial pollution, simultaneous sharp increase of mutations level in the erythrocytes and downregulation of serotonin-modulating anticonsolidation protein (SMAP; Mekhtiev 2000) in the livers of the sturgeon juveniles (Acipenser gueldenstaedtii persicus) is observed. Mutation level was evaluated by the micronucleus analysis and SMAP level-by the indirect ELISA-test utilizing anti-SMAP immunoglobulins. Intramuscular administration of SMAP leads to significant decrease of micronucleus amount in the erythrocytes of the sturgeon juveniles exposed to sediments polluted with PAH and heavy metals. Pre-conditioning of sazans by low dose of insecticide actara (100 mg/l) leads to upregulation of SMAP and to survival of all the animals in the experimental group, kept under high concentration of actara (400 mg/l), while all animals in the control group succumbed under these conditions. I.m. administration of SMAP prior to putting the sazans into the water containing high levels of actara (400 mg/l), in contrast to controls, leads to their total survival. Participation of serotonergic system in the mechanisms of antimutagenic protection and survival promotion under damaging conditions is concluded.
MeSH Terms
- Animals
- DNA Damage
- Fish Proteins
- Fishes
- Gene Expression Regulation
- Longevity
- Mutation
- Petroleum
- Serotonin
- Water Pollutants, Chemical
Keywords
- Adverse environmental factors
- Antimutagenic protection
- Mutations
- Serotonin-modulating anticonsolidation protein
- Survival promotion
Phenylalanine hydroxylase (PAH) is a key tyrosine-biosynthetic enzyme involved in neurological and melanin-associated physiological processes. Despite extensive investigations in holometabolous insects, a PAH contribution to insect embryonic development has never been demonstrated. Here, we have characterized, for the first time, the PAH gene in a hemimetabolous insect, the aphid Acyrthosiphon pisum. Phylogenetic and sequence analyses confirmed that ApPAH is closely related to metazoan PAH, exhibiting the typical ACT regulatory and catalytic domains. Temporal expression patterns suggest that ApPAH has an important role in aphid developmental physiology, its mRNA levels peaking at the end of embryonic development. We used parental dsApPAH treatment to generate successful knockdown in aphid embryos and to study its developmental role. ApPAH inactivation shortens the adult aphid lifespan and considerably affects fecundity by diminishing the number of nymphs laid and impairing embryonic development, with newborn nymphs exhibiting severe morphological defects. Using single nymph HPLC analyses, we demonstrated a significant tyrosine deficiency and a consistent accumulation of the upstream tyrosine precursor, phenylalanine, in defective nymphs, thus confirming the RNAi-mediated disruption of PAH activity. This study provides first insights into the role of PAH in hemimetabolous insects and demonstrates that this metabolic gene is essential for insect embryonic development.
MeSH Terms
- Animals
- Aphids
- Fertility
- Gene Expression Regulation, Developmental
- Gene Expression Regulation, Enzymologic
- Longevity
- Parthenogenesis
- Peas
- Phenylalanine Hydroxylase
- Phylogeny
Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood Industries region of the Elizabeth River, Virginia, have passed polycyclic aromatic hydrocarbon (PAH) resistance to their offspring as evidenced by early life stage testing of developmental toxicity after exposure to specific PAHs. Our study focused on environmentally relevant PAH mixtures in the form of Elizabeth River sediment extract (ERSE). Juvenile (5 month) F1 progeny of pollution-adapted Atlantic Wood (AW) parents and of reference site (King's Creek [KC]) parents were exposed as embryos to ERSE. Liver alterations, including nonneoplastic lesions and microvesicular vacuolation, were observed in both populations. ERSE-exposed KC fish developed significantly more alterations than unexposed KC fish. Interestingly, unexposed AW killifish developed significantly more alterations than unexposed KC individuals, suggesting that AW juveniles are not fully protected from liver disease; rapid growth of juvenile fish may also be an accelerating factor for tumorigenesis. Because recent reports show hepatic tumor formation in adult AW fish, the differing responses from the 2 populations provided a way to determine whether embryo toxicity protection extends to juveniles. Future investigations will analyze older life stages of killifish to determine differences in responses related to chronic disease.
MeSH Terms
- Adaptation, Physiological
- Aging
- Animals
- Animals, Newborn
- Fundulidae
- Geologic Sediments
- Liver
- Polycyclic Aromatic Hydrocarbons
- Rivers
- Water Pollutants, Chemical
Keywords
- Elizabeth River
- Fundulus heteroclitus
- adaptation
- creosote-contaminated site
- developmental exposure
- hepatic lesions
- polycyclic aromatic hydrocarbons (PAHs)
Non-muscle myosin regulatory light chain (nmMLC20) is reported to exert transcriptional function in regulation of gene expression, and NADPH oxidase (NOX)-derived reactive oxygen species contribute to vascular remodeling of pulmonary artery hypertension (PAH). This study aims to determine if nmMLC20 can promote endothelial progenitor cells (EPCs) senescence and dysfunction through up-regulation of NOX in PAH rats. The rats were exposed to10% hypoxia for 3 weeks to establish a PAH model, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, and the accelerated senescence and impaired functions in EPCs, accompanied by an increase in Rho-kinase (ROCK) and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil, a selective inhibitor of ROCK. Next, normal EPCs were cultured under hypoxia to induce senescence in vitro. Consistent with the in vivo findings, hypoxia increased the senescence and dysfunction of EPCs concomitant with an increase in ROCK and NOX activities, p-nmMLC20 level, NOX expression and H2O2 content; these phenomena were reversed by fasudil. Knockdown of nmMLC20 showed similar results to that of fasudil except no effect on ROCK activity. Based on these observations, we conclude that nmMLC20 could promote the senescence and dysfunctions of EPCs in PAH through up-regulation of NOX in a phosphorylation-dependent manner.
MeSH Terms
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
- Animals
- Cellular Senescence
- Endothelial Progenitor Cells
- Hypertension, Pulmonary
- Hypoxia
- Male
- Myosin Light Chains
- Myosin-Light-Chain Phosphatase
- NADPH Oxidases
- Phosphorylation
- Protein Kinase Inhibitors
- Rats, Sprague-Dawley
- Up-Regulation
- rho-Associated Kinases
Keywords
- Endothelial progenitor cell (EPC)
- NAPDH oxidase
- Non-muscle myosin regulatory light chain (nmMLC(20))
- Pulmonary arterial hypertension
- Senescence
Human immunodeficiency virus (HIV) is now managed as a chronic disease. Non-infectious pulmonary conditions have replaced infection as the biggest threat to lung health, particularly as HIV cohorts age, but there is no consensus on how best to maintain long-term lung health. We review the epidemiology and pathogenesis of chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and lung cancer in HIV-seropositive individuals. Diagnoses of COPD are now up to 50% more prevalent in HIV-seropositive individuals than HIV-uninfected controls, and prospective pulmonary function studies find significant impairment in 7% to more than 50% of HIV-seropositive individuals. The prevalence of HIV-PAH is 0.2-0.5%, and lung cancer is two to three times more prevalent in HIV-seropositive individuals. Although host factors such as age and smoking have a role, HIV is an independent contributor to the pathogenesis of COPD, PAH, and lung cancer. Chronic inflammation, immune senescence, oxidative stress, and direct effects of viral proteins are all potential pathogenetic mechanisms. Despite their prevalence, non-infectious lung diseases remain underrecognized and evidence for effective screening strategies in HIV-seropositive individuals is limited. COPD, PAH, and lung cancer are a growing threat to lung health in the highly active antiretroviral therapy era necessitating early recognition.
MeSH Terms
- Aging
- Antiretroviral Therapy, Highly Active
- Comorbidity
- HIV Infections
- Humans
- Hypertension, Pulmonary
- Lung
- Oxidative Stress
- Pulmonary Disease, Chronic Obstructive
- Respiratory Tract Infections
- Risk Factors
- Smoking
- Spirometry
- Substance Abuse, Intravenous
Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Bone Morphogenetic Protein Receptors, Type II
- Cell Membrane Permeability
- Densitometry
- Endothelial Cells
- Gene Expression Profiling
- Gene Knock-In Techniques
- Growth Differentiation Factor 2
- Heart Ventricles
- Humans
- Hypertension, Pulmonary
- Immunoblotting
- JNK Mitogen-Activated Protein Kinases
- Male
- Mice, Inbred C57BL
- Monocrotaline
- Phosphorylation
- Pulmonary Artery
- Rats
- Rats, Sprague-Dawley
- Systole
- Transcription, Genetic
Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (N(ω)-hydroxy-nor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH.
MeSH Terms
- Aging
- Animals
- Arginase
- Cell Hypoxia
- Enzyme Activation
- Hypertension
- Lung
- Male
- Nitrates
- Nitric Oxide Synthase Type I
- Nitric Oxide Synthase Type III
- Nitrites
- Pulmonary Artery
- Rats, Sprague-Dawley
- Tyrosine
Keywords
- age
- arginase
- intermittent hypoxia
- pulmonary arterial hypertension
- sleep apnea syndrome
Pulmonary arterial hypertension (PAH) is a chronic, life threatening illness that affects primarily women. The purpose of this study was to describe the prevalence of PAH symptoms and to determine whether there are differences in symptom severity and HRQOL in PAH symptoms among young, middle, and older adults with PAH. A cross sectional design was utilized. For all the age groups, shortness of breath (SOB) on exertion and fatigue were the two most prevalent symptoms. SOB on exertion had the highest symptom severity scores followed by fatigue for all groups. Symptom severity was significantly different among the groups for palpitations, abdominal swelling and nausea. For components of HRQOL, physical functioning worsened with age. All groups had diminished general health, role physical and vitality levels. There are some differences in symptom prevalence, symptom severity and HRQOL among young, middle and older adults. Awareness of these differences is important for healthcare providers to know and assess overtime. Palliative care should be an integral part of caring for patients with PAH.
MeSH Terms
- Adult
- Age Factors
- Aged
- Cross-Sectional Studies
- Dyspnea
- Fatigue
- Female
- Health Status
- Humans
- Hypertension, Pulmonary
- Male
- Mental Health
- Middle Aged
- Prevalence
- Quality of Life
- Severity of Illness Index
Keywords
- aging
- hypertension
- pulmonary
- quality of life
- severity
- symptoms
There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug. Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration. Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL). We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.
MeSH Terms
- Adolescent
- Aging
- Antihypertensive Agents
- Bosentan
- Carbolines
- Child
- Child, Preschool
- Female
- Humans
- Hypertension, Pulmonary
- Infant
- Male
- Sulfonamides
- Tadalafil
- Vasodilator Agents
This study compared fish longevity, growth, and oxidative stress between normal and deformed Aphanius fasciatus collected from the Gulf of Gabes. For this purpose, fish were collected from control (S1) and polluted (S2) sites in Tunisian coast and percentages of spinal deformities were determined. Oxidative stress biomarkers were also compared between normal and deformed fish, including levels of protein sulfhydryl (SH), malondialdehyde (MDA), and metallothioneins (MT), as well as activities of superoxide dismutase (SOD) and alkaline phosphatase (AP). Levels of heavy metals (Cd, Cu, and Zn) and polycyclic aromatic hydrocarbons (PAH) were also measured. Data showed that the highest occurrence of deformities was observed in younger fish and decreased significantly thereafter with age. Chemical analysis demonstrated high levels of heavy metals and PAH at polluted sites compared to a reference location. In deformed fish, a growth perturbation marked by a decrease of growth rate and condition index (CI), a high accumulation of Cd was noted. In addition, oxidative stress marked by changes in the studied biomarkers was observed. Taken together, oxidative stress, diminished longevity, and a disturbance of growth may be considered to be responsible factors contributing to spinal deformities.
MeSH Terms
- Animals
- Biomarkers
- Environmental Exposure
- Environmental Monitoring
- Fish Diseases
- Gas Chromatography-Mass Spectrometry
- Geologic Sediments
- Killifishes
- Liver
- Longevity
- Metals
- Oxidative Stress
- Polycyclic Aromatic Hydrocarbons
- Prevalence
- Spectrophotometry, Atomic
- Spine
- Tunisia
- Water Pollutants, Chemical
Children and adults with pulmonary arterial hypertension (PAH) have similarities and differences in their background characteristics, hemodynamics, and clinical manifestations. Regarding genetic background, mutations in BMPR2-related pathways seem to be pivotal; however, it is likely that other modifier genes and bioactive mediators have roles in the various forms of PAH in children and adults. In pediatric PAH, there are no clear sex differences in incidence, age at onset, disease severity, or prognosis but, as compared with adults, syncope incidence, pulmonary vascular resistance, and mean pulmonary artery pressure are higher, and vasoreactivity to acute drug testing is more frequent, among children. Nevertheless, the pharmacokinetic effects of 3 major pulmonary vasodilators appear to be similar in children and adults with PAH. This review focuses on the specific pathophysiologic features of PAH in children.
MeSH Terms
- Adult
- Age Factors
- Age of Onset
- Aging
- Blood Pressure
- Bone Morphogenetic Protein Receptors, Type II
- Child
- Child, Preschool
- Female
- Humans
- Hypertension, Pulmonary
- Infant
- Infant, Newborn
- Male
- Syncope
- Vascular Resistance
- Vasodilator Agents
Recent reports from pulmonary arterial hypertension (PAH) registries suggest that the mean age at diagnosis is increasing, outlining a growing proportion of elderly male patients. As a consequence, the classical description of the disease is shifting and may no more be described as a rare disease typically affecting young women. Potential explanations of this changing picture may include an aging of populations in western countries, the increase in life expectancy and the growing awareness of PAH and emergence of potential efficient treatments. Diagnostic workup of severe pulmonary hypertension (PH) in the elderly should be performed in such a way as to discriminate between the expected consequences of aging, pulmonary vascular disease, and other frequent causes of secondary PH (left heart failure or lung disease). Careful exploration by right heart catheterization is mandatory, but special attention should be paid to several pitfalls specific to this procedure in this age group. This is a matter of concern as clinical trials that aim to study new specific drug therapy for PAH might be biased by the inclusion of misdiagnosed patients. The aim of this review is to highlight the main difficulties in diagnosing PAH in the elderly and to propose a practical approach to distinguish PAH from the other frequent causes of PH in this population.
MeSH Terms
- Aged
- Aging
- Algorithms
- Appetite Depressants
- Cardiac Catheterization
- Exercise Test
- Familial Primary Pulmonary Hypertension
- Heart Failure
- Humans
- Hypertension, Pulmonary
- Life Expectancy
- Pulmonary Artery
- Pulmonary Circulation
- Pulmonary Disease, Chronic Obstructive
- Pulmonary Wedge Pressure
- Stroke Volume
The study investigated the effects of postnatal exposure to polycyclic aromatic hydrocarbons (PAHs) on the development of the rat ovary. Neonates were injected on each postnatal day 1-14 with benzo(a)pyrene (BaP), benz(a)anthracene (BaA) and benzo(k)fluoranthene (BkF) (0.1, 1.0, 5.0 or 10.0 mg kg(-1)), ethynylestradiol (EE; 1.0 µg kg(-1)) or a vehicle (control group). The rats were killed on day 23. Postnatal exposure to BaP increased the total number of antral follicles in ovaries (P < 0.05) and the number of nonatretic follicles (P < 0.01) as a result of a lower degree of apoptosis of granulosa cells, and the thickness of theca cell layers (P < 0.01). Similar histological findings were observed after BaA administration. Conversely, BkF exposure caused a decrease in the number of antral follicles, but did not alter the other investigated parameters. Degeneration of primordial oocytes after exposure to PAHs was observed only after exposure to BaP. Treatment with BaP at doses of 1.0 and 10.0 mg kg(-1) impaired 28.1 and 60.3% of the primordial follicles, respectively. Substantial alterations in ovarian ERβ expression were detected in the rats; their intensity differed with the type of PAH. Response of the ovaries to EE (three injections of 1.0 µg kg(-1) on postnatal days 20-22) in rats exposed to PAHs was suppressed in contrast to the controls. The study showed that postnatal exposure to BaP, BaA and BkF altered ovarian ERβ expression, disturbed morphological development of the ovaries and caused ovarian dysfunction in immature rats.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Apoptosis
- Endocrine Disruptors
- Environmental Exposure
- Female
- Ovarian Diseases
- Ovary
- Polycyclic Aromatic Hydrocarbons
- Rats
- Rats, Wistar