PM2.5-bound PAHs exposure linked with low plasma insulin-like growth factor 1 levels and reduced child height

Background: Exposure to atmospheric fine particle matter (PM2.5) pollution and the absorbed pollutants is known to contribute to numerous adverse health effects in children including to growth. Objective: The aim of this study was to evaluate exposure levels of atmospheric PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in an electronic waste (e-waste) polluted town, Guiyu, and to investigate the associations between PM2.5-PAH exposure, insulin-like growth factor 1 (IGF-1) levels and child growth. Methods: This study recruited 238 preschool children (3–6 years of age), from November to December 2017, of which 125 were from Guiyu (an e-waste area) and 113 were from Haojiang (a reference area). Levels of daily PM2.5 and PM2.5-bound ∑16 PAHs were assessed to calculate individual chronic daily intakes (CDIs). IGF-1 and IGF-binding protein 3 (IGFBP-3) concentrations in child plasma were also measured. The associations and further mediation effects between exposure to PM2.5 and PM2.5-bound PAHs, child plasma IGF-1 concentration, and child height were explored by multiple linear regression models and mediation effect analysis. Results: Elevated atmospheric PM2.5-bound ∑16 PAHs and PM2.5 levels were observed in Guiyu, and this led to more individual CDIs of the exposed children than the reference (all P < 0.001). The median level of plasma IGF-1 in the exposed group was lower than in the reference group (91.42 ng/mL vs. 103.59 ng/mL, P < 0.01). IGF-1 levels were negatively correlated with CDIs of PM2.5, but not with CDIs of PM2.5-bound ∑16 PAHs after adjustment. An increase of 1 μg/kg of PM2.5 intake per day was associated with a 0.012 cm reduction of child height (95% CI: −0.014, −0.009), and similarly, an elevation of 1 ng/kg of PM2.5-bound ∑16 PAHs intake per day was associated with a 0.022 cm decrease of child height (95% CI: −0.029, −0.015), both after adjustment of several potential confounders (age, gender, family cooking oil, picky eater, eating sweet food, eating fruits or vegetables, parental education level and monthly household income). The decreased plasma IGF-1 concentration mediated 15.8% of the whole effect associated with PM2.5 exposure and 23.9% of the whole effect associated with PM2.5-bound ∑16 PAHs exposure on child height. Conclusion: Exposure to atmospheric PM2.5-bound ∑16 PAHs and PM2.5 is negatively associated with child height, and is linked to reduced IGF-1 levels in plasma. This may suggest a causative negative role of atmospheric PM2.5-bound exposures in child growth

Elevated expression of AhR and NLRP3 link polycyclic aromatic hydrocarbon exposure to cytokine storm in preschool children

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs), as a group of persistent organic pollutants, are linked to impaired immune function and low-grade inflammation in adults and children. However, the potential of PAHs to lead to a cytokine storm associated with AhR (aryl hydrocarbon receptor) and NLRP3 (NLR family pyrin domain containing 3) in humans has been poorly studied. OBJECTIVES: We aimed to investigate the associations between PAH exposure, AhR and NLRP3 expression, and cytokines associated with a cytokine storm in healthy preschoolers. METHODS: Basic demographic surveys and physical examinations were conducted on 248 preschoolers from an electronic waste (e-waste) recycling area (Guiyu, n = 121) and a reference area (Haojiang, n = 127). Ten urinary PAH metabolite (OH-PAH) concentrations were measured. We also measured the expression levels of AhR and NLRP3 and seventeen serum cytokine levels. RESULTS: The concentrations of multiple OH-PAHs were significantly higher in the exposed group than those in the reference group, especially 1-hydroxynaphthalene (1-OH-Nap) and 2-hydroxynaphthalene (2-OH-Nap). PAH exposure was closely related to a child's living environment and hygiene habits. Expression levels of AhR and NLRP3 were significantly higher in the exposed group than in the reference group. Similarly, serum IL-1β, IL-4, IL-5, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-22, IL-23, and IFN-γ levels were notably higher in the e-waste-exposed children than in the reference children. After adjusting for age, gender, BMI, family income, parental education level, and second-hand smoke exposure, we found that increased PAH exposure was associated with higher AhR and NLRP3 expression and elevated IL-4, IL-10, IL-12p70, IL-18, IL-22, IL-23, TNF-α, and IFN-γ levels. The associations between PAH exposure and IL-1β, IL-18, IFN-γ, and TNF-β were mediated by NLRP3 expression, and the relationships between PAH exposure and IL-4, IL-10, IL-12p70, IL-22, IL-23, and TNF-α were mediated by AhR expression. CONCLUSIONS: Our findings suggest that the association between PAH exposure and a cytokine storm may be mediated by AhR and NLRP3 expression among preschoolers

PAH exposure is associated with enhanced risk for pediatric dyslipidemia through serum SOD reduction

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) is linked to abnormal lipid metabolism, but evidence regarding PAHs as risk factors for dyslipidemia is lacking. Objective: To investigate the respective role and interaction of PAH exposure and antioxidant consumption in the risk for pediatric dyslipidemia. Methods: We measured the concentrations of serum lipids, superoxide dismutase (SOD) and urinary hydroxylated PAHs (OH-PAHs) in 403 children, of which 203 were from an e-waste-exposed area (Guiyu) and 200 were from a reference area (Haojiang). Biological interactions were calculated by additive models. Results: Guiyu children had higher serum triglyceride concentration and dyslipidemia incidence, and lower serum concentration of high-density lipoprotein (HDL) than Haojiang children. Elevated OH-PAH concentration, and concomitant SOD reduction, were both associated with lower HDL concentration and higher hypo-HDL risk (S3OH-Phes: B for lgHDL = 0.048, P <0.01; OR for hypo-HDL = 3.708, 95% CI: 1.200, 11.453; SOD: BT3 for lgHDL = 0.061, P <0.01; ORT3 for hypo-HDL = 0.168, 95% CI: 0.030, 0.941; all were adjusted for confounders). Biological interaction between phenanthrol exposure and SOD reduction was linked to dyslipidemia risk (RERI = 2.783, AP = 0.498, S = 2.537). Children with both risk factors (higher S3OH-Phes and lower SOD) had 5.594times (95% CI: 1.119, 27.958) the dyslipidemia risk than children with neither risk factors (lower S3OH-Phes and higher SOD). Conclusion: High PAH exposure combined with SOD reduction is recommended for predicting elevated risk for pediatric dyslipidemia. Risk assessment of PAH-related dyslipidemia should take antioxidant concentration into consideration

A Targeted Lipidomic Reveals CYP450-Derived Oxylipin Linked to the Inflammatory Response by Polycyclic Aromatic Hydrocarbon Exposure in Children

Polycyclic aromatic hydrocarbon (PAH) exposure is a cause of chronic inflammation. The effect of PAHs on bioactive lipid mediators involved in the inflammatory process remains largely unknown. This study measured ten urinary monohydroxy-PAHs (OH-PAHs), 54 plasma oxylipins, and inflammation-related markers. Children with high PAH exposure had higher levels of ten OH-PAHs, (±)18-HETE, 19(S)-HETE, 5,6-DiHETrE, 9,10-DiHOME, more monocytes, interleukin (IL)-10, tumor necrosis factor (TNF)-α and IL-6 than those with low PAH exposure (all p &lt; 0.05). The ƩOH-PAHs were inversely correlated to the levels of anti-inflammatory oxylipins, including 5,6-EET (p for trend = 0.007), 11,12-EET (p for trend = 0.035), 14,15-EET (p for trend = 0.022), and 16(17)-EpDPE (p for trend = 0.043), but positively associated with pro-inflammatory 9,10-DiHOME (p for trend &lt; 0.001). Mediation analyses indicated that cytochrome P450 (CYP)-derived 9,10-DiHOME mediated a separate 42.7%, 31.1%, 57.8%, and 38.5% of the associations between OH-PAHs and monocytes, IL-6, IL-10, TNF-α (p = 0.017, 0.014, 0.005 and 0.012, respectively). Our study suggests that CYP-derived oxylipins can be considered sensitive lipid mediators to signal the early inflammation response to PAH exposure.</p

The potential for targeted rewriting of epigenetic marks in COPD as a new therapeutic approach

Chronic obstructive pulmonary disease (COPD) is an age and smoking related progressive, pulmonary disorder presenting with poorly reversible airflow limitation as a result of chronic bronchitis and emphysema. The prevalence, disease burden for the individual, and mortality of COPD continues to increase, whereas no effective treatment strategies are available. For many years now, a combination of bronchodilators and anti-inflammatory corticosteroids has been most widely used for therapeutic management of patients with persistent COPD. However, this approach has had disappointing results as a large number of COPD patients are corticosteroid resistant. In patients with COPD, there is emerging evidence showing aberrant expression of epigenetic marks such as DNA methylation, histone modifications and microRNAs in blood, sputum and lung tissue. Therefore, novel therapeutic approaches may exist using epigenetic therapy. This review aims to describe and summarize current knowledge of aberrant expression of epigenetic marks in COPD. In addition, tools available for restoration of epigenetic marks are described, as well as delivery mechanisms of epigenetic editors to cells. Targeting epigenetic marks might be a very promising tool for treatment and lung regeneration in COPD in the future

Dual role of YM1+ M2 macrophages in allergic lung inflammation

Abstract Alternatively activated (M2 or YM1+) macrophages have been associated with the development of asthma but their contribution to disease initiation and progression remains unclear. To assess the therapeutic potential of modulating these M2 macrophages, we have studied inhibition of M2 polarisation during and after development of allergic lung inflammation by treating with cynaropicrin, a galectin-3 pathway inhibitor. Mice that were treated with this inhibitor of M2 polarisation during induction of allergic inflammation developed less severe eosinophilic lung inflammation and less collagen deposition around airways, while the airway α-smooth muscle actin layer was unaffected. When we treated with cynaropicrin after induction of inflammation, eosinophilic lung inflammation and collagen deposition were also inhibited though to a lesser extent. Unexpectedly, both during and after induction of allergic inflammation, inhibition of M2 polarisation resulted in a shift towards neutrophilic inflammation. Moreover, airway hyperresponsiveness was worse in mice treated with cynaropicrin as compared to allergic mice without inhibitor. These results show that M2 macrophages are associated with remodeling and development of eosinophilic lung inflammation, but prevent development of neutrophilic lung inflammation and worsening of airway hyperresponsiveness. This study suggests that macrophages contribute to determining development of eosinophilic or neutrophilic lung inflammation in asthma

Induction of autoantibodies against lung matrix proteins and smoke-induced inflammation in mice

<p>Abstract</p> <p>Background</p> <p>Smoking is the major etiologic factor in COPD, yet the exact underlying pathogenetic mechanisms have not been elucidated. Since a few years, there is mounting evidence that a specific immune response, partly present as an autoimmune response, contributes to the pathogenesis of COPD. Increased levels of anti-Hep-2 epithelial cell and anti-elastin autoantibodies as well as antibodies against airway epithelial and endothelial cells have been observed in COPD patients. Whether the presence of these autoantibodies contributes to the pathogenesis of COPD is unclear.</p> <p>Methods</p> <p>To test whether induction of autoantibodies against lung matrix proteins can augment the smoke-induced inflammatory response, we immunized mice with a mixture of the lung extracellular matrix (ECM) proteins elastin, collagen, and decorin and exposed them to cigarette smoke for 3 or 6 months. To evaluate whether the immunization was successful, the presence of specific antibodies was assessed in serum, and presence of specific antibody producing cells in spleen and lung homogenates. In addition, the presence of inflammatory cells and cytokines was assessed in lung tissue and emphysema development was evaluated by measuring the mean linear intercept.</p> <p>Results</p> <p>We demonstrated that both ECM immunization and smoke exposure induced a humoral immune response against ECM proteins and that ECM immunization itself resulted in increased macrophage numbers in the lung. The specific immune response against ECM proteins did not augment the smoke-induced inflammatory response in our model.</p> <p>Conclusions</p> <p>By demonstrating that smoke exposure itself can result in a specific immune response and that presence of this specific immune response is accompanied by an influx of macrophages, we provide support for the involvement of a specific immune response in the smoke-induced inflammatory response as can be seen in patients with COPD.</p

The role of endogenous H2S formation in reversible remodeling of lung tissue during hibernation in the Syrian hamster

During hibernation, small mammals alternate between periods of metabolic suppression and low body temperature ('torpor') and periods of full metabolic recovery with euthermic temperatures ('arousal'). Previously, we demonstrated marked structural remodeling of the lung during torpor, which is rapidly reversed during arousal. We also found that cooling of hamster cells increased endogenous production of H2S through the enzyme cystathionine-beta-synthase (CBS). H2S suppresses the immune response and increases deposition of collagen. Therefore, we examined inflammatory markers and matrix metalloproteinase (MMP) activity in relation to CBS expression and H2S levels in lungs of euthermic and hibernating Syrian hamsters. Lung remodeling during torpor was confirmed by a strong increase in both collagenous and non-collagenous hydroxyproline content. The number of leukocytes in lung was unchanged in any phase of hibernation, while adhesion molecules VCAM-1 and ICAM-1, and the inflammatory marker NF-kappa B (P65) were modestly upregulated in torpor. Gelatinase activity was decreased in lungs from torpid animals, indicating inhibition of the Zn2+-dependent MMP-2 and MMP-9. Moreover, expression of CBS and tissue levels of H2S were increased in torpor. All changes normalized during arousal. Inhibition of gelatinase activity in torpor is likely caused by quenching of Zn2+ by the sulphide ion of H2S. In accord, inhibition of CBS normalized gelatinase activity in torpid animals. Conversely, NaHS decreased the gelatinase activity of euthermic animals, which was attenuated by excess Zn2+. Similar results were obtained on the activity of the Zn2+-dependent angiotensin converting enzyme. Our data indicate that increased production of H2S through CBS in hamster lungs during torpor contributes to remodeling by inhibition of gelatinase activity and possibly by suppression of the inflammatory response. Although administration of H2S is known to induce metabolic suppression in nonhibernating mammals ('suspended animation'), this is the first report implying endogenous H2S production in natural hibernation

Sexual maturation protects against development of lung inflammation through estrogen.

Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of \u22puberty\u22 appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen-mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII

Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ- and sex-specific

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis