Epidemiological studies have found strong associations between air pollution and respiratory effects including development and/or exacerbation of asthma and chronic obstructive pulmonary disease (COPD) as well as increased occurrence of respiratory infections and lung cancer. It has become increasingly clear that also polycyclic aromatic hydrocarbons (PAHs) may affect processes linked to non-malignant diseases in the airways. The aim of the present paper was to review epidemiological studies on associations between gas phase and particle-bound PAHs in ambient air and non-malignant respiratory diseases or closely related physiological processes, to assess whether PAH-exposure may explain some of the effects associated with air pollution. Based on experimental in vivo and in vitro studies, we also explore possible mechanisms for how different PAHs may contribute to such events. Epidemiological studies show strongest evidence for an association between PAHs and asthma development and respiratory function in children. This is supported by studies on prenatal and postnatal exposure. Exposure to PAHs in adults seems to be linked to respiratory functions, exacerbation of asthma and increased morbidity/mortality of obstructive lung diseases. However, available studies are few and weak. Notably, the PAHs measured in plasma/urine also represent other exposure routes than inhalation. Furthermore, the role of PAHs measured in air is difficult to disentangle from that of other air pollution components originating from combustion processes. Experimental studies show that PAHs may trigger various processes linked to non-malignant respiratory diseases. Physiological- and pathological responses include redox imbalance, oxidative stress, inflammation both from the innate and adaptive immune systems, smooth muscle constriction, epithelial- and endothelial dysfunction and dysregulated lung development. Such biological responses may at the molecular level be initiated by PAH-binding to the aryl hydrocarbon receptor (AhR), but possibly also through interactions with beta-adrenergic receptors. In addition, reactive PAH metabolites or reactive oxygen species (ROS) may interfere directly with ion transporters and enzymes involved in signal transduction. Overall, the reviewed literature shows that respiratory effects of PAH-exposure in ambient air may extend beyond lung cancer. The relative importance of the specific PAHs ability to induce disease may differ between the biological endpoint in question.

/pdf/potential-role-of-polycyclic-aromatic-hydrocarbons-in-air-5b1q12a79n.pdf

Potential role of polycyclic aromatic hydrocarbons in air pollution-induced non-malignant respiratory diseases

Background: Studies suggest that phthalate exposures may adversely affect child respiratory health.Objectives: We evaluated associations between asthma diagnosed in children between 5 and 11 years ...

/pdf/asthma-in-inner-city-children-at-5-11-years-of-age-and-1c240lyz88.pdf

Asthma in Inner-City Children at 5–11 Years of Age and Prenatal Exposure to Phthalates: The Columbia Center for Children’s Environmental Health Cohort

Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.

Perinatal and Early-Life Nutrition, Epigenetics, and Allergy.

Phosphodiesterases as therapeutic targets for respiratory diseases.

Despite attempts and some successes to improve air quality over the decades, current US national trends suggest that exposure to outdoor and indoor air pollution remains a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Emerging science also suggests that environmental exposures during the prenatal period and early childhood years increase the risk of asthma. Multiple mechanisms mediate this risk because a wide range of deleterious air pollutants contribute to the pathogenesis of asthma across a variety of complex asthma phenotypes. In this review we will consider the role of altered innate and adaptive immune responses, gene-environment interactions, epigenetic regulation, and possibly gene-environment-epigene interactions. Gaining a greater understanding of the mechanisms that underlie the effect of exposure to air pollution on asthma, allergies, and other airway diseases can identify targets for therapy. Such interventions will include pollutant source reduction among those most exposed and most vulnerable and novel pharmaceutical strategies to reduce asthma morbidity.

/pdf/environmental-effects-on-immune-responses-in-patients-with-1wk6cf33oo.pdf

Environmental effects on immune responses in patients with atopy and asthma

Incomplete combustion produces a pollutant mixture that includes polycyclic aromatic hydrocarbons (PAHs). Previous work by the Columbia Center for Children's Environmental Health (CCCEH) and others linked exposure to PAH with symptoms of asthma and other adverse health effects in young children. Inhaled β2-adrenergic agonists are mainstays in the treatment of reactive airway diseases. These exogenous catecholamines engage membrane-bound β2-adrenergic receptors (β2AR) on airway epithelial and smooth muscle cells to cause airway dilation. We hypothesized that exposure to PAH might similarly interfere with the function of β2AR in airway epithelial or smooth muscle cells, reducing the efficacy of a medication important for the treatment of asthma symptoms. A PAH mixture was devised, based on ambient levels measured prenatally among a cohort of pregnant women participating at the CCCEH. Primary airway epithelial and smooth muscle cells were exposed to varying concentrations of the PAH mixture, and expression, function, and signaling of β2AR were assessed. Murine tracheal epithelial cells and human airway smooth muscle cells, after exposure to a PAH mixture, exhibited reduced expression and function of β2AR. These findings support our hypothesis that environmentally relevant PAHs can impede β2AR-mediated airway relaxation, and suggest a new paradigm where air pollutants not only contribute to the pathogenesis of childhood asthma, but also diminish responsiveness to standard therapy.

Polycyclic aromatic hydrocarbons impair function of β2-adrenergic receptors in airway epithelial and smooth muscle cells.

Asthma in parents is associated with increased risk of asthma in children, with maternal asthma more strongly associated with risk compared to paternal (1) This pattern suggests that maternal exposures, particularly during gestation, may alter developmental programming, leading to molecular, physiologic, and metabolic adaptations in the offspring (1, 2) For example, prenatal allergen exposure may ‘prime’ T-helper (Th) cells toward a more proallergic Th2 phenotype (3) Previous studies of prenatal exposures on the development of allergy have been mixed, with exposures linked to both increased (4) and decreased (5) allergy in the offspring, likely due to differing effects of dose, timing of exposure during gestation, and other methodological variations

An emerging paradigm is that epigenetic regulation of genes important to Th gene transcription and cytokine production may be responsible for the development of allergy (6) Cell systems have shown that site-specific CpG methylation of Th gene promoters can steer differentiation toward the Th2 phenotype (7, 8) In particular, the CpG−53 of the interferon (IFN)-γ promoter was shown to undergo rapid methylation during Th2 polarization that blocked ATF2-c/Jun and CREB transcription factor binding (7) More limited in vivo studies have been conducted In one study, our group showed that combined exposure to diesel exhaust particles and allergen in mice altered methylation patterns at CpG sites in the IFN-γ and IL-4 promoters that correlated with changes in immunoglobulin (Ig) E production (9)

Epigenetic regulation also may explain partially the heritability of asthma (2) A gestational diet high in folic acid, a methyl donor for methylation reactions, induced allergic airway inflammation in offspring mice (F1) in association with hypermethylation of RUNX3, a T-cell regulator (10) Differences in levels of global DNA methylation among dendritic cells, and in their antigen-presenting activity, derived from offspring mice also were associated with the presence or absence of an asthma-like phenotype in the mother (11) Epidemiologic studies additionally have demonstrated associations between prenatal exposures, including tobacco smoke and polycyclic aromatic hydrocarbons (PAH), with differential methylation patterns in several asthma candidate genes and symptoms in children (12, 13) Also, prenatal smoking, determined using retrospective questionnaire, was associated with greater asthma risk in the grandchildren (14) Others have suggested that the timing of exposure during gestation may be important, with folic acid supplementation either during the first trimester or during late pregnancy being associated with asthma-related symptoms in young children in separate studies (15, 16)

We hypothesized that allergen exposure during gestation may alter the allergic phenotype through multiple generations of mice and that such changes would be associated with DNA methylation of Th genes We also hypothesized that these associations may vary depending on the timing of prenatal exposure Given our previous report that prenatal Aspergillus fumigatus (A fumigatus) administration combined with diesel exhaust particles was associated with reduced IgE in sensitized offspring (F1) (17), here we exposed female mice (F0) to multiple doses of A fumigatus during the early or late period of gestation and determined the effects on IgE, airway eosinophilia, and Th gene IFN-γ and IL-4 promoter methylation in the lungs of their grandoffspring (F2)

/pdf/prenatal-exposure-to-allergen-dna-methylation-and-allergy-in-3e5nmr3w8u.pdf

Prenatal exposure to allergen, DNA methylation, and allergy in grandoffspring mice.

Intra-Individual Variation in DNA Methylation of IFNγ and IL4 Over Days

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Polycyclic aromatic hydrocarbons impair function of β2-adrenergic receptors in airway epithelial and smooth muscle cells.

Prenatal exposure to allergen, DNA methylation, and allergy in grandoffspring mice.

Intra-Individual Variation in DNA Methylation of IFNγ and IL4 Over Days