One of our era's greatest scourges is air pollution, on account not only of its impact on climate change but also its impact on public and individual health due to increasing morbidity and mortality. There are many pollutants that are major factors in disease in humans. Among them, Particulate Matter (PM), particles of variable but very small diameter, penetrate the respiratory system via inhalation, causing respiratory and cardiovascular diseases, reproductive and central nervous system dysfunctions, and cancer. Despite the fact that ozone in the stratosphere plays a protective role against ultraviolet irradiation, it is harmful when in high concentration at ground level, also affecting the respiratory and cardiovascular system. Furthermore, nitrogen oxide, sulfur dioxide, Volatile Organic Compounds (VOCs), dioxins, and polycyclic aromatic hydrocarbons (PAHs) are all considered air pollutants that are harmful to humans. Carbon monoxide can even provoke direct poisoning when breathed in at high levels. Heavy metals such as lead, when absorbed into the human body, can lead to direct poisoning or chronic intoxication, depending on exposure. Diseases occurring from the aforementioned substances include principally respiratory problems such as Chronic Obstructive Pulmonary Disease (COPD), asthma, bronchiolitis, and also lung cancer, cardiovascular events, central nervous system dysfunctions, and cutaneous diseases. Last but not least, climate change resulting from environmental pollution affects the geographical distribution of many infectious diseases, as do natural disasters. The only way to tackle this problem is through public awareness coupled with a multidisciplinary approach by scientific experts; national and international organizations must address the emergence of this threat and propose sustainable solutions.

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Environmental and Health Impacts of Air Pollution: A Review.

Air quality in Europe : 2013 report

BACKGROUND: Exposure to ambient air pollution is suspected to cause cognitive effects, but a prospective cohort is needed to study exposure to air pollution at the home address and the incidence of ...

Traffic-Related Air Pollution and Dementia Incidence in Northern Sweden: A Longitudinal Study.

fine particle hypothesis stating that ambient ultrafine particles (UFP; < 0.1 μm in aerodynamic diameter) may cause adverse health effects at the first Colloquium for Particulate Air Pollution and Human Mortality and Morbidity in Irvine, California, it was met with friendly skepticism as well as out-right dismissal. Arguments were that UFP are very short-lived and disappear through heterogeneous and homogeneous aggregation within seconds or minutes and therefore are toxicologically irrelevant. These arguments did not recognize that UFP are continuously generated or that ambient UFP contribute very little, if any, mass to ambient PM10 (particles < 10 μm in aerodynamic diameter) or PM2.5 (particles < 2.5 μm in aerodynamic diameter). Indeed, the mass distribution of a typical urban aerosol among the different particle sizes may support this point (Figure 1). This attitude of skepticism has changed considerably. Research teams across the world are working now on UFP, forming multidisciplinary alliances between atmospheric scientists, engineers, epidemiologists, clinicians, and toxicologists. They investigate UFP sources, generation, physicochemical characteristics, behavior in ambient air, and potential effects and underlying mechanisms following their inhalation. Still, sound skepticism lingers, as demonstrated by the title of a presentation at the 2002 meeting of the Health Effects Institute: “Nanoparticles: Are They Real?” Obviously, there is no question that UFP are real, but it is also clear that we still do not know enough about them, despite significant progress in our understanding since 1994. Atmospheric UFP derived from gas-to-particle conversions have many sources, natural and anthropogenic, the latter being mostly derived from internal combustion processes. Diesel fuel, gasoline, and even compressed natural gas—considered to be “clean”—powered engines all emit high numbers of UFP. If these anthropogenic UFP cause significant health effects, is the conversion of dieselpowered buses to compressed natural gas—as practiced now in several cities—really a good idea? We should be more cautious about introducing technologies based on the assumption that they result in cleaner air with fewer and less toxic contaminants. The experience with methyl tert-butyl ether as a fuel additive should serve as a reminder of the potential unintended health and environmental consequences of altering fuels and resulting emissions on a large scale without an adequate understanding of toxicity. Since vehicular emissions are regulated by mass output, modern technologies for internal combustion engines favor the generation and formation of UFP because they contribute minimally to the mass output of fine particles (Figure 1). It should come as no surprise that “clean” engines are built to conform to present standards of mass output, despite emitting high numbers of UFP. A standard based on particle number would be more appropriate to reduce UFP emissions. A standard based on particle surface area—as is also proposed—may not be helpful to control UFP because fine particles comprise most of the total particle surface area (Figure 1). In recent measurements made during road-chase studies in Minnesota, UFP concentrations were as high as 1 × 107 particles/cm3 (Kittelson et al. 2001). A short distance from the highways, these high UFP concentrations are lower, but individuals in automobiles on the highways are directly exposed to the high concentrations. Moreover, these UFP are freshly generated, and if results of earlier toxicologic studies with UFP generated from thermodegradation products of polymers are an indication of a general principle of UFP toxicity, freshness and proximity to the source are key requirements for inducing acute adverse effects of UFP. Do UFP emitted from internal combustion engines cause adverse health effects? We still need to know more, but results from our controlled clinical and animal studies using ultrafine elemental carbon particles permit some preliminary conclusions: The high deposition of inhaled UFP (0.007–0.1 μm) in the human respiratory tract as predicted by ICRP (1994) could be confirmed; moreover, deposition was even higher during exercise and in asthmatics. Unlike larger fine particles, UFP seem to escape phagocytosis by alveolar macrophages and are translocated to extrapulmonary organs, as was determined in rodents using ultrafine 13C particles, although such translocation was only minimal with ultrafine iridium particles. Cardiovascular effects in humans and animals and mild pulmonary inflammation in animals were also found following ultrafine carbon particle exposures. Although health effects data and understanding of mechanisms are still limited, there are intriguing data from other disciplines, in particular the field of drug delivery: Intravenously administered UFP were found to cross the blood–brain barrier (Kreuter, 2001), and a transport function of caveolae for macromolecules with molecular radii of several

Ultrafine Particles in the Urban Air: To the Respiratory Tract-And beyond? Is the Central Nervous System Yet Another Target for Ultrafine Particles? (Editorial)

The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300μg/m3 for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.

Neurotoxicity of traffic-related air pollution

Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health.

https://downloads.hindawi.com/journals/jt/2012/782462.pdf

The adverse effects of air pollution on the nervous system.

Importance of the field: Erythropoietin (EPO) is a growth hormone and cytokine that plays an important role in erythropoiesis and neuroprotection. However, EPO treatment for neurological diseases requires repeated injections or high-dose systemic administration, which may cause systemic side effects. The lack of any effective treatment of acute and chronic neurodegenerative diseases and the promising outcome by EPO in animal models in vivo demand a critical evaluation of intranasal EPO delivery to the brain as an alternative administration method. Areas covered in this review: The current use and intranasal administration of EPO and its derivatives in preclinical studies and recent clinical trials with EPO in neurological diseases. What the reader will gain: This paper gives an overview of the therapeutic considerations of intranasal EPO and EPO derivatives for neuroprotection. Take home message: Intranasal delivery (ID) of neuroprotective drugs is an area of great interest. Among the administration strat...

Intranasal erythropoietin therapy in nervous system disorders

Background/aims Notch expression is not yet determined in hepatoblastoma. In this study the effect of chemotherapeutics (cisplatin, doxorubicin, cytosin arabinoside); differentiating agent (13 cis-retinoic acid) and apoptotic agents (5-aza-2'-deoxycytidine, arsenic trioxide) on notch expression in hepatoblastoma were evaluated. Methodology After HepG2 cell line was cultured and the agents and their combinations were applied for 24 hour in pre-optimized 50% lethal doses, RNA isolation and cDNA converting, expression of 84 custom array genes of notch signaling pathway (SABiosciences, PAT059F-24) was determined by Real Time PCR. The methylation status of 6 genes that showed more than 5 fold changes compared with control group were explored by Methylation qPCR Assay. High expressed genes are HDAC1, NFKB1, CHUK, CDKN1A, and CBL. Low expressed genes are DLL1, CD44, FZD2, GLI1, IL17B, LMO2, NOTCH1, LOR, PAX5, PT-CRA, SH2D1A, and WISP1. The genes searched for methylation (DLL1, HEY1, DTX1, HDAC1, NOTCH2 and JAG1) were not found to be related with methylation. Results The high expressed genes are related with cell proliferation. The main signaling genes that are closed to notch in signaling pathway are low expressed in hepatoblastoma. The agents do not show prominent effect of gene expression in many genes and methylation is not the reason of expression changes. The use of retinoic acid in the control of minimal residual disease of hepatoblastoma should be discussed. 5 aza "cytidin" the demethylating agent is not advised in treatment according to our results. Conclusion Cisplatin as main chemotherapeutic agent treatment is shown to change gene expression levels in notch signalling pathway in hepatoblastoma.

The effect of differentiating and apoptotic agents on notch signalling pathway in hepatoblastoma.

Understanding migration, population and differentiation of primordial neural crest cells will help in evolving biology of neuroblastoma. P16 is a tumour suppressor gene contributing in cell cycle arrest as cyclin dependent kinase inhibitor. Methylation is an important mechanism for silencing tumor suppressor genes. The aim of this study was to evaluate the role of p16 and its methylation pattern in neuroblastoma tumorigenesis. This study included 23 cases (11 male; 12 female) and 31 samples from archival paraffin embedded tissues. P16 was studied in 5 samples of normal adrenal medullar tissue, 5 samples of adrenal tissue including blastic rests, 5 samples of neuroblastoma in situ tissue and in 8 samples of neuroblastoma tissues primary and after chemotherapy in each group. The adrenal gland tissues were obtained from paediatric autopsy cases. Expression of p16 was searched by immunohistochemistry. Methylation specific PCR was used to detect the methylation rate of p16. The age range of autopsy cases was between 20 weeks of foetal age and 36 months of infant age. The mean age of neuroblastoma cases was 45 months. P16 expression was positive in normal adrenal tissues, in one of 5 samples of adrenal blastic rest tissue and in all of samples of after chemotherapy; while no expression was observed in neuroblastoma and neuroblastoma in situ tissues. P16 methylation was observed in samples of neuroblastoma in situ and primary neuroblastoma tissues. Our results suggest that p16 and its methylation seems to play role in neuroblastoma tumorigenesis and in the migration, population and differentiation of primordial neural crest cells. Inhibitors of DNA methylation may provide a useful tool for restoring p16 activity in neuroblastoma treatment.

Expression and methylation pattern of p16 in neuroblastoma tumorigenesis.

Objectives: The aim of the present study is to investigate the clinical significance of epigenetic changes in neuroblastoma, we evaluated the relationship between therapeutic variables and the pattern of gene methylation in neuroblastoma cell lines. Methods: In this minimal residual disease model, cytotoxic effects of blocked p14ARF by a demethylating agent on KELLY and SHSY-5Y human neuroblastoma cell lines were assessed following addition of the drugs used in the Turkish Pediatric Oncology Group (TPOG) chemotherapy protocol. Drug induced effects on cell viability, cell damage and apoptotic cell death ratio were assessed with trypan blue dying. Cytotoxic effects differed among the used neuroblastoma cell lines. For the investigation of mechanisms of this effect, p14 ARF gen methylation and expression levels, and MYCN expression levels were targeted. Expressions of mRNA and protein were determined with real-time PCR and ELISA, respectively. Results: The p14 ARF gene expression levels in KELLY 5-aza-CdR, Vincristin, Vincristin+5aza-CdR, Dacarbazine, Ifosfamide+5-aza-CdR, Doxorubicine+5-aza-CdR, Etoposide+5aza-CdR groups were found to be significantly higher than those measured in corresponding groups of SHSY-5Y (p<0.05). The percentages of p14ARF gene promoter unmethylation were higher in MYCN (-) groups than MYCN (+) groups (p=0.034). Conclusion: In this pioneering study we suggest not only a new therapeutic approach for early or late relapses following the standard treatment protocols, but also demonstrate the effect of chemoterapeutic agents on p14 ARF gene. The present study suggests that clinically aggressive neuroblastoma cell lines have aberrant methylation of p14ARF genes and provides a

https://www.journalagent.com/tjb/pdfs/TJB_37_2_129_138.pdf

Zeynep Zadeoglulari

Papers

The adverse effects of air pollution on the nervous system.

Intranasal erythropoietin therapy in nervous system disorders

The effect of differentiating and apoptotic agents on notch signalling pathway in hepatoblastoma.

Expression and methylation pattern of p16 in neuroblastoma tumorigenesis.

The role of p14ARF methylation in neuroblastoma minimal residual disease