Ecotoxicology and Environmental Safety 128 (2016) 67–74

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Ecotoxicology and Environmental Safety journal homepage: www.elsevier.com/locate/ecoenv

Review

The health effects of ambient PM2.5 and potential mechanisms Shaolong Feng a,n, Dan Gao a, Fen Liao a, Furong Zhou a, Xinming Wang b,nn a b

The School of Public Health, University of South China, Hengyang 421001, China The State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China

art ic l e i nf o

a b s t r a c t

Article history: Received 7 December 2015 Received in revised form 29 January 2016 Accepted 29 January 2016

The impacts of ambient PM2.5 on public health have become great concerns worldwide, especially in the developing countries. Epidemiological and toxicological studies have shown that PM2.5 does not only induce cardiopulmonary disorders and/or impairments, but also contributes to a variety of other adverse health effects, such as driving the initiation and progression of diabetes mellitus and eliciting adverse birth outcomes. Of note, recent findings have demonstrated that PM2.5 may still pose a hazard to public health even at very low levels (far below national standards) of exposure. The proposed underlying mechanisms whereby PM2.5 causes adverse effects to public health include inducing intracellular oxidative stress, mutagenicity/genotoxicity and inflammatory responses. The present review aims to provide an brief overview of new insights into the molecular mechanisms linking ambient PM2.5 exposure and health effects, which were explored with new technologies in recent years. & 2016 Elsevier Inc. All rights reserved.

Keywords: PM2.5 Health effect Oxidative stress Genotoxicity Inflammation

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Health effects of ambient PM2.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Airway damages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Cardiovascular impairments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Induction/exacerbation of diabetes mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Adverse effects in infancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Potential mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Metabolic activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Oxidative stress and damages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Mutagenicity/genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Inflammation and immunity disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion and perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction We breathe in, more or less, airborne particulate matters (PM), most of which are readily removed by mucociliary clearance

n

Corresponding author. Corresponding author. E-mail addresses: [email protected] (S. Feng), [email protected] (X. Wang).

nn

http://dx.doi.org/10.1016/j.ecoenv.2016.01.030 0147-6513/& 2016 Elsevier Inc. All rights reserved.

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(Pinkerton et al., 2000; Pozzi et al., 2003), yet the PM2.5 fraction, the so-called alveolar fraction with aerodynamic diameter less than 2.5 μm, largely retains in our lung and accounts for 96% of particles observed in human pulmonary parenchyma (Churg and Brauer, 1997). PM2.5 cannot only penetrate into the lung's gasexchange region (Pinkerton et al., 2000), but also further pass through the respiratory barrier and enter the circulatory system, and hence spread to the whole body (Xu et al., 2008; Wang et al.,

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2013). The greater specific surface area of PM2.5 also facilitates itself to be bound to toxic compounds, such as transition metals and polycyclic aromatic hydrocarbons (PAHs) (Pandey et al., 2013). PM2.5 is therefore more closely associated with adverse health effects than larger particles, and the 2006 World Health Organization Air Quality Guidelines recommended PM2.5 rather than PM10 (particles with aerodynamic diameter less than 10 μm) as the indicator of air particle pollution, which has increasingly become public concern worldwide (WHO's, 2006). In addition to increases in cardiopulmonary morbidity and mortality (Hu, 2009; Kloog et al., 2013; Madrigano et al., 2013; Crouse et al., 2012; Evans et al., 2013; Janssen et al., 2013; Burnett et al., 2014), recent large-population-covered epidemiological investigations have shown that PM2.5 exposure can also contribute to the incidence and development of diabetes mellitus (DM) and adverse birth outcomes (Watterson et al., 2007; Chen et al., 2013; Kloog et al., 2012; Zanobetti et al., 2014). Moreover, a number of studies have shown that PM2.5 still poses a nontrivial risk to public health even at very low levels (far below national standards) (Franklin et al., 2007; Fann et al., 2012; Elliott and Copes, 2011). But till present, the mechanisms underlying these effects have not been fully understood. Here we briefed recent investigations into the health effects of PM2.5 based on 132 articles extracted from 940 candidate papers published during 2005–2015 after searching the PubMed electronic preference databases. Though we attempted to summary new insights into the molecular mechanisms explored with new emerging technologies, this kind of review is an extremely challenging task and we would like to apologize in advance if some works were not cited or well recognized. We hope this review serves as a kind of roadmap to those new to the field.

2. Health effects of ambient PM2.5 2.1. Airway damages As the initial site of PM2.5 deposition, the lung is one of the primary targets of its toxicity. Numerous studies have shown that PM2.5 can cause airway inflammation (Habre et al., 2014; Duan et al., 2013; Wang et al., 2013; Davel et al., 2012), decline in lung function (Thaller et al., 2008; Jacobson Lda et al., 2012; Wu et al., 2013) and incidence and exacerbation of asthma and chronic obstructive pulmonary disease (COPD) (Habre et al., 2014; Nachman and Parker, 2012; Tsai et al., 2013; Jung et al., 2012; Gleason et al., 2014; Ogino et al., 2014; Zhao et al., 2013; Torres-Ramos et al., 2011; Montoya-Estrada et al., 2013; Willers et al., 2013; Vempilly et al., 2013), and render the lung susceptible to infections (Duan et al., 2013; Vempilly et al., 2013; Gurley et al., 2013; Belleudi et al., 2010; Darrow et al., 2014; Psoter et al., 2015; Jedrychowski et al., 2013; Zhao et al., 2014). After inhalation and deposition to the surface of pulmonary bronchioli and alveoli, PM2.5 is internalized into lung cells, such as epithelial cells and alveolar macrophages (AMs) (Gualtieri et al., 2011). As a result, PM2.5 elicits the oxidative stress by a variety of ways (discussed later) and trigges a series of impairments to the normal functions of those cells, or even causes them to death by ways of apoptosis, autophage or others (Gualtieri et al., 2011; Huang et al., 2013; Deng et al., 2013; Longhin et al., 2013). Meanwhile, the inflammatory responses are induced, with infiltration of inflammatory cells and release of inflammatory mediators (discussed later) (Duan et al., 2013; Wang et al., 2013; Davel et al., 2012). The cytokine net disordered by PM2.5 may further worsen the injury of lung tissue and lead to the alveolar collapse (Duan et al., 2013; Riva et al., 2011). In addition, the crosstalk between immune and epithelial cells may increase the expression

and release of the epidermal growth factor receptor (EGFR) ligands, including amphiregulin, transforming growth factor-alpha (TGFα) and -beta (TGFβ) and heparin-binding EGF-like growth factor, all of which are involved in proinflammatory and repair responses (Riva et al., 2011; Rumelhard et al., 2007; Dysart et al., 2014; Zaiss et al., 2015). The interactions between these cytokines and their receptors would contribute to bronchial remodeling, resutling in the thickening of bronchial wall and tissue fibrosis and further worsen lung impedance (Riva et al., 2011; Rumelhard et al., 2007; Dysart et al., 2014; Zaiss et al., 2015). As a result, the lung fucntion would be significantly dereased, even for healthy subjects (Thaller et al., 2008; Jacobson Lda et al., 2012; Wu et al., 2013). Persistent oxidative and inflammatory injury attributable to chronic PM2.5 exposure would be responsible for the development and maintenance of chronic bronchitis, COPD and asthma (Duan et al., 2013; Riva et al., 2011). Moreover, PM2.5 exposure may alter and impair the normal immune responses of the lung, rendering it susceptible to infections. Firstly, PM2.5 can impair the bronchial mucociliary system and result in the decrease of bacterial clearance (Duan et al., 2013). Secondly, PM2.5 and PM2.5-induced disorder of inflammatory cytokine net may trigger the death of lung epithelial cells and fibroblasts and inhibit the gap junctional intercellular communication between these cells, increasing the epithelial barrier permeability and impairing their function as the physical barriers for pulmonary innate immunity (Duan et al., 2013; Gualtieri et al., 2011; Huang et al., 2013; Deng et al., 2013; Longhin et al., 2013; Jacquemin et al., 2009). Thirdly, AMs are the important regulators of inflammation and indispensable in their antimicrobial activities in lower airway. Recently, increasing findings have shown that PM2.5 does not only derease the phagocytosis of AMs through disrupting the normal physical and immunological function of the lung surfactant, such as di-palmitoyl-phosphatidylcholine and amino acids related to opsonin proteins, which generally act as opsonins and enhance the phagocytosis of AMs to bacteria (Kendall, 2007), and impairing the response of natural killer (NK) cells, which enhance the phagocytosis ability of AMs (Zhao et al., 2014), but also directly impairs the antibacterial functions of AMs by various mechanisms, including impacting on the transferrinmediated Fe3 þ delivery to AMs, altering the expresssion of tolllike receptors (TLRs), disturbing the organization of microtubules and deceasing their phagocytic activities (Gualtieri et al., 2011; Huang et al., 2008; Doherty et al., 2007; Zhao et al., 2012; Corsini et al., 2013). All of these effects would lead to the decline in pulmonary immunity and facilitate infectious diseases. Altogether, increasing the oxidative stress and inflammation and altering the immune responses are the important mechanisms by which PM2.5 reduces the pulmonary function, mediates the development, maintenance and exacerbation of airway obstructive diseases and favors infectious diseases. However, there are still numerous open questions to be answered. For example, what a role does the crosstalk between immune and epithelial cells act in the airway allergic responses and tissue remodeling in chronic bronchitis, COPD and asthma? What moleclular signaling pathways are involved in these patho-physiological processes? All these issues will require of our great efforts to elucidate in future. 2.2. Cardiovascular impairments Numerous studies have shown that PM2.5 exposure does not only contribute to changes in subclinical indicators of cardiovascular function, but also consistently links to cardiovascular morbidity and mortality (Madrigano et al., 2013; Chiu and Yang, 2013; Hsieh et al., 2013; Chang et al., 2013; Leiva et al., 2013; Bell et al., 2014). A number of studies have shown that PM2.5 can impair the

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function of cardiac autonomic nervous system (ANS) and lead to decline in heart rate variability (HRV), which is considered as an independent risk factor for cardiovascular morbidity and mortality (Thayer et al., 2010; He et al., 2011; Wang et al., 2013; Kamal et al., 2011). Inducing oxidative stress and inflammatory impairments in the central nervous system, especially in the hypothalamus, was suggested to be the important mechanisms underlying this abnormal activation of the ANS (Wang et al., 2013; Ying et al., 2014; Maes et al., 2014). The PM2.5-induced oxidative stress and inflammation in the hypothalamus may lead to dysfunctions of its neuroendocrine, such as increase of norepinephrine and 5-hydroxy-indole acetic acid in its paraventricular nucleus and corticotrophin releasing hormone levels in the median eminence, which can activate the paraventricular nucleus to cause an increase in sympathetic nervous system and/or stress axis activity (Maes et al., 2014; Balasubramanian et al., 2013). As a result, PM2.5 exposure would elicit the dysfunctions of the ANS, leading to decline in HRV and ultimately increasing cardiovascular diseases. PM2.5 can also trigger a battery of patho-physiological responses that increase blood pressure and result in the development of hypertension (Wang et al., 2013a; Wang et al., 2013b; Ying et al., 2014; Wellenius et al., 2013; Krishnan et al., 2012; Jedrychowski et al., 2012; Chen et al., 2013). The specific biological mechanisms have been suggested to include an increase in sympathetic tone and/or the modulation of basal systemic vascular tone (Ying et al., 2014) and the endothelial and vascular dysfunctions (Davel et al., 2012; Wellenius et al., 2013; Krishnan et al., 2012; Kile et al., 2013). The endothelium acts to maintain vascular homeostasis. Recent studies have found that PM2.5 cannot only upregulate the endothelin system, but also decrease endotheliumdependent relaxation by inhibiting the expression of eNOS and iNOS in endothelium of arteries (Davel et al., 2012; Kile et al., 2013). Moreover, superoxides elicited by PM2.5 may also inhibit the actions of nitrous oxide in inducing vasodilatation (Kannan et al., 2006). Thus, the systemic inflammation and oxidative stress following PM2.5 exposure will trigger the endothelial dysfunction and lead to vasoconstriction (Kannan et al., 2006). These effects will decrease the artery diameter and flow-mediated dilation (Krishnan et al., 2012). Meanwhile, systemic alterations in rheological factors, including blood coagulability and whole blood viscosity, will change the vascular hemodynamics, resulting in higher vascular resistance and lower blood flow velocity (Wellenius et al., 2013). Ultimately, these integrative effects of PM2.5 exposure will induce the hypertension (Wang et al., 2013a; Wang et al., 2013b; Ying et al., 2014; Jedrychowski et al., 2012; Chen et al., 2013; Kannan et al., 2006). Moreover, PM2.5 exposure has been shown to link to cardiovascular diseases via accelerated atherosclerosis (AS), which is a chronic disease of the arterial wall (Adar et al., 2013). Both inflammation and endothelial dysfunction are considered to be the important mechanisms to trigger AS (Libby et al., 2011). Endothelial cells were shown to play a central role in response to PM2.5 due to their involvement in pro-inflammatory events simultaneously (Montiel-Davalos et al., 2007). The endothelial dysfunctions and injuries attributable to PM2.5 exposure caused the inflammation, leading to monocytic/macrophagical adhesion via increasing the expression and release of adhesion molecules, such as E-selectin, P-selectin and ICAM-1 (Wang et al., 2013a; Davel et al., 2012; Wang et al., 2013b; Montiel-Davalos et al., 2007). On the other hand, PM2.5 exposure has been found to decrease the levels of circulating endothelial progenitor cells (EPCs), which contribute to postnatal endothelial repair and regeneration, via preventing the mobilization of EPCs from the bone marrow to the peripheral blood (Niu et al., 2013; Haberzettl et al., 2012). These results showed that the crosstalk between endothelial and inflammatory cells attributable to PM2.5 exposure plays an important

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role in patho-physiological processes of AS. Also, PM2.5 may directly act on the heart and induce cardiac tissue remodeling and function altering, leading to the occurrence and development of cardiac diseases. Cardiac histopathology results have revealed PM2.5 deposition and myocardial inflammation in the tested rats (Wang et al., 2013). Long-term PM2.5 exposure could induce obvious myocardial ultra-structural changes (with increased hypertrophic markers), and lead to adverse ventricular remodeling (with myosin heavy chain isoform switch and fibrosis, decreased fractional shortening and mitral inflow patterns consistent with diastolic dysfunction) (Wang et al., 2013; Wold et al., 2012). In vitro cardiomyocyte function revealed depressed peak shortening and increased time-to-90% shortening and re-lengthening, which were associated with up-regulation of profibrotic markers and decreased total antioxidant capacity (Wold et al., 2012). Whole-heart SERCA2a levels and the ratio of alpha/betaMHC were both significantly decreased in the PM2.5-exposed animals, suggesting a switch to fetal programming (Wold et al., 2012). In addition, PM2.5 was found to exacerbate virus-induced myocarditis through the increase in Th17-mediated viral replication, perforin response and imbalance of MMP-2/TIMP-1 (Xie et al., 2013). Taken together, these results have elucidated various mechanisms underlying the trigger of cardiovascular diseases attributable to PM2.5 exposure. Both endothelial dysfunction and inflammation were suggested to play important roles in these patho-physiological processes. However, it is not yet clearly answered how endothelial cells interact with immune cells and what factors and which signal pathways are involved in. These questions are of critical importance and warrant additional studies to dissect the etiopathogenesis of cardiovascular diseases due to PM2.5 exposure. 2.3. Induction/exacerbation of diabetes mellitus Recently, chronic PM2.5 exposure was found to promote the development of diabetes mellitus (DM), inducing multiple abnormalities associated with the pathogenesis of type 2 diabetes mellitus (T2DM), including insulin resistance (IR), visceral adipose inflammation, brown adipose mitochondrial adipose changes and hepatic endoplasmic reticulum (ER) stress (Chen et al., 2013; Reis et al., 2009; Brook et al., 2013; Xu et al., 2013; Mendez et al., 2013; Liu et al., 2014). Moreover, PM2.5 exposure, even at low levels, has also been identified as an increased risk of mortality attributable to DM (Zanobetti et al., 2014; Brook et al., 2013). Alterations in inflammatory pathways and ER stress have been proposed to be the important mechanisms, by which PM2.5 induces IR and T2DM and activates its patho-physiological responses (Xu et al., 2013; Mendez et al., 2013; Liu et al., 2014; Sun et al., 2013; Schneider et al., 2010). For example, CC-chemokine receptor 2 dependent pathways were found to play a critical role in PM2.5mediated IR by regulating visceral adipose inflammation, hepatic lipid metabolism and glucose utilization in skeletal muscle (Liu et al., 2014). Modification of cell-surface co-stimulatory molecules, which mediates the activation of innate immune cell, in circulating monocytes by PM2.5, was also shown to play an important role in the pathogenesis of these effects (Liu et al., 2014; Schneider et al., 2011). Additionally, PM2.5 was observed to trigger the unfolded protein response (UPR), an intracellular ER stress signaling that regulates cell metabolism and survival in vivo, through phosphorylation of the inositol-requiring 1alpha in hepatic cells (Mendez et al., 2013). Moreover, the UPR or UPR-mediated ER stress have been revealed to be connected to inflammatory pathways and contribute to the production of inflammatory mediators. Meanwhile, inflammation can also induce or propagate the intracellular UPR (Hummasti and Hotamisligil, 2010). Thus, the interaction between inflammation and ER stress might make a

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positive feedback loop that amplifies the effects of PM2.5 on DM. 2.4. Adverse effects in infancy Protecting the environmental health of mothers and infants remains a top global priority (Kannan et al., 2006). However, a host of epidemiologic evidence suggested that maternal PM2.5 exposure during pregnancy was linked with adverse birth outcomes, including preterm birth, lower birth weight and post-neonatal infant mortality (Kloog et al., 2012; Savitz et al., 2013; Bell et al., 2012; Pereira et al., 2013; Hyder et al., 2014; Fleischer et al., 2014; Woodruff et al., 2006; Jedrychowski et al., 2006). Five possible albeit not exclusive biological mechanisms, oxidative stress, inflammation, coagulation, endothelial function and hemodynamic responses, have been put forth in the literature to explain these effects (Kannan et al., 2006). These disorders in pregnant women exposed to PM2.5 could cause endocrine disruption and impair oxygen and nutrition transport across the placenta, potentially leading to low birth weight and preterm birth (Kannan et al., 2006; Barrett, 2014). Alternatively, PM2.5 may also bind receptors for placental growth factors, resulting in decreased fetal–placental exchange of oxygen and nutrients (Kannan et al., 2006). Aside from the immediate consequences in infancy, lower birth weight and preterm birth attributable to PM2.5 exposure will affect health throughout childhood and in adulthood. Prenatal exposure to PM2.5 has been observed to increase susceptibility to respiratory (broncho-pulmonary) infections and program respiratory morbidity in early childhood (Jedrychowski et al., 2013; Jedrychowski et al., 2013). Immune system development, particularly in the prenatal period, has far-reaching consequences for health during early childhood, as well as throughout life (Hertz-Picciotto et al., 2008). Environmental disturbance of the complex balances of Th1 and Th2 response mechanisms can alter the normal development of immune system. Dysregulation of this process or an aberrant trajectory or timing of events may result in atopy, asthma, a compromised ability to ward off infection, or other autoimmune disease (Hertz-Picciotto et al., 2008). A wide range of chemical, physical and biological agents appear to be capable of disrupting immune development. Prenatal ambient PAHs and PM2.5 exposures have been shown to be associated with altered lymphocyte immunophenotypic distributions in cord blood and possible changes in cord serum IgE levels (Hertz-Picciotto et al., 2008). These findings indicated that aberrant immume system development is another important mechanism by which prenatal PM2.5 exposure may not only cause the immediate adverse effects in infancy, but also further affect health throughout childhood and in adulthood. However, owing to the lack of animal model experiments in this respect, the specific biological mechanisms underlying these effects of PM2.5 exposure are not yet fully understood. Thus, further intensive studies will be necessary to uncover the molecular mechanisms in future.

3. Potential mechanisms 3.1. Metabolic activation After being absorbed into the targeting cells, PM2.5 are often localized in laminar organelles, although particles without apparent plasma membrane covering are also seen (Wang et al., 2013; Gualtieri et al., 2011; Corsini et al., 2013). The release of organic chemicals (such as volatile organic compounds and PAHs) from PM2.5 may activate the aryl hydrocarbon receptor (AhR) in those cells, resulting in increased expression of the AhR-regulated genes, including the phase I xenobiotic-metabolizing cytochrome P450

enzymes (such as CYP1A1, CYP1A2, CYP1B1, CYP2E1 and CYP2F1), the phase II enzymes (e.g. NQO1, ALDH3A1, EPHX1, GST-pi1 and GST-mu3) and AhRR (Gualtieri et al., 2011; Longhin et al., 2013; Abbas et al., 2009; Gualtieri et al., 2012; Dieme et al., 2012; Feng et al., 2013). Subsequently, the organic chemicals released from PM2.5 will be metabolically activated by this xenobiotic-metabolizing enzyme system into reactive electrophilic metabolites (REMs), which will pose various toxic effects to the targeting cells (Gualtieri et al., 2011; Longhin et al., 2013; Gualtieri et al., 2012; Dieme et al., 2012). 3.2. Oxidative stress and damages Although the mechanisms underlying the relationships between PM2.5 exposure and adverse health effects have not been fully elucidated, PM2.5-induced oxidative stress has been considered as an important mechanism of PM2.5-mediated toxicities (Deng et al., 2013; Weichenthal et al., 2013). A number of studies have shown that PM2.5 exposure may contribute to systemic oxidative stress and damages in human or animal cells (Longhin et al., 2013; Gualtieri et al., 2012; Yang et al., 2013; Kouassi et al., 2010; Dergham et al., 2012; Reche et al., 2012). Firstly, there are environmentally persistent free radicals in PM2.5, especially for the combustion-derived particles (Gehling and Dellinger, 2013; Gehling et al., 2014). Secondly, numerous organic chemicals coated on PM2.5 can be metabolically activated into REMs, which may produce or increase intracellular reactive oxygen species (ROS) (Torres-Ramos et al., 2011; Longhin et al., 2013; Gualtieri et al., 2012; Kouassi et al., 2010). Thirdly, transition metals, such as Fe, Cu, Vn and Mn, presented in PM2.5 may also induce ROS via the Fenton Reaction or disrupting the function of some related enzymes (discussed later) (Torres-Ramos et al., 2011; Huang et al., 2013; Maciejczyk et al., 2010). Additionally, oxidative stress may be arised from the PM2.5-mediated activation of inflammatory cells, which are capable of generating ROS and reactive nitrogen species (RNS) (Kannan et al., 2006). On the other hand, PM2.5 can impair the antioxidant system and decrease the antioxidant capacity of the exposed cells. Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, is the primary intracellular defense mechanisms against oxidative stress (Deng et al., 2013). PM2.5-induced ROS may function as signaling molecules to trigger translocation of Nrf2 into nucleus, resulting in altering transcription of antioxidant enzyme system (Deng et al., 2013). Indeed, PM2.5 exposure has been found to alter the expression of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and GSH-Px, and trigger decrease of their activities (Wang et al., 2013; Davel et al., 2012; Deng et al., 2013; Wang et al., 2013; Kouassi et al., 2010). Nrf2 over-expression suppressed and Nrf2 knockdown increased PM2.5-induced ROS generation in human cells (Deng et al., 2013). Simultaneously, PM2.5 may also cause significantly decreased activities of glutathione metabolism enzymes, such as G6PD, GR, GPx and PTPase, resulting in the decline of total SH groups in biological systems (Torres-Ramos et al., 2011; Kouassi et al., 2010). In addition, abnormal activities of other oxidant enzymes, such as plasma paraoxonase, myeloperoxidase and heme oxygenase (HO), have also been shown to be associated with PM2.5 exposure, especially in populations susceptible to oxidative stress (Montoya-Estrada et al., 2013; Jedrychowski et al., 2013; Gualtieri et al., 2012). These results indicated that PM2.5 can impair the antioxidant system and decrease the antioxidant capacity of the exposed cells by various mechanisms. These ROS, due to PM2.5 exposure, will cause various adverse effects on cells via reacting to bio-macromolecules, such as plasmatic lipids, proteins and DNA, impairing their structure and function, ultimately increasing damages to the target cells and

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tissues. Many markers of protein oxidation (such as gamma-glutamyl semialdehyde in hemoglobin, 2-aminoadipic semialdehyde in hemoglobin and plasma proteins) and lipid oxidation (measured as malondialdehyde in plasma) have been identified to be associated with increased PM2.5 exposure levels (Wang et al., 2013; Dergham et al., 2012). Increasing levels of 7-hydro-8-oxo-2′deoxyguanosine (8-oxodG) and other nucleotide oxides, which are important predictors of oxidative DNA damage (discussed later), in the PM2.5-exposed organisms, have also been reported (Longhin et al., 2013; Dergham et al., 2012; Reche et al., 2012). Moreover, the excess ROS may activate several signaling pathways, such as NFκB, ASK1, JNK and p53, and cause a series of adverse effects to cells (Nam et al., 2004; Soberanes et al., 2009). Intriguingly, these adverse effects are often significantly inhibited or attenuated by the antioxidants (Longhin et al., 2013; Yang et al., 2013), indicating a promising strategy to prevent or alleviate the effects of PM2.5 exposure by antioxidation approaches. 3.3. Mutagenicity/genotoxicity A number of studies have shown that the organic extracts from PM2.5 have mutagenic properties, evaluated by the Ames test using different Salmonella typhimurium strains with or without S9 mix metabolic activation, revealing a constant presence of direct-acting mutagens and promutagens on PM2.5 (Traversi et al., 2009; de Brito et al., 2013; Andre et al., 2011). PAHs and/or nitro-compounds (i.e. nitro-PAHs and hydroxylamines) were considered to be the main carcinogen compounds transported by PM2.5 (Traversi et al., 2009; Gilli et al., 2007). Moreover, both PM2.5 and thermally desorbed PM2.5 have also been found to cause a dose-response mutagenicity in the Ames test, indicating mutagenic properties of the core of the particles (Andre et al., 2011). Also, PM2.5 has been found to cause various DNA damages in terms of 8-oxodG, strand breaks, endonuclease III- and fapyguanine glycosylase-sensitive sites and polyaromatic hydrocarbon adducts in human or animal cells (Longhin et al., 2013; Corsini et al., 2013; Gualtieri et al., 2012; Dergham et al., 2012; Reche et al., 2012). Moreover, PM2.5 can increase the frequencies of chromosomal aberration and micronucleus in human cells, demonstrating its clastogenic activity (Gualtieri et al., 2011; Longhin et al., 2013; de Brito et al., 2013; Xu et al., 2008). Besides organic compounds, both heavy metals coated on and the core of PM2.5 were also found to play important roles on their genotoxic potential to human cells (Longhin et al., 2013; de Brito et al., 2013; Andre et al., 2011; Oh et al., 2011). Interestingly, these PM2.5-induced genotoxic effects were significantly blocked by antioxidants, ROS scavenging agents and alpha-naphthoflavone, suggesting the involvement of ROS and REMs formed via a P450-dependent reaction (Longhin et al., 2013; Reche et al., 2012; Oh et al., 2011). The DNA-damage responses triggered by PM2.5, such as increased phosphorylation of ATM, Chk2 and H2AX, may cause a series of alterations in cellular biochemical and physiological processes, especially in gene expression profiles, altering the functions and/or fates of the cells (Gualtieri et al., 2011; Longhin et al., 2013; Gualtieri et al., 2012). Therein, the epigenetic effect of PM2.5, such as modulation of the methylation in the promoter region of genes, was found to be an important mechanism to alter a handful of genes expression in cells (Kile et al., 2013). But what effects of PM2.5 on the DNA-repairing systems are? It is not yet answered currently. Further in-depth works are worthwhile to elucidate the effects and underlying mechanisms. 3.4. Inflammation and immunity disorder As mentioned above, inflammation has been shown to be involved in most, if not all of the adverse health effects of PM2.5,

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demonstrating its central role in mediating the impacts of PM2.5 on public health. In vitro, PM2.5 has been shown to induce inflammatory responses in various human and animal cells, with a time- and dosedependent increases of the gene expression and protein secretion of pro-inflammatory mediators (i.e., TNFα, IL-1β, IL-6, IL-8, MCP-1) (Corsini et al., 2013; Dieme et al., 2012; Dergham et al., 2012; Mitkus et al., 2013; Gioda et al., 2011). Increases of IL-1R1, IL-6R, IL-1 receptor associated kinase-1 (IRAK) protein, phosphorylated STAT3 protein, IL-20 and major histocompatibility complex peptide class-1 (MICA) have also been observed, indicating that PM2.5 is able to activate both IL-1R- and IL-6R-mediated signaling pathways in human lung cells (Watterson et al., 2007). In addition, PM2.5 has also been found to enhance the mRNA expression and protein secretion of amphiregulin, TGFα and heparin-binding EGFlike growth factor, ligands of the EGFR involved in pro-inflammatory and repair responses, in airway epithelial cells (Rumelhard et al., 2007). In vivo, PM2.5 has also been shown to result in local and systemic inflammation. Nasal inflammation, with increase in percentage of eosinophils and albumin, urea and alpha1-antitrypsin concentrations, was observed in asthmatic allergic children exposed to elevated levels of PM2.5 (Nikasinovic et al., 2006). Lung inflammation was also found to increase in a dose-dependent manner in humans and animals exposed to PM2.5 (Duan et al., 2013; Wang et al., 2013; Riva et al., 2011). In BALF, the cell number, protein, sialic acid, pro-inflammatory mediators, such as TNFα and IL-6, were increased (Duan et al., 2013; Wang et al., 2013; Zhao et al., 2014; Xu et al., 2013). Meanwhile, the expression of proinflammatory cytokines, transcription factor (NF-κB) and inflammatory responsive neurotrophins were up-regulated in lung tissues (Davel et al., 2012; Win-Shwe et al., 2013). The release of chemokines, such as ICAM-1 and MCP-1, a monocyte/macrophage attractant in blood, may facilitate the infiltration of inflammatory cells to lung tissues, confirmed by lung histopathology (Duan et al., 2013; Wang et al., 2013; Zhao et al., 2012; Xu et al., 2013; Mitkus et al., 2013). Indeed, the number of foreign-body granulomas (formed by monocytes–macrophages) in the lungs of PM2.5-exposed rats became more and more as times went on (Xu et al., 2008). As mentioned above, the increased EGFR ligands may further contribute to the release of granulocyte-macrophage colonystimulating factor in bronchial epithelial cell, suggesting that they could elicit and sustain the PM2.5-induced airway pro-inflammatory response and contribute to bronchial remodeling (Rumelhard et al., 2007). Furthermore, systemic inflammation has also been observed in humans (Zhao et al., 2013; Niu et al., 2013; Schneider et al., 2010) and animals (Xu et al., 2008; Zhao et al., 2012; Wang et al., 2013; Ying et al., 2014) exposed to PM2.5, with enhanced levels of inflammation biomarkers, such as C-reactive protein, oxidized low-density lipoproteins, IL-6, TNFα and vascular endothelial growth factor in the blood. In addition, PM2.5 has also been found to increase an inflammatory response in other target organs, such as the arcuate nucleus of hypothalamus, liver, spleen, heart and kidney, evidenced by increased expression of pro-inflammatory genes, NF-ĸB pathway activation and inflammatory cells infiltration (Xu et al., 2008; Ying et al., 2014; Xie et al., 2013; Xu et al., 2013). Interestingly, inhalational exposure to PM2.5 was found to result in the increase of macrophage infiltration and significantly up-regulating pro-inflammatory genes of TNFα, MCP1 and leptin; While IL-10 and adiponectin, known as anti-inflammatory genes, were reduced in both epicardial adipose tissue and perirenal adipose tissue in the tested rats (Sun et al., 2013). At the same time, altered immune function has been observed in numerous studies (Xu et al., 2008; Zhao et al., 2012; Schneider et al., 2011; Williams et al., 2011). PM2.5 could decrease TLR4 or TLR2 positive cells, but increase the Th2 related cytokines IL-4, IL-

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5, IL-10 and IL-13, in both BALF and blood of the tested animals, driving a Th2-biased immune response by an inflammasome-associated mechanism (Ogino et al., 2014; Zhao et al., 2012). Also, PM2.5 may synergistically activate basophils and significantly increase antigen-specific IgE in Balb/c mice, suggesting its important role in the aggravation of IgE-mediated allergic diseases (Schober et al., 2006). Moreover, the immune parameters (IgA, IgG, IgM and IgE) and lymphocyte profiles (CD4 T cells, CD8 T cells, CD4/CD8 T cells) in blood of participants were altered by PM2.5 exposure (Zhao et al., 2013; Williams et al., 2011). Furthermore, the expression of the cell-surface co-stimulatory molecules, including CD80, CD40, CD86, HLA-DR, and CD23, which mediate innate immune and inflammatory responses, were significantly increased in monocyte at 2- to 4-day lag times after PM2.5 exposure (Schneider et al., 2011). In addition, PM2.5 was found to significantly decrease the NK cells recruited into the airways following subsequent S. aureus infection and decrease the phagocytosis of AMs to S. aureus (Zhao et al., 2014). Further, adoptive transfer of naive NK cells to the lung of prior PM2.5-exposed rats could restore PM2.5-impaired antibacterial host defense (Zhao et al., 2014). Also, PM2.5 could up-regulate the expressions of IL17A, perforin, TGFβ, RORgammat and matrix metalloproteinases-2, along with an increase in CD4 þ IL-17 þ cells in the spleen and heart, but decreased interferon-gamma (IFNγ) and metalloproteinases-1 in BALB/c mice (Xie et al., 2013). These results indicated that PM2.5 may result in the alteration of immune functions, which might link to various adverse health effects, including asthma, pulmonary infectious diseases, myocarditis and DM. Cellular NF-κB is one of the key transcription factors that are involved in the inflammatory responses to PM2.5. In vitro PM2.5 was shown to activate the NF-κB complexes through phosphorylation of nuclear p65 and cytoplasmic IKK-alpha, leading to nuclear p65/p50 DNA binding in a concentration-/and time-dependent manner in human lung epithelial cells (Maciejczyk et al., 2010; Dagher et al., 2007). In vivo PM2.5 may also activate the NFκB pathway and trigger inflammatory responses in lung and/or other target organs (Xu et al., 2008; Davel et al., 2012; Ying et al., 2014; Xie et al., 2013; Xu et al., 2013; Win-Shwe et al., 2013). Intriguingly, the NF-κB activation by PM2.5 and consequential inflammatory responses can be inhibited by a pre-treatment of the cells with antioxidants N-acetyl-L-cysteine and dimethylthiourea or an iNOS inhibitor L-N6-1-iminoethyl-lysine, indicating that PM2.5 induces NF-κB activity via the pathways involving ROS and/ or RNS generation (Nam et al., 2004). Considering the fact that NFκB also induces ROS and NO generation, they may generate a positive feedback loop that amplifies the downstream responses (Nam et al., 2004; Dagher et al., 2007). In addition, PM2.5-induced IL-8 release was completely blocked by the selective inhibitor SB203580 in both THP-1 and A549 cells, indicating a role of p38 MAPK activation in this process (Corsini et al., 2013). The Ca2 þ -CaN-NFAT signal pathway was also identified to be involved in the regulation of IL-2 in Jurkat T cells exposed to PM2.5 (Tong et al., 2013). Thus, various signal pathways may be involved in the regulation of inflammatory responses induced by PM2.5. But it is currently not known how these signal pathways are coordinated with each other to accurately modulate the inflammatory processes caused by PM2.5 and what are the exact mechanisms underlying the downstream biological effects. Thus, further in-depth studies will be necessary to clarify them in future.

4. Conclusion and perspective As shown above, PM2.5 may not only contribute to increase in cardiopulmonary morbidity and mortality, but also facilitate the

Mechanisms PM2.5

Metabolic activation Oxidative stress Genotoxicity others ...

Pulmonary diseases Cardiovascular diseases Diabetes mellitus Adverse birth outcomes others ...

Fig. 1. The health effects of PM2.5 and mechanisms. After being absorbed into target cells, PM2.5 may impair the cellular physiological/biochemical processes by the mechanisms of inducing oxidative stress, genotoxicity, inflammation and others, altering the normal physiological functions and/or fates of target cells, resulting in the damages of the tissues and organs, and finally facilitate the incidence and development of cardiopulmonary diseases, diabetes mellitus, adverse birth outcomes and others.

incidence and development of DM and cause adverse birth outcomes. Notably, PM2.5 was shown to still pose a certain risk to public health even at very low levels (far below national standards). This should raise concern for the policymakers in decisions to regard further reductions in permitted levels of PM2.5 emissions. Therein, oxidative stress, genotoxicity and inflammation were suggested to be the central mechanisms by which PM2.5 induced a series of adverse effects to public health (Fig. 1). These findings have provided fundamental insights into the mechanisms linking PM2.5 exposure and health effects. But there are still many knowledge gaps in our understanding of the intricate signal pathways which are involved in the cellular responses to PM2.5. A better understanding of the mechanisms will enable the development of new strategies to protect individuals at risk and reduce the detrimental effects of PM2.5 on public health. On the other hand, understanding of the PM2.5 constituents that are most responsible for adverse health outcomes is critical for efforts to develop pollution abatement strategies that may maximize benefits to public health. Due to the chemical composition and physicochemical characteristics of particles varying spatially and temporally, it remains uncertainty about which chemical constituents of PM2.5 are most harmful to public health. To better address this knowledge gap, research priorities should be focused on the molecular mechanism (s) by which PM2.5 and its constituents act on public health.

Disclosure statement All authors do not have any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations.

Acknowledgment This paper was funded by the Natural Science Foundation of China (41025012), the Foundation of Educational Department of Hunan Province (12A118) and the University of South China, China (2012XQD44).

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