Cardiovascular effects of airborne particulate matter: A review of rodent model studies

Chemosphere 242 (2020) 125204

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Chemosphere journal homepage: www.elsevier.com/locate/chemosphere

Review

Cardiovascular effects of airborne particulate matter: A review of rodent model studies Mostafa Hadei a, b, Kazem Naddafi a, c, * a

Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran c Center for Air Pollution Research (CAPR), Institute for Environmental Research (IER), Tehran University of Medical Sciences, Tehran, Iran b

h i g h l i g h t s
We reviewed cardiovascular studies on rodent models.
Animal models have been successful study PM-induced cardiovascular diseases.
There are some areas that the exact mechanisms are still unclear.
in vivo studies should account for the role of different PM compositions.

a r t i c l e i n f o

a b s t r a c t

Article history: Received 16 August 2019 Received in revised form 21 October 2019 Accepted 22 October 2019 Available online 23 October 2019

In recent year, animal models have been growingly used to increase our knowledge about the toxicity of PM and underlying mechanisms leading to cardiovascular diseases. In this article, we review the current state of knowledge and findings of studies investigating the cardiovascular effects of PM in rats and mice. The six main areas covered in this review include: I) nature of particulate matter and toxicity mechanisms, II) systemic inflammation, III) heart rate and heart rate variability, IV) histopathological effects, V) atherosclerosis, VI) thrombosis, and VI) myocardial infarction. This review showed that animal model studies have been successful to bring new insights into the mechanisms underlying PM-induced cardiovascular diseases. However, there are some areas that the exact mechanisms are still unclear. In conclusion, investigating the cardiovascular effects of PM in vivo or interpreting the results should attempt to justify the role of different PM compositions, which may vastly affect the overall cytotoxicity of particles. © 2019 Elsevier Ltd. All rights reserved.

Handling Editor: A. Gies Keywords: PM2.5 Toxicology Air pollution Rat Mice Heart diseases

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Nature of particulate matter and toxicity mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Systemic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Heart rate and heart rate variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Histopathological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

* Corresponding author. School of Public Health, Tehran University of Medical Sciences, Enghelab Square, Tehran, Iran. E-mail addresses: knadafi@tums.ac.ir, [email protected] (K. Naddafi). https://doi.org/10.1016/j.chemosphere.2019.125204 0045-6535/© 2019 Elsevier Ltd. All rights reserved.

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M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction A rising trend of particulate air pollution has been observed worldwide during the past decades (WHO, 2014; Likhvar et al., 2015). Particulate matter is a mixture of different elements and compounds. Many epidemiological studies have proved that shortand long-term exposures to airborne particulate matter (PM) are associated with cardiovascular effects in human. These adverse health effects may include ischemic heart disease (IHD), myocardial infarction (MI), arrhythmia, thrombosis, atherosclerosis, etc. (Brunekreef and Forsberg, 2005; Goldberg, 2008; Hoek et al., 2013). In addition, the systemic inflammation caused by circulatory levels of inflammatory cytokines is known to trigger many cardiovascular effects (Siponen et al., 2015; Xia et al., 2017). These led to an increase in number of studies investigating the toxicology of PM and mechanisms of cardiovascular effects using animal models, especially the rodent ones. This review aims to study the current state of knowledge and findings of studies that have investigated the systemic inflammation and cardiovascular effects of PM in rodent models. We defined six main areas for this review, including: I) nature of particulate matter and toxicity mechanisms, II) systemic inflammation, III) Heart rate and heart rate variability, IV) Histopathological effects, V) Atherosclerosis, VI) thrombosis, and VI) myocardial infarction. We have selected the relevant studies about the particular subjects according to their relevancy, meaningfulness, importance, and validity by judgment, and tried to gather the evidence from several types of PM, doses, and exposure methods. 2. Nature of particulate matter and toxicity mechanisms Particulate matter is the mass of compounds and elements aggregated together, and is normally defined and classified as their aerodynamic diameter. The most important and studied fractions of PM are particles with an aerodynamic diameter less than 10 mm (PM10), less than 2.5 mm (PM2.5), less than 0.1 mm (ultrafine particles i.e. UFP), and between 10 mm and 2.5 mm (coarse particles i.e. PM2.510) (Perrone et al., 2010; Clifford et al., 2018). The smaller fractions of particles have the ability to penetrate the respiratory tract and lung deeper, and consequently induce more and stronger health effects (Kumar et al., 2014). Smaller fractions can also enter the circulatory system, and affect many organs such as heart, brain, vascular system, etc. In addition to diameter, chemical composition, surface area and other characteristics of PM influence its toxicity (Nel, 2005). In some cases, there are a relationship between diameter and chemical composition. It is reported that UFP contribute comparably more redox cycling chemicals such as quinones than larger PM, as indicated by the increased ability of these particles in producing greater amounts of reactive species (Cho et al., 2005). PM consists of elements, heavy metals, ions, organic compounds, etc. (Zarandi et al., 2019b). The overall cytotoxicity of PM differs from those of each species separately. In the other word, the presence of endpoint-specific toxicologically inert PM species may interfere with the response to the active species. This is possibly due to the physical form of species (Bein and Wexler, 2015). Therefore, several characteristics of PM can affect its toxicity. To compare the results of various studies, it should be noted that the studied particles may have different characteristics,

but PM is usually studied based on the mass. Three possible hypotheses have been suggested for explaining the association between exposure to PM and cardiovascular diseases (Brook et al., 2010; Chin, 2015). The first hypothesis indicates that PM in the lung promotes pulmonary oxidative stress and inflammation, leading to systemic oxidative stress and inflammation. Increased circulating pro-inflammatory cytokines develop a range of cardiovascular diseases such as atherosclerosis, thrombosis, alteration in vasoconstriction, etc. (Du et al., 2016). The two other hypotheses are less supported, comparing to the abovementioned one. The second hypothesis explains that activation of pulmonary autonomic nervous system (ANS) arcs specific lung receptors cause an ANS imbalance, which leads to the increased vasoconstriction, heart rate variability and arrhythmia potential, etc. (Wu et al., 2018). The third possible mechanism asserts the translocation PM and especially ultrafine particles into blood stream via lung or gut, and interacting with remote organs directly. This may leads to increased vasoconstriction, atherosclerosis, platelet aggregation, etc. (Du et al., 2016). In general, oxidative stress is possibly the main toxicological mechanism of PM for induction of adverse health effects (Yang et al., 2014). Reactive oxygen species (ROS), such as oxygen and hydroxyl radicals, as well as other reactive forms of O2 such as hydrogen peroxide and singlet O2, that are linked to exposure to PM trigger oxidative stress. Particle-induced ROS stem from the particles and the chemical species on the surface. Additional ROS can be produced by the interactions of the particles and their components with cellular enzymes and organelles (Xia et al., 2007). ROS can damage cellular proteins, lipids, membranes, and DNA (Nel, 2005; Yang et al., 2014). The oxidative potential of PM in most cases is independent of PM mass, because a major part of particles is biologically inactive, and only a small part can potentially induce oxidative stress (Ayres et al., 2008; Delfino et al., 2010). It is known that several PM components such as pro-oxidative organic hydrocarbons, like polycyclic aromatic hydrocarbons and quinones, and transition metals, such as copper, vanadium, chromium, nickel, cobalt, and iron are capable to produce ROS and initiate oxidative stress (Nel, 2005; Zarandi et al., 2019a). ROS could originate from a variety of subcellular sources, including catalytic production of quinones from of polycyclic aromatic hydrocarbons by cytochrome P450 1A1; quinone redox cycling by NADPH-dependent P450 reductase in microsomes; mitochondrial perturbation leading to electron leakage in the inner membrane; and NADPH oxidase activity in the macrophage surface membrane and associated phagosomes. The transition metals present in PM also can produce ROS. The overall cellular effect of PM is the result of all chemical species aggregated in PM (Xia et al., 2007; Wei et al., 2018). 3. Systemic inflammation The relationship between particulate matter and systemic inflammation is a well-documented topic. Many epidemiological, human toxicological, in vivo, and in vitro studies have been conducted to explore this relationship. The summary of characteristics and main results of some selected studies investigating PMinduced systemic inflammation in rodents are presented in Table 1. Once particles were inhaled, local pulmonary inflammation is

M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204 Table 1 Summary of characteristics and main results of studies on PM-induced systemic inflammation in rodents Ref.

Model

Jiang et al. 6-week-old male Balb/c (2018) mice He et al. (2017) 6e8 weeks old female Sprague-Dawley rats He et al. (2017) 6e8 weeks old female Sprague-Dawley rats Liu et al. (2017) Marchini et al. (2015) Armstead et al. (2015) Armstead et al. (2015) Emmerechts et al. (2010) Emmerechts et al. (2010) Nemmar et al. (2011) Hullmann et al. (2017a) Zhu et al. (2019) Guan et al. (2017) Chen et al. (2013) a b

8-week-old female ICR mice Female Swiss mice 8e9 weeks old male Sprague-Dawley rats 8e9 weeks old male Sprague-Dawley rats 8e10 weeks old male C57Bl6/n mice 8e10 weeks old male C57Bl6/n mice Male TO mice

3

a,b

.

PM type

Exposure method

Dose/conc.

Exposure duration

Results

PM2.5

Inh.

576.66 mg/m3

8 h/d, 7 d/w, 4 w

Increase in serum IL-6 and TNF- a

PM2.5, PM10 and PM1 were 20.4, 24.1, and 18.4 mg/m3 PM2.5, PM10 and PM1 were 1.5, 1.5, and 1.5 mg/m3

4 h/d, 5 d/w, for 1, 3, 5, and 7 months 4 h/d, 5 d/w, for 1, 3, 5, and 7 months

Increase in serum MCP-1, IL-6, IFN-g, and TNF-a Increase in serum EPO, IL-17, MCP-1, IL-6, G-CSF, IL-1a, IFN-g, and TNF-a

Biomass fuel Inh. Motor vehicle exhaust PM2.5

Inh.

i.t.

15 mg/kg

ROFA

i.n.

1 mg/kg

On GD 3, 6, 9, 12, and Increase in serum IL-2, IL-6, and IL-8 15 One time Increase in serum TNF-a and IL-6

400 mg/animal

One time

Only IL-6

CeO2 i.t. nanoparticles WC-Co i.t. nanoparticles PM i.t.

0, 25, 50, 250, 500 mg/animal

One time

No effect.

100 mg/animal

One time

Only IL-6

DEP

i.t.

100 mg/animal

One time

No effect.

DEP

i.t.

30 mg/animal

One time

IL-6

10-week-old female 5XFAD mice

DEE

Inh.

0.95 mg/m3

6 h/day, 5 d/w, 3 or 13 No effect. w

8-week-old male ApoE e/e mice 6-week-old male Sprague-Dawley rats 10-week-old male ApoE e/e mice

PM2.5

Inh.

30 mg/kg

8w

PM2.5

Inh.

44 mg/m

Every day for 12 w

PM10 and PM2.5

Inh.

PM10 ¼ 99.5 mg/m3 PM2.5 ¼ 61.0 mg/m3

3

24 h/d, 7 d/w, for 2 months

IL-6, TNF-a, iNOS, IL-12, arginase-1, and CD206 IL-6, TNF-a, MCP-1, IFN-g, VCAM-1, and iNOS TNF-a

Inh.: inhalation, i.t.: intratracheal instillation, i.n.: intranasal instillation. ROFA: residual oil fly ash, DEP: diesel exhaust particle, DEE: diesel engine exhaust.

induced, and this in turn leads to the systematic inflammation (Inoue et al., 2006; Finnerty et al., 2007; Dianat et al., 2016; He et al., 2017; Radan et al., 2019). Inoue et al. (2006) studied the effect of diesel particles on systemic inflammation related to pulmonary inflammation in mice. They observed that exposure to diesel exhaust particles induced lung inflammation and increased vascular permeability. In addition, elevated levels of proinflammatory cytokines such as interlukin-1b (IL-1 b), interlukin6 (IL-6), and keratinocyte chemoattractant (KC) in blood were observed alongside with lung inflammation (Inoue et al., 2006). Similar observations were reported in another study, where both pulmonary and systematic inflammation were observed, and instillation with a mixed solutions such as coarse ash particles increased tumor necrosis factor-a (TNF-a) in a lower dose comparing to IL-6 (Finnerty et al., 2007). Circulatory levels of pro-inflammatory cytokines in mice and rats are related to acute and chronic exposure to various types of PM, such as increase of TNF-a and IL-6 due to chronic inhalation of PM2.5 (Jiang et al., 2018), changes of erythropoietin (EPO), IL-17, monocyte chemoattractant protein (MCP-1), IL-6, granulocytemacrophage colony-stimulating factor (G-CSF), IL-1a, Interferon gamma (IFN-g), and TNF-a due to chronic inhalation of biomass fuel PM and motor vehicle exhaust (He et al., 2017), IL-2, IL-6, and IL-8 after intratracheal instillation of PM2.5 solution in mice (Liu et al., 2017), TNF-a and IL-6 following an acute exposure by intratracheal instillation to residual oil fly ash in mice (Marchini et al., 2015), IL-6 after intratracheal instillation of CeO2 nano-particles in rat (Armstead et al., 2015), IL-6 after one single exposure to urban particulate matter in mice (Emmerechts et al., 2010), and IL-6 following the intratracheal instillation of diesel exhaust particles in mice (Nemmar et al., 2011), respectively. In general, the relationship between exposure to airborne particles and systemic inflammation is almost proven. Some insignificant increases in

systemic inflammation after exposure to particles is possibly due to the insufficient dose and exposure duration (Wang et al., 2013). In this regard, no changes were observed in levels of IL-1b, RANTES gene (regulated upon activation, normal T cell expressed and secreted), G-CSF (granulocyte-colony stimulating factor), and MCP1 (monocyte chemoattractant protein-1) after sub-chronic inhalation of diesel exhaust in mice (Hullmann et al., 2017b), TNF-a after intratracheal instillation of PM2.5 solution in mice (Liu et al., 2017), TNF-a and IFN-g after intratracheal instillation of tungsten carbide cobalt and CeO2 nano-particles in mice (Armstead et al., 2015), and IL-1b after single exposure to diesel exhaust particles and urban particulate matter in mice (Emmerechts et al., 2010). The relationship between systemic inflammation and cardiovascular disorders is also well known. Previous studies showed that gaseous and PM reached the respiratory system, eliciting inflammation and leading to endothelium dysfunction and alteration of the HRV, probably by activation of irritant receptors in the airways (Lamb et al., 2011; de Brito et al., 2018). Acute exposure to residual oil fly ash is known to cause systemic inflammation and cardiac dysfunction (oxygen metabolism and contractile function) in mice (Marchini et al., 2015). Other studies also have found the simultaneous increase in systemic inflammation markers and different cardiovascular disorders (Chen et al., 2010, 2013; Quan et al., 2010; Nemmar et al., 2017). 4. Heart rate and heart rate variability Heart rate (HR) and heart rate variability (HRV) are two indicators for performance of heart’s autonomic nervous system (ANS) (Camm et al., 1996). The neural receptors in lungs are stimulated by exposure to PM, and this can cause a reflex in the central nervous system (CNS), followed by sending some autonomic signals to heart (Widdicombe and Lee, 2001). These signals alter the

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M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204

failed to observe such relationship (Liu et al., 2013). In addition to dose, subject’s age can affect the changes of HR and HRV. Bennett et al. (2018) studied about the effect modification of age in the relationship between exposure to PM (0.3e3.5 mm) and HR and HRV changes in three age groups of male mice, including early adulthood (3 months of age), mid-life (12 months of age), and old age (18 months of age). They observed a decrease in HR, an increase in HRV, and change in the measures of homeostasis in mid-life mice after exposure to particulate matter. However, such alterations were not observed for younger and older mice, indicating that middle-age mice are more susceptible to short-term exposure to PM (Bennett et al., 2018). However, in another study, juvenile (4 weeks of age) and older (10 months of age) mice were more susceptible for PM than adult mice (4 months of age), and suffered from the increased HR and cardiac dysfunction (Qin et al., 2018). An explanation may be the different genders of mice in these two studies, as elevated estrogen level is known to have a possible effect for reducing cardiovascular events in females. Qin et al. (2018) found that estradiol 2 levels in juvenile and older mice were increased after PM exposure (Qin et al., 2018). Further investigations are required for better understanding underlying mechanisms of the effect of exposure to PM on HR and HRV changes in different age groups of males and females separately.

HR and HRV measures (Watkinson et al., 1997). The summary of characteristics and main results of some selected studies investigating HR and HRV in rodents are presented in Table 2. The results of studies about the effect of PM on HR and HRV are inconsistent. While, a group of studies have reported that PM cause an increase in HR (Nemmar et al., 2012b; Hazari et al., 2018; Qin et al., 2018), the others found that PM decreases HR (Amatullah et al., 2012; Liu et al., 2013; Pei et al., 2016; Bennett et al., 2018). The same inconsistency can be observed in case of HRV. Some studies have observed that exposure to PM leads to an increase in HRV (Bennett et al., 2018; Hazari et al., 2018); while, the others observed an inverse relationship (Amatullah et al., 2012; Jia et al., 2012; Wang et al., 2012; Keebaugh et al., 2015; Pei et al., 2016). This inconsistency can be due to the different sizes and chemical composition of particles, and exposure periods applied in these studies (Amatullah et al., 2012; Hazari et al., 2018). It is shown that PM increased heart rate of mice after 1 h comparing to the mice with longer exposure times or those exposed with ozone (Hazari et al., 2018). With respect to their previous studies (Peters et al., 1999; Lamb et al., 2011; Unosson et al., 2013), the authors concluded that exposure to different composition of air pollutants causes different responses in HR and HRV (Hazari et al., 2018). Long-range transported particles and Ni- and carbon-rich particles induced opposite alterations in HRV (Chen et al., 2010). Same differences in HRV were also observed for residual oil combustion PM versus secondary sulfate PM, and refinery PM versus cement/line and coal/secondary sulfate PM (Lippmann et al., 2005; Rohr et al., 2011). The size also plays an important role in these fluctuations. Amatullah et al. (2012) showed that with decreasing size of PM from coarse (PM10-2.5) to fine (PM2.5-0.15) and quasi-fine (PM0.2), HR and HRV increases and decreases, respectively (Amatullah et al., 2012). Studies indicate a dose-dependent relationship between PM levels and HR or HRV changes. Pei et al. (2016) reported that shortterm exposure to PM2.5 caused a decrease in HRV with a doseeresponse way. HR were decreased after instillation of three high doses of PM2.5 (Pei et al., 2016). The same pattern was observed in other studies (Jia et al., 2012); however, some reports

Table 2 Summary of characteristics and main results of studies on HR and HRV in rodents

5. Histopathological effects The summary of characteristics and main results of some selected studies investigating PM-induced histopathological changes in rodents are presented in Table 3. Exposure to particles causes mitochondrial abnormalities, including swelling, damaged or missing cristae, and disrupted cell nucleus (Sartoretto et al., 2009). In addition, the myocardial structures of PM-exposed group have been reported to be abnormal. This included irregularly arrangement of fibers, edema, damages in muscle membrane, fractures in muscle fibers, degeneration, necrosis, hypertrophy, myocardial myofibril disorder, myocardial gap expansion, inflammatory cell infiltration, hyperemia, and cardiac injury (Sartoretto et al., 2009; Tong et al., 2009; Weldy et al., 2013; Xie et al., 2013;

a,b

.

Ref.

Model

PM type

Exposure method

Dose/conc.

Exposure duration

HR

HRV

Amatullah et al. (2012) Amatullah et al. (2012) Hazari et al. (2018) Nemmar et al. (2012b) Qin et al. (2018) Liu et al. (2013)

6e8 weeks old female BALB/c mice

PM0.2

Inh.

401 mg/m3

4h

Decrease

Decrease in SDNN

PM2.5 and PM2.5-10 13e15 weeks old female C57BL/6 mice PM2.5

Inh.

4h

Not significant

Not significant

Inh.

793 and 254 for PM2.5 and PM2.5-10 1.04 mg/m3

4h

Increase in SDNN

Male TO mice

DEP

i.t.

15 mg/animal

One time

Increase and then decrease Increase

e

4-week, 4-month, and 10-month-old female C57BL/6 mice 10-week-old male C57BL/6 mice

PM2.5

OA

3 mg/kg

Increase

e

DEP

Inh.

300e400 mg/m

Decrease

e

Pei et al. (2016) 8-week-old male C57BL/6 mice

PM2.5

i.t.

3, 10, 30 mg/kg

Every day, for 4 w 6 h/d, 5d/w, 4w 3d

Decrease

Bennett et al. 12-week-old male DBA/2 (D2) mice (2018) Jia et al. (2012) 9-week-old male C57BL/6 mice

PM0.3-3.5

A

100 mg

One time

Significant decrease in higher dose. Decrease

CB

i.t.

Three times

e

Keebaugh et al. 7-week-old male ApoE / mice (2015) Wang et al. 20-week-old CREBA133 mice (2012)

UFP

Inh.

0.05, 0.15 and 0.6 mg/ kg 58 mg/m3

Increase

PM

i.t.

20 mg/kg

5 h/d, 4 d/w for 8 w One time

Decrease in 0.15 and 0.6 doses Decrease

e

Decrease

a b

6e8 weeks old female BALB/c mice

3

Inh.: inhalation, i.t.: intratracheal instillation, i.n.: intranasal instillation, OA: oropharyngeal aspiration, A: aspiration. ROFA: residual oil fly ash, DEP: diesel exhaust particle, DEE: diesel engine exhaust, CB: carbon black, UFP: ultrafine particles.

Increase

M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204 Table 3 Summary of characteristics and main results of some selected studies on PM-induced histopathological changes in rodents’ heart Ref.

Model

PM type

Exposure Dose/conc. Exposure duration method

PM2.5

i.t.

0.375, 1.5, Five times 6.0 and 24.0 mg/kg

12e16 weeks old Tong et al. female CD-1 mice (2009)

OA

10 or 40 mg One time

Weldy et al. (2013) Xie et al. (2013) Zhang et al. (2016) Nemmar et al. (2010) Qin et al. (2018)

Inh.

300 mg/m3 During pregnancy and until offspring were 3 weeks: 6 h/d, 5 d/w 10 mg/kg One time

Li et al. Male SD rats (2015)

Nanoparticles (SWCNT, AFSWCNT, UCB, AFUCB) 12e14 weeks old male DEP C57BL/6 J mice

4e6 weeks old male BALB/c mice 6e8 weeks old male C57BL/6 mice 12-week-old male Wistar rats

PM2.5

i.t.

PM2.5 þ SO2 and NO2

i.n.

DEP

SA

4-week, 4-month, and PM2.5 10-month-old female C57BL/6 mice 12-week-old male and PM2.5 female FVB mice

Tanwar et al. (2017) Liu et al. 12-week-old male (2016) C57BL/6 mice

DEP

5

a,b

.

Results All groups except for the 0.375 mg/kg dose: the myocardial myofibril disorder, myocardial gap expansion, inflammatory cell infiltration (mainly including lymphocytes) in myocardium, myocardial interstitial edema, and hyperemia Only in AF-SWCNT and 40 mg dose group: myofiber degeneration, small clusters of myocytes that were shrunken, rounded, hypereosinophilic, and contained pyknotic nuclei in the papillary muscle and interventricular septum Cardiac fibrosis, cardiac hypertrophy, increase ventricle weight,

increased inflammatory responses and injury

Irregularly arrangement in muscle fibers, edema in interstitial substance, damage in muscle membrane, and degeneration, necrosis and fractures in muscle fibers 0.02 mg/kg 6 h, 18 h, 48 h and 168 h No inflammatory cells infiltration in any of times, however, there was particle deposition 1 and 10 mg/kg

28 d

OA

3 mg/kg

Every day, for 4 w

Collagen deposition/myocardial fibrosis

Inh.

73.61 mg/ m3

6 h/d, 7 d/w during pregnancy

Collagen deposition

Inh.

300 mg/m3 During pregnancy and until offspring were 3 weeks: 6 h/d, 5 d/w

No effect

a

Inh.: inhalation, i.t.: intratracheal instillation, i.n.: intranasal instillation, OA: oropharyngeal aspiration, SA: systemic administration. DEP: diesel exhaust particle, SWCNT: single-walled carbon nanotubes, AF-SWCNT: acid-functionalized SWCNT, UFCB: ultrafine carbon black (UFCB), AF-UFCB: acidfunctionalizedeUFCB, CAP: concentrated ambient particles. b

Li et al., 2015; Zhang et al., 2016). Some of these histological changes were associated with the increase in COX-2 and iNOS (Zhang et al., 2016), which are known to be responsible for pathogenesis of myocardial dysfunction (Zhu et al., 2012). However, due to low dose and time-points, histological changes were not observed in some cases in response to diesel exhaust (Nemmar et al., 2010; Li et al., 2015). In a study, several genes that may cause PM-induced heart or lung pathology were identified in heart tissue (Gunnison and Chen, 2005). PM2.5-induced cardiac fibrosis was studied by Qin et al. (2018), and it was found that oropharyngeal aspiration of 3 mg/kg body weight (bw) of PM2.5 caused collagen deposition/fibrosis in left ventricular of juvenile and adult mice. In addition, exposure to PM2.5 was associated with the elevated transcription of Col1a1 and Col3a1 as two major genes for production of collagen. Expression of Col1a1 and Col3a1 was stopped two weeks after the exposure. These indicate a link between PM2.5, transcription of Col1a1 and Col3a1, and cardiac fibrosis (Qin et al., 2018). In another study, adulthood collagen deposition/fibrosis was observed after in utero exposure to diesel exhaust (Weldy et al., 2013; Tanwar et al., 2017), but not in mice with transverse aortic constriction (TAC) (Liu et al., 2016). A pathway for PM-induced fibrosis may include activation of NADPH oxidase, generation of reactive oxygen species (ROS), expression of NOX-4 and TGFb1 protein, and activations of Smad2 and Smad3 that stimulate matrix-component synthesis such as collagens (Li et al., 1999; Privratsky et al., 2003; Hu et al., 2008). However, it is reported that withdrawal from exposure causes the fibrosis area to be reduced (Qin et al., 2018). 6. Atherosclerosis Atherosclerosis as a basic cause of cardiovascular diseases is defined as the deposition of fat, cholesterol, calcium, and other

substances, and formation of plaque inside arteries (Lusis, 2000). This can cause serious health problems such as stroke and myocardial infarction. In general, disruption in metabolism of lipid, and inflammatory responses triggered by nucleotide-binding oligomerization domain-like receptor protein (NLRP3) form the atherosclerosis plaques (Hansson and Hermansson, 2011; Hoseini et al., 2018). The relationship between respiratory exposure to particulate matter and initiating or progression of atherosclerosis is well-studied. The summary of characteristics and main results of some selected studies investigating PM-induced atherosclerosis in rodents are presented in Table 4. Progression of atherosclerosis plaques have been observed in mice after 8-week exposure to PM2.5 with a dose of 30 mg/kg/day (Zhu et al., 2019), in rats after 12 weeks (not 6 weeks) exposure to 44 mg/m3 PM2.5 (Guan et al., 2017), in mice after two months of exposure to PM10 (71.2 mg/m3) and PM2.5 (63.1 mg/m3) (Wan et al., 2014), in mice after two months exposure to UFP (28.6 mg/m3) (Keebaugh et al., 2015), in mice after 4 weeks of exposure to diesel exhaust particle (10 mg/animal, twice a week) (Miller et al., 2013), in mice after two months of exposure to PM10 (99.5 mg/m3) and PM2.5 (61.0 mg/m3) (Chen et al., 2013). However, no sign of atherosclerosis was observed after in utero exposure to diesel exhaust with average 250e300 mg/m3 concentration of PM2.5 for 16 weeks (Harrigan et al., 2017), or after 6 weeks of exposure to PM2.5 with an average concentration of 27 mg/m3 (Guan et al., 2017), or after 12 weeks carbon black exposure with a dose of 85.3 or 256 mg/mouse (Christophersen et al., 2016). Inflammatory responses are known as the possible mechanism for inducing atherosclerosis by airborne particulate matter. In a study by Du et al. (2018), PM2.5 increased activation of NLRP3 inflammasome and cluster of differentiation 36 (CD36), and created atherosclerosis plaques in mice. These changes were related to the increase in oxidized low-density lipoprotein (ox-LDL) and LDL-

6

M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204

Table 4 Summary of characteristics and main results of some selected studies on PM-induced atherosclerosis in rodents

a,b

.

Ref.

Model

PM type

Exposure method

Dose/conc.

Exposure duration Results

Zhu et al. (2019)

8-week-old male ApoE mice 6-week-old male Sprague-Dawley rats 6-week-old male Sprague-Dawley rats 8-week-old male ApoE e/e mice 7-week-old male ApoE e/e mice 8-week-old male ApoE/  mice 10-week-old male ApoE e/e mice 16-week-old ApoE e/e mice 10-week-old female ApoEe/e mice 6-week-old male ApoE e/e mice

PM2.5

Ins.

30 mg/kg

8w

PM2.5

Inh.

27 mg/m3

Every day for 6 w No effect

Inh.

44 mg/m

Every day for 12 w Middle cerebral artery (MCA) narrowing and thickening

Inducing atherosclerotic plaques

e/e

Guan et al. (2017) Guan et al. (2017) Wan et al. (2014) Keebaugh et al. (2015) Miller et al. (2013) Chen et al. (2013) Harrigan et al. (2017) Christophersen et al. (2016) Du et al. (2018) a b

PM2.5

3

PM10 and Inh. PM2.5 UFP Inh.

PM10 ¼ 71.2 mg/m3 PM2.5 ¼ 63.1 mg/m3 58 mg/m3

DEP

10 mg/animal

OA

PM10 and Inh. PM2.5 DEP Inh.

PM10 ¼ 99.5 mg/m PM2.5 ¼ 61.0 mg/m3 250e300 mg/m3

CB

i.t.

0.2 mg/animal

PM2.5

Inh.

70.3 mg/m3

3

24 h/d, 7 d/w, for 2 months 5 h/d, 4 d/w for 8w Twice a week, for 4w 24 h/d, 7 d/w, for 2 months 6 h/d, 5 d/w during gestation Once a week for 10 w 8 h/day, 7 d/w for 16 w

Increased plaque area and visfatin protein Increased size of arterial plaque Increased plaque area and plaques per section of artery Increased plaque area No difference in average atherosclerotic lesion area, but a higher frequency of lesions No progression of plaque in aorta or brachiocephalic artery Formation of atherosclerosis plaque

Ins.: instillation, Inh.: inhalation, i.t.: intratracheal instillation, OA: oropharyngeal aspiration. DEP: diesel exhaust particle, CB: carbon black.

cholesterol (LDL-C), upregulation of apoptosis associated speck like protein (ASC), caspase-1, and inflammatory cytokines (IL-1b, IL-18) in both circulation and aorta (Du et al., 2018). CD36 is also known to have a critical role in progression of atherosclerosis through irregular accumulations of oxidized lipids like 7-ketocholesterol (7KCh) in another study (Rao et al., 2014). Upregulation of visfatin as an adipokine has been introduced as another mechanism of PMinduced atherosclerosis (Wan et al., 2014). Exposure to PM2.5 caused atherosclerosis in mice, as well as increased damage to endothelial cells, adhesion of platelets and leukocytes, inflammatory factors, pro-inflammatory cytokines such as IL-6 and TNF-a, M1 factors such as iNOS and IL-12 as pro-inflammatory factors triggering atherosclerosis, and decreased M2 factors like CD206 and arginase-1 as anti-inflammatory factors (Zhu et al., 2019). Other studies have also reported the elevation of inflammatory and adhesion factors after exposure to PM (Chen et al., 2013; Miller et al., 2013; Wan et al., 2014; Guan et al., 2017). These results show that exposure to particulate matter decreases antiinflammation factors and activates inflammatory responses that are associated with induction and progression of atherosclerosis plaques. 7. Thrombosis Thrombosis is the obstruction of the blood flow inside an artery or a vein after the creation of a blood clot. Arterial and venous thrombosis are different phenomenon. Arterial thrombosis is associated with platelets, and occurs near broken atherosclerosis plaques. Venous thrombosis is associated with fibrin and red blood cells, and happens despite an intact endothelial wall (Corkrey et al., 2016). Arterial thrombi are initiated by the decrease of ROS and nitrogen oxide (NO) due to the reaction with protein disulfide isomerases (PDI, ERp5, ERp57) released by platelets and activated endothelial cells. PDI activates tissue factor, generates fibrin, causes aggregation of platelets, and increases the production of thrombin from platelets (Furie and Furie, 2008; Reinhardt et al., 2008; Corkrey et al., 2016). Venous thrombi are triggered after inflammation and activation of endothelium. These lead to the increase in expressing selectin and regulation of von Willebrand factor, and in turn attachment of platelets and leukocytes, and finally activation

of coagulation cascade by over-expression of tissue factor. Red blood cells are also important for the formation of clot and resistance to fibrinolysis (Torisu et al., 2013; Cines et al., 2014; Corkrey et al., 2016). The summary of characteristics and main results of some selected studies investigating PM-induced thrombosis in rodents are presented in Table 5. The effect of particulate matter on thrombosis using animal models has been less documented, comparing to other cardiovascular disorders. However, the evidences seem to be enough to indicate the effect, and determine the underlying mechanisms. Short-term exposure to urban particulate matter induced arterial thrombosis in mice, not the venous thrombosis. In the same study, DEP could not develop neither types of thrombosis under the similar conditions (Emmerechts et al., 2010). However in another study, in higher applied doses to the previous study, DEP showed greater thrombotic effects in terms of acceleration of thrombosis, and aggregation of platelet-monocyte, comparing to carbon black and quartz particles (Tabor et al., 2016). In addition, UFP have shown to develop prothrombotic state (Cascio et al., 2007). Several studied have investigated the mechanism underlying the effect of exposure to particulate matter and tendency toward thrombosis in rodent models. PM elevates IL-6 levels in lung, and decreases platelets in blood and plasma clotting time, and increases fibrinogen and activity of factors II, VIII, and X, and accelerates platelet aggregation and arterial thrombosis (Mutlu et al., 2007; Nemmar et al., 2011). Three-day inhalation exposure to concentrated PM2.5 (88.5 mg/m3) or instilled PM caused coagulation induced by IL-6 in mice’ lung, and transcription of PAI-1 (plasminogen activator inhibitor type 1) as a major regulator of thrombolysis by a TNF-a-induced mechanism in lung and adipose tissue (Budinger et al., 2011). Release of IL-6 in lung is associated with the activation of b2-adrenergic receptor (b2AR) by alveolar macrophages (Chiarella et al., 2014). Similar results were observed in another study investigating the effect of DEP. DEP increased CRP, TNF-a, D-dimer (as a product of fibrin degradation), and PAI-1, and caused pial arteriolar thrombosis in mice after 4 times intratracheal instillations of 15 mg/animal of DEP (Nemmar et al., 2012a). The venous thrombosis is less documented than the arterial one. Nemmar et al. (2009) found the dose-dependent effects of diesel exhaust particles on decrease of tail bleeding duration and number

M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204 Table 5 Summary of characteristics and main results of some selected studies on PM-induced thrombosis in rodents Ref.

Model

PM type

Emmerechts et al. (2010) Emmerechts et al. (2010) Tabor et al. (2016)

8e10 weeks old male C57Bl6/n mice

Urban i.t. PM

8e10 weeks old male C57Bl6/n mice

a,b

.

Exposure duration

Results

100 mg/ animal

One time

Increases in factor (F)VII, FVIII and fibrinogen

Urban i.t. PM

100 mg/ animal

One time

No increase in the proinflammatory and procoagulant status

Male Wistar Rats

DEP

i.t.

500 mg/ animal

One time

Tabor et al. (2016)

Male Wistar Rats

CB

i.t.

500 mg/ animal

One time

Tabor et al. (2016)

Male Wistar Rats

DQ12 i.t. quartz

125 mg/ animal

One time

Tabor et al. (2016)

Male Wistar Rats

DEP

i.v.

0.5 mg/kg

One time

Tabor et al. (2016)

Male Wistar Rats

CB

i.v.

0.5 mg/kg

One time

Cascio et al. (2007)

6e10 weeks old male ICR mice

UFP

i.t.

100 mg

One time

Mutlu et al. (2007) Nemmar et al. (2011) Budinger et al. (2011) Nemmar et al. (2012a) Nemmar et al. (2009) Liang et al. (2019)

6e8 weeks old male C57BL/6 mice Male TO mice

PM10

i.t.

One time

DEP

i.t.

10 mg/ animal 30 mg/ animal

One time

-Reducing time to thrombotic occlusion only 6 h after instillation -Reduced plasma t-PA and increased PAI-1 -Increase in platelet-monocyte aggregation -No effect on time to thrombotic occlusion -Reduced plasma t-PA and increased PAI-1 -No effect on platelet-monocyte aggregation -No effect on time to thrombotic occlusion -Reduced plasma t-PA and increased PAI-1 -No effect on platelet-monocyte aggregation -Reducing time to thrombotic occlusion only 2 h after instillation -Reduced plasma t-PA and increased PAI-1 -Increase in platelet-monocyte aggregation after 2 h -Reducing time to thrombotic occlusion only 2 h after instillation -Reduced plasma t-PA and increased PAI-1 -No effect on platelet-monocyte aggregation Altering endothelial-dependent and -independent regulation of systemic vascular tone; increasing platelet number, plasma fibrinogen, and soluble P-selectin levels; and reducing bleeding time Shortened bleeding time, decreased prothrombin and partial thromboplastin times, increased levels of fibrinogen, and increased activity of factor II, VIII, and X Reduced platelet numbers and aggravated thrombosis in pial arterioles

Increase in PAI-1

Cascio et al. (2007) a b

Exposure Dose/conc. method

7

8e12 weeks old male C57BL/6 and IL-6/ mice Male TO mice

PM2.5

Inh.

88.5 mg/m3

8 h/d, 3 d

DEP

i.t.

15 mg/ animal

Every 2 d for Pial arteriolar thrombosis and increase in PAI-1 6 d (4 times)

Male TO mice

DEP

i.t.

15 or 30 mg/ Every 2 d for Decrease in number of platelets and the tail bleeding time for 30 mg/animal dose animal 6 d (4 times)

8e12 weeks old male SD rats

PM2.5

i.t.

0, 1.8, 5.4 and 16.2 mg/kg

6e10 weeks old male ICR mice

UFP

i.t.

100 mg

Every 3 d, 1 Downregulation of thrombomodulin expression, increase in adhesion molecules month (ICAM-1 and VCAM-1) and tissue factor (TF) and the coagulation factor of FXa, decrease in vWF, increase in thrombin-antithrombin complex (TAT) and fibrinolytic factor (t-PA), no change in the expression of anticoagulant factors (TFPI and AT-III) One time Increasing platelet number, plasma fibrinogen, and soluble P-selectin levels; and reducing bleeding time

Inh.: inhalation, i.t.: intratracheal instillation, i.v.: intravenous injection. DEP: diesel exhaust particle, CB: carbon black, UFP: ultrafine particles.

of platelets in blood, and proaggregatory effect of platelets in mouse pial cerebral venules (Nemmar et al., 2009). However, shortterm exposure to PM and DEP showed that PM can induce arterial thrombosis in healthy mice, not the venous type. DEP could not create neither types of thrombosis under the same condition (Emmerechts et al., 2010). In a recent study, several changes in indices of venous thrombosis such as thrombomodulin, adhesion factors, TF, coagulation factor of FXa (factor Xa), vWF (von Willebrand-factor), thrombin-antithrombin complex (TAT), and fibrinolytic factor (t-PA) were reported after long-term instillation of PM2.5 to rats (Liang et al., 2019). It seems that as expected, for both types of thrombosis only a single PM-related mechanism is not responsible for development of thrombosis (Budinger et al., 2011).

8. Myocardial infarction Myocardial infarction (MI) occurs when blood flow to a coronary artery has stopped, or extremely decreased. The most common cause of MI is atherosclerosis. However, in some rare cases, MI can

be caused by congenital abnormalities of the coronary arteries, hypercoagulability, collagen vascular diseases, etc. In addition, MI is associated with circulatory pro-inflammatory cytokines (Marchini et al., 2016). In previous sections of this review, we mentioned that exposure to airborne particulate matter in mouse and rat models has been related to the systemic inflammation, atherosclerosis, and thrombosis that are among the main causes of MI. The summary of characteristics and main results of some selected studies investigating PM-induced MI in rodents are presented in Table 6. Several studies on mice and rats have found that exposure to different types of particulate matter such as PM2.5, fly ash, ultrafine particles and coarse particles can increase the size of infarct as an index of MI (Tong et al., 2010; Marchini et al., 2016; Li et al., 2017; Tong and Zhang, 2018). Effects of different fractions of PM on MI indices have been also investigated. UFP-exposed mice have shown lower post-ischemic functional recovery and greater infarct size in comparison to those exposed with PM2.5 and coarse PM. In addition, UFP caused a significant reduction in coronary flow rate (Tong et al., 2010). Short- and long-term exposure to PM2.5 reduced

8

M. Hadei, K. Naddafi / Chemosphere 242 (2020) 125204

Table 6 Summary of characteristics and main results of some selected studies on PM-induced MI in rodents

a,b

.

Ref.

Model

PM type

Exposure method

Dose/conc.

Exposure duration

Li et al. (2017) Marchini et al. (2016) Tong and Zhang (2018) Tong et al. (2010)

Male C57/BL6 mice 8-week-old male C57BL/6 J mice SD rats Male

PM2.5 ROFA PM2.5

i.n. i.n. i.t.

Twice a week, 5 w Increase in the infarct size One time Increase in the infarct size One time Increase in the infarct size

OA

10 mg 1 mg/kg 2 mg/ animal 100 mg

One time

No effect on infarct size

PM2.5 UFP DEP

OA OA Inh.

100 mg 100 mg 350 mg/m3

One time One time 4h

UFP UFP

i.t. i.t.

100 mg 100 mg

One time One time

No effect on infarct size Increase in the infarct size Enhanced vasoconstriction in veins but not arteries. Increase in the infarct size Increase in the infarct size

12e16 weeks old male CD-1 mice PM2.510

Tong et al. (2010) 12e16 weeks old male CD-1 mice Tong et al. (2010) 12e16 weeks old male CD-1 mice Knuckles et al. (2008) 8e10 weeks old male C57BL/6 mice Cascio et al. (2007) 6e10 weeks old male ICR mice Cozzi et al. (2006) 6e10 weeks old ICR mice a b

Results

Inh.: inhalation, i.t.: intratracheal instillation, OA: oropharyngeal aspiration, i.n.: intranasal instillation. ROFA: residual oil fly ash, UFP: ultrafine particles, DEP: diesel exhaust particle.

fibrous cap thickness, which is an index for vulnerable plaques in atherosclerosis and can increase the risk of MI (Geng et al., 2019). In a study by Marchini et al. (2016), the acute exposure to a PMsurrogate i.e. residual oil fly ash increased infarct area, inflammatory cell recruitment, circulatory pro-inflammatory cytokines (TNFa, IL-6, and MCP-1), activated myeloid and endothelial cells, and enhanced leukocyte recruitment to the peritoneal cavity and the vascular endothelium. This study showed that the alveolar macrophages are the initial causes of increased cytokine levels after exposure to airborne particles, and this can worsens the course of MI (Marchini et al., 2016). In addition, exposure to PM was known to induce cellular apoptosis, which could be due to the activation of IkBa and NFkB (Li et al., 2017). The use of b-Adrenoceptor blocker and agonist could decrease mortality rate in rats after MI, suggesting a new possible toxicological pathway for the effect of PM on MI (Gao et al., 2014). Limited evidences are published about the venoconstriction effect of PM on heart and most of them are ex vivo studies (Campen et al., 2005; Li et al., 2005; Radmanesh et al., 2017), but one study demonstrated that exposure to the complex of diesel emission caused venoconstriction in veins, but not in arteries (Knuckles et al., 2008). In addition, exposure to PM is repeatedly reported to worsen the injury after ischemiareperfusion (Cozzi et al., 2006; Cascio et al., 2007; Li et al., 2017; Tong and Zhang, 2018). In another study, upregulation of farnesoid-X-receptor (FXR) was reported to elevate the myocardial injury after MI (Tong and Zhang, 2018). 9. Conclusions Cardiovascular effects of exposure to airborne particulate matter in vivo have been studied well, and the number of such studies are growing. Animal model studies have been successful to bring new insights into the mechanisms underlying PM-induced diseases. However, there are some areas that the exact mechanisms are still unclear. The differences in mechanisms could be due to this fact that particulate matter with different origins have different chemical compositions that can activate multiple pathways. Therefore, investigating the cardiovascular effects of PM in vivo or interpreting the results should attempt to justify the role of different PM compositions. In addition, most of the studies have used other exposure methods rather than inhalation such as intratracheal and intranasal instillation. Although, these methods are reliable techniques for lung exposure, inhalation-based techniques will provide a better simulation for airborne PM studies, given that the physical form and chemical composition of PM will be preserved through inhalation. Furthermore, limited research has been carried out to explore the effects of urban PM from different

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