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PhysicalActivity,AirPollutionandtheBrain

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IngeBos

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PatrickDeBoever

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LucLRIntPanis

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RomainMeeusen

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REVIEW ARTICLE1

2 Physical Activity, Air Pollution and the Brain

3 Inge Bos • Patrick De Boever • Luc Int Panis •

4 Romain Meeusen

56 � Springer International Publishing Switzerland 2014

7 Abstract This review introduces an emerging research

8 field that is focused on studying the effect of exposure to

9 air pollution during exercise on cognition, with specific

10 attention to the impact on concentrations of brain-derived

11 neurotrophic factor (BDNF) and inflammatory markers. It

12 has been repeatedly demonstrated that regular physical

13 activity enhances cognition, and evidence suggests that

14 BDNF, a neurotrophin, plays a key role in the mechanism.

15 Today, however, air pollution is an environmental problem

16 worldwide and the high traffic density, especially in urban

17 environments and cities, is a major cause of this problem.

18 During exercise, the intake of air pollution increases

19considerably due to an increased ventilation rate and par-

20ticle deposition fraction. Recently, air pollution exposure

21has been linked to adverse effects on the brain such as

22cognitive decline and neuropathology. Inflammation and

23oxidative stress seem to play an important role in inducing

24these health effects. We believe that there is a need to

25investigate whether the well-known benefits of regular

26physical activity on the brain also apply when physical

27activity is performed in polluted air. We also report our

28findings about exercising in an environment with ambient

29levels of air pollutants. Based on the latter results, we

30hypothesize that traffic-related air pollution exposure dur-

31ing exercise may inhibit the positive effect of exercise on

32cognition.

33

341 Introduction

35Many health promotion activities use physical activity as

36intervention because it contributes to healthy aging and

37reduces morbidity and mortality rates due to coronary heart

38disease, diabetes, hypertension, and certain types of cancer

39[1–4]. Regular physical activity also supports brain health

40and function; for instance, it improves cognition [5, 6] and

41psychological health [7], delays the onset of neurodegen-

42erative diseases such as Alzheimer’s disease (AD) [8, 9],

43and acts therapeutically in depression [10]. Growing evi-

44dence suggests an important role for the neurotrophin

45brain-derived neurotrophic factor (BDNF) in the molecular

46mechanism through which exercise enhances neural plas-

47ticity and improves cognition [11].

48Today, air pollution is a growing environmental prob-

49lem worldwide and the high traffic density in urban envi-

50ronments and cities is a major cause of this problem [12].

51Recently, air pollution exposure has been linked to adverse

A1 Electronic supplementary material The online version of thisA2 article (doi:10.1007/s40279-014-0222-6) contains supplementaryA3 material, which is available to authorized users.

A4 I. Bos � R. Meeusen (&)

A5 Department of Human Physiology, Faculty of Physical

A6 Education and Physiotherapy, Vrije Universiteit Brussel,

A7 1st floor, U-residence, Generaal Jacqueslaan 271,

A8 1050 Brussels, Belgium

A9 e-mail: rmeeusen@vub.ac.be

A10 I. Bos � P. De Boever � L. Int Panis

A11 Environmental Risk and Health, Flemish Institute

A12 for Technological Research (VITO), Mol, Belgium

A13 P. De Boever

A14 Center for Environmental Sciences (CMK),

A15 Hasselt University, Diepenbeek, Belgium

A16 L. Int Panis

A17 Transportation Research Institute (IMOB),

A18 Hasselt University, Diepenbeek, Belgium

A19 R. Meeusen

A20 School of Public Health, Tropical Medicine and Rehabilitation

A21 Sciences, James Cook University, Townsville, QLD, Australia

123

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52 effects on the brain such as cognitive decline, neuroin-

53 flammation and neuropathology [13–16]. Inflammation is

54 considered one of the common and basic mechanisms

55 through which air pollution exposure induces negative

56 health effects [14]. It is envisioned that the latter effects

57 may be aggravated when doing physical activity outdoor in

58 an urban environment. Ventilation rate increases during

59 exercise and in polluted environments, which results in a

60 substantial enhancement of air pollution inhalation [17].

61 The first studies addressing the impact of pollution on

62 cognition, BDNF and inflammation have appeared [18–20].

63 The question can be raised whether known benefits of

64 regular physical activity on the brain also apply when

65 physical activity is performed in polluted air.

66 In this review, we will describe the possible impact of

67 air pollution on the brain and briefly address the existing

68 literature regarding the effect of physical activity on cog-

69 nition, focusing on the important role of BDNF in medi-

70 ating the positive effects of physical activity on cognition.

71 We discuss the first findings on the combined impact of air

72 pollution and physical activity on cognition, BDNF and

73 inflammatory markers, and address possible mechanisms.

74 Literature incorporated in this review was collected over

75 a period of 4 years (November 2009 to November 2013)

76 when the different studies on this research topic were

77 designed and performed by our group. A literature search

78 was conducted on PubMed in which the following key-

79 words were included individually and in various combi-

80 nations: ‘physical activity’, ‘aerobic training’, ‘exercise’,

81 ‘cycling’, ‘active transport’, ‘active mobility’, ‘air pollu-

82 tion’, ‘particulate matter’, ‘ultrafine particles’, ‘traffic’,

83 ‘traffic exhaust’, ‘diesel exhaust particles’, ‘urban’, ‘brain’,

84 ‘hippocampus’, ‘cognition’, ‘neural plasticity’, ‘BDNF’,

85 ‘neuroinflammation’, and ‘oxidative stress’. A number of

86 reviews were included and provided additional articles.

87 2 Air Pollution: Important Causes, Components

88 and Sources

89 Although air pollution levels in developed nations such as

90 Europe and the US are now dramatically lower than

91 50 years ago, millions of people worldwide are still

92 exposed to airborne concentrations well above WHO rec-

93 ommendations and legal safety standards [12, 21]. The

94 driving forces of the observed air pollution levels in

95 developed nations are motorization, the high demand for

96 transportation, economic development, energy consump-

97 tion, urbanization and population growth, especially in

98 cities [12]. Due to urbanization, more than half of the

99 world’s population lives in urban areas where high traffic

100 counts provoke high levels of air pollution [22]. Air pol-

101 lution is a heterogeneous mixture of gases (e.g. ozone,

102carbon monoxide, sulfur dioxide, nitrogen oxides) and

103particulate matter (PM) [15, 23]. PM is an air-suspended

104mixture of solid and liquid particles that vary in origin,

105chemical composition and physical properties, and appears

106to be one of the most widespread and harmful components

107of air pollution [23–27]. PM particles are categorized based

108on their aerodynamic diameter as coarse particles or PM10

109particles (\10 lm), fine particles or PM2.5 particles

110(\2.5 lm), and ultrafine particles or UFP (\0.1 lm) [24].

111Early hypotheses suggest that the smaller particles might

112have greater toxicity than larger ones because they might

113enter the body, tissue and cells more easily [28]. PM10 is

114mainly derived from the suspension and resuspension of

115dust from human and natural mechanical processes, while

116PM2.5 and UFP are predominantly derived from combus-

117tion processes [29]. Motor vehicles are a leading source of

118UFP emissions and concentrations in an urban environment

119[30, 31]. This is evidenced by a strong horizontal gradient

120in UFP levels exponentially decreasing with downwind

121distance from major roadways [30, 31].

1223 Air Pollution and the Brain

1233.1 Epidemiological Studies

124The health impact of ambient air pollution is most often

125associated with PM, because PM levels can be estimated

126worldwide and have been linked consistently to adverse

127health effects [26, 27, 32]. In 2010, ambient PM pollution

128was ranked ninth among the leading risk factors for global

129disease burden and accounted for 3.1 million deaths

130worldwide due to respiratory, cardiovascular and cerebro-

131vascular diseases [32]. It has been established for some

132decades that both short-term and prolonged PM exposure

133are associated with increased morbidity and mortality rates

134due to ischemic but not hemorrhagic stroke [23, 33–36].

135Early evidence that showed a link between urban air pol-

136lution and neuropathology emerged from studies that were

137carried out postmortem on animals that were exposed to the

138polluted urban environment of Mexico City, including high

139levels of PM and ozone [37, 38]. These analyses showed

140histopathological findings that relate to a breakdown of

141nasal and olfactory barriers, alteration of the blood-brain

142barrier (BBB), chronic neuroinflammation, neurodegener-

143ation and accelerated AD-like pathology, and DNA dam-

144age [37, 38]. Subsequent postmortem analyses that were

145carried out on human inhabitants from Mexico City sup-

146ported the previous findings showing ultrafine particle

147deposition, oxidative stress, microglia activation, infiltra-

148tion of inflammatory cells, an increase in inflammatory

149markers such as cyclooxygenase (COX)-2, interleukin

150(IL)-1b and CD14, BBB damage, endothelial cell

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151 activation, and the accumulation of amyloid b and a-syn-

152 uclein. The latter two are the pathological hallmarks of AD

153 and Parkinson’s disease (PD), respectively [39, 40].

154 Since the early findings from Calderon-Garciduenas

155 et al. [37–40], a number of epidemiological studies have

156 emerged that show an inverse association between urban-

157 and traffic-related air pollution exposure and cognition.

158 Long-term PM exposure has been linked to cognitive

159 decline in children, adolescents and adults, and with mild

160 cognitive impairment in the elderly. In a birth cohort, a

161 significant association was observed between residential

162 black carbon exposure and a significant decrease of global

163 IQ, non-verbal IQ and memory in children 9 years of age

164 [41]. Calderon-Garciduenas et al. [13] found that children

165 living in Mexico City, where concentrations of air pol-

166 lutants are chronically very high in particular PM10,

167 PM2.5 and ozone levels, performed significantly behind

168 the normative level of cognitive development, e.g. global

169 IQ, verbal IQ, and other tests including memory and

170 executive function. Also in adults (20–59 years), in age-

171 and sex-adjusted models, residence exposure to PM10 and

172 ozone predicted reduced cognitive functions [42]. How-

173 ever, the association between PM10 and cognitive func-

174 tion disappeared after adjustment for sociodemographic

175 factors. Ranft et al. [43] found a significant reduction in

176 cognitive function in elderly who lived for more than

177 20 years within a distance of 50 m from a busy road

178 (traffic density more than 10,000 vehicles/day). In a

179 cohort of community-dwelling older adults, residential

180 proximity to a major roadway was found to be associated

181 with poorer performance on cognitive tests of verbal

182 learning and memory, psychomotor speed, language, and

183 executive functioning [44]. In this study, participants

184 residing less than 100 m from a major roadway performed

185 worst, while performance improved monotonically with

186 increasing distance. Weuve et al. [45] found that long-

187 term exposure to PM2.5–10 and PM2.5 at levels typically

188 experienced by many individuals in the US is associated

189 with significantly more cognitive decline in older women.

190 For more information on neuropsychological effects of air

191 pollution, we refer to the review of Guxens and Sunyer

192 [16].

193 3.2 Controlled Exposure Studies in Rodents

194 Controlled exposure studies in rodents have provided fur-

195 ther support for an association between air pollution and

196 adverse effects in the brain, including neuroinflammation

197 (electronic supplementary material [ESM] Table S1) [46–

198 62], impaired neurobehavioral functioning (ESM Table S2)

199 [52, 58, 59, 62–67], and other effects (ESM Table S3) such

200 as impaired neural plasticity and neuropathological

201alterations [46, 47, 49, 52, 56–62, 65–70]. Rodent studies

202that have investigated acute effects of PM exposure on the

203brain have found a tissue-specific response with alterations,

204mostly increases, in the messenger RNA (mRNA) and

205protein levels of inflammatory markers, e.g. tumor necrosis

206factor (TNF)-a, IL-1b, COX-2, inducible nitric oxide

207synthase (iNOS) and the levels of neurotransmitters (e.g.

208noradrenaline [NA]) in response to PM exposure for 2, 4 or

2098 h [71–73]. The findings of Sirivelu et al. [72], showing

210increased levels of NA in the paraventricular nucleus and

211increased serum levels of corticosterone a day after an 8-h

212inhalation exposure to concentrated ambient PM2.5, sug-

213gest that PM2.5 exposure can activate the stress axis. Early

214subchronic responses to PM exposure include neuroin-

215flammatory changes, e.g. increased levels of proinflam-

216matory cytokines, such as IL-1a and TNFa, and the

217activation of the immune-related transcription factor

218nuclear factor kappa B (NFjB), which are found in the

219brains of ovalbumin-sensitized mice after an inhalation

220exposure of 2 weeks to ultrafine and fine concentrated

221ambient particles [48]. Furthermore, other effects (ESM

222Table S3) of PM exposure have been detected, such as

223altered expression of genes involved in endothelial

224(dys)function, neuronal apoptosis, neurotransmission and

225synaptic plasticity and oxidative damage, i.e. lipid perox-

226idation in the brain of rodents after PM exposure [49, 52,

22765, 66, 68]. Already after short periods (days to weeks) of

228PM exposure, functional impairments are found, such as

229disturbances in motor/exploratory behavior and emotion-

230ality and impairments in spatial and non-spatial learning

231and memory (ESM Table S2) [52, 65, 66, 68]. In addition

232to the early neuroinflammatory changes, microglia activa-

233tion, a sign of neuroinflammation, is found in different

234brain regions, such as cerebral cortex and hippocampus in

235studies with PM exposure for 4 weeks and longer [53, 55,

23657, 60]. Neuroinflammation seems to precede neuro-

237pathological alterations which were found after more

238extended air pollution exposures of 4–6 months, including

239neurodegeneration of dopaminergic neurons, and elevation

240of the level of a-synuclein (in the midbrain), amyloid b42

241(in the frontal lobe), and Tau phosphorylation at the serine

242199 residue (in the frontal and temporal lobe) which are

243markers of PD- and AD-like pathology and frontotemporal

244dementia [60, 61]. These findings suggest that air pollution

245might be associated with the progression of PD- and AD-

246like pathology [61]. Finally, histological evidence for a

247negative effect of air pollution exposure on neural plas-

248ticity was described in the study by Fonken et al. [62]

249showing a reduced apical dendritic spine density and

250dendritic branching in the hippocampal CA1 and CA3

251regions, respectively, in response to 10 months of PM

252exposure.

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253 4 Physical Activity, Cognition, and the Role

254 of Brain-Derived Neurotrophic Factor

255 Cross-sectional and longitudinal studies in humans have

256 repeatedly shown that higher amounts of physical activity

257 or higher fitness levels are positively associated with cog-

258 nitive performance [74–78]. Interventional studies in

259 humans have demonstrated cognitive benefits of partici-

260 pation in an aerobic training program [5, 79, 80]. Meta-

261 analyses show selective improvements in processing speed,

262 memory and executive function, and, less consistently, also

263 in attention and motor function [6, 81]. The largest benefits

264 of physical activity seem to occur in the executive function,

265 which is described as a set of cognitive skills responsible

266 for the planning, initiation, and monitoring of complex,

267 goal-directed behavior [6, 81].

268 Experiments in rodents have shown that in addition to

269 enhanced learning and memory, exercise stimulates

270 mechanisms of neural plasticity, which is broadly defined

271 as the capacity of the brain to learn, remember and forget,

272 as well as its capacity to reorganize and recover from injury

273 [82]. Exercise, for example, stimulates long-term potenti-

274 ation (LTP), which is a physiological form of synaptic

275 plasticity and the proposed mechanism of learning [83, 84].

276 It also stimulates adult neurogenesis [83, 84], dendritic

277 plasticity [84, 85] and synaptogenesis [86]. The use of

278 neuroimaging techniques in intervention studies has shown

279 that aerobic training induces structural and functional

280 changes in the human brain, such as increased brain

281 (regional) volumes [80] and improved intrinsic connectiv-

282 ity [87, 88]. Furthermore, observational studies have linked

283 aerobic fitness with enhanced activity patterns during

284 cognitive tasks [89]. Evidence suggests an important role

285 for neurotrophic growth factors in molecular mechanism,

286 in particular for the neurotrophin BDNF [11, 90–92].

287 BDNF is abundantly expressed throughout the brain, with

288 the highest expression in the hippocampus, cerebral cortex,

289 cerebellum and amygdala [93]. As a member of the neu-

290 rotrophin family of growth factors, a classical function of

291 BDNF is to support neuronal differentiation, growth and

292 survival [94, 95]. BDNF is also importantly involved in

293 synaptic neurotransmission [96] and activity-dependent

294 synaptic plasticity [97, 98]. Mature BDNF has a high (pi-

295 comolar) affinity for the tyrosine kinase B (TrkB) receptor,

296 which is an important regulator of hippocampal LTP [99,

297 100]. Binding of BDNF to the TrkB receptor leads to the

298 activation of the cytoplasmic signaling pathways, including

299 mitogen-activated protein kinase/extracellular signal-regu-

300 lated protein kinase (MAPK/ERK), phospholipase C-c301 (PLC-c), and phosphatidylinositol-3 kinase (PI3-K) [95,

302 100]. The activation of these signaling pathways induces a

303 multitude of downstream events such as phosphorylation

304 of synapsin leading to increased vesicle docking

305presynaptically and enhanced presynaptic release of

306excitatory neurotransmitters, phosphorylation of the glu-

307tamate receptor subunits resulting in enhanced receptor

308sensitivity postsynaptically [95], and the activation of the

309transcription factor cyclic adenosine monophosphate

310(cAMP) response element-binding protein (CREB) which

311activates the transcription of several genes involved in

312synaptic plasticity and memory formation, including

313BDNF, synapsin and synaptophysin [94]. It was shown that

314the BDNF/TrkB pathway not only stimulates LTP but also

315influences the morphology of axons, dendrites and spines,

316stimulates neurogenesis, and seems to be involved in syn-

317aptogenesis [94, 101]. It is therefore evident that BDNF

318plays an essential role in learning and memory [95]. Mice

319genetically deprived of BDNF demonstrate an impaired

320capacity for LTP [98], and for learning and memory [102].

321The role of circulating BDNF in human samples is still

322not clear. In the periphery, BDNF is expressed in many

323tissues, namely adipose tissue, skeletal and smooth muscle,

324and liver, where it is suggested to have a role in energy

325metabolism [101]. It is also expressed in immune cells,

326where it is considered to have a role in cell-to-cell com-

327munication [103]. In rodents, it was shown that BDNF is

328able to cross the BBB via a high capacity, saturable

329transporter system [104]. The findings of Rasmussen et al.

330[105] suggest that the human brain contributes to approx-

331imately 72 % of circulating BDNF during rest and its

332contribution increases during exercise to approximately

33384 %.

334Studies in rodents have demonstrated that acute and

335chronic exercise increases BDNF expression in the hip-

336pocampus, a brain region critical for spatial learning and

337memory [106–111]. Cassilhas et al. [111] found evidence

338showing that aerobic exercise may affect spatial memory

339through increased BDNF signaling, while resistance exer-

340cise seems to affect spatial memory via insulin-like growth

341factor (IGF)-1 signaling. There seems to be a positive

342relationship between distance run and BDNF expression

343[108, 109, 112]. Vaynman et al. [11] found that blocking

344the action of BDNF in the hippocampus during training

345inhibited the exercise-induced enhancement of learning

346and memory. In humans, an acute bout of exercise tran-

347siently increases peripheral BDNF levels [90, 113, 114].

348Indirect evidence suggests that the brain is the main source

349of the increased BDNF level in response to exercise [105].

350The findings regarding the chronic effect of exercise or

351aerobic training on basal levels of circulating BDNF in

352humans are less consistent with a few studies [115, 116]

353showing increased or decreased BDNF levels, and most

354studies [117–119] showing no effect [113]. The inconsis-

355tency of the findings might be attributed to the fact that

356basal circulating BDNF levels vary extremely because they

357are influenced by a wide variety of factors, including time

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358 of day, stress, sex, hormones, chronic diseases, etc. [120].

359 The studies that did find increases seem to use more

360 intensive training protocols [113]. Moreover, via arterial

361 and internal jugular venous blood sampling, Seifert et al.

362 [110] showed that the output of BDNF from the brain is

363 increased after 3 months of training, whereas there is no

364 measurable increase in the arterial BDNF level. Erickson

365 et al. [80] found an increased hippocampal volume and

366 improved spatial memory in a randomized controlled trial

367 of 1-year moderate-intensity exercise in the elderly. They

368 found a correlation between serum levels of BDNF and

369 hippocampal volume changes, which suggests that there

370 might be a mechanistic link between the exercise-induced

371 increases in BDNF levels and the hippocampal volume

372 changes in humans [80].

373 5 Physical Activity in Polluted Air: Implications

374 for the Brain

375 Ventilation rate increases during exercise, concomitantly

376 increasing air pollution exposure. Atkinson [121] showed

377 that an athlete running at 70 % of maximal oxygen uptake

378 for the length of a marathon (circa 3 h) inhales the same

379 volume of air as a sedentary person would in 2 days. Int

380 Panis et al. [17] measured ventilation during commuter

381 cycling and concluded that minute ventilation while

382 cycling is, on average, 4.3-fold higher and quantities of

383 inhaled particles are between 400 and 900 % higher com-

384 pared with driving a car. Also, the deposition fraction, the

385 fraction of inhaled particles that are retained in the lungs

386 after inhalation of UFP, seems to increase with exercise

387 [122, 123]. Daigle et al. [122], for example, found that the

388 total number of deposited UFP particles was more than 4.5-

389 fold higher during moderate exercise on a bicycle ergom-

390 eter than at rest because of a combined increase in depo-

391 sition fraction and minute ventilation. The lung deposition

392 of the particles during exercise was greater than expected

393 from changes in minute ventilation and greatest for the

394 finest particles. The regional deposition of UFP is pre-

395 dominantly alveolar, suggesting that exercise, in particular,

396 increases UFP dose in the alveolar region of the lung [122].

397 The issue of the potential harmful health effects of air

398 pollution has received attention in the recent past during

399 several Olympic Games, where there was a concern for the

400 health and performance of the competing athletes [124,

401 125]. Exercise in polluted air may lead to acute pulmonary

402 effects, e.g. temporary decreases in lung function [126,

403 127], increased levels of inflammatory markers and altered

404 immune function in the pulmonary system [126, 128]. It

405 may lead to acute cardiovascular effects, e.g. reduced

406 vasodilation [129] and impairments in exercise perfor-

407 mance [130]. Long-term exercise in a polluted environment

408may lead to diminished lung function and even incidences

409of asthma in athletes. We further refer to the review of

410Cutrufello et al. [131] and Giles and Koehle [132] for more

411details on the cardiopulmonary effects of air pollution

412exposure during physical activity.

413Since the recent discovery of a link between air pollu-

414tion exposure and adverse effects on the brain, one might

415wonder whether the well-known benefits of regular phys-

416ical activity on the brain also apply when physical activity

417is performed in polluted air. A new line of research

418therefore examines the balance between the negative

419effects of air pollution exposure and the positive effects of

420physical activity on the brain. The first studies, conducted

421by our group, have addressed this issue, focusing on cog-

422nition, BDNF and inflammation [18–20].

423Studies that have demonstrated an acute increase in the

424level of BDNF in serum after exercise have mostly been

425performed in controlled laboratory settings [90, 113, 114,

426133]. To our knowledge, possible effect modifications by

427environmental factors, except for temperature [134], have

428not yet been investigated. Therefore, a crossover study in

429humans was set-up to investigate the acute effect of traffic-

430related air pollution exposure during exercise on serum

431BDNF levels. In this study, volunteers performed two

432identical cycling tests in terms of duration and intensity,

433but one in a clean room where particles were removed from

434the air and one along a busy road. We found, in agreement

435with previous studies, increased BDNF levels in serum

436after a cycling test in the clean room. In contrast, the serum

437BDNF level was not increased after cycling along the busy

438road with levels of PM10, PM2.5 and UFP that were

439moderate but substantially higher than in the clean room

440[20]. The findings suggest that exposure to traffic-related

441air pollution during exercise inhibits the exercise-induced

442increase of the BDNF level in serum [20].

443In the context of earlier findings [105] pointing to the

444brain as the main source of the exercise-induced increase of

445the BDNF level in serum, it could be speculated that

446traffic-related air pollution exposure during exercise might

447inhibit the acute exercise-induced increase of central

448BDNF production/secretion. This hypothesis was explored

449in a controlled intervention study in rodents where the

450acute effect of UFP exposure during exercise on BDNF

451gene expression in the rat hippocampus was examined. The

452findings showed that the mRNA level of BDNF in the rat

453hippocampus was increased 24 h after 90 min of treadmill

454running at a moderate speed in ambient air compared with

455the control group that rested in ambient air [19]. In con-

456trast, there was no increase of the BDNF mRNA level after

457the same running bout in air with high UFP levels, which

458suggests that there might be a negative effect of UFP

459exposure on the exercise-induced increase of BDNF gene

460expression. The absence of an exercise-induced increase in

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461 BDNF gene expression might be the result of a negative

462 effect of UFP exposure on basal gene expression of BDNF.

463 Since there was only a trend towards a decreased BDNF

464 mRNA level in rats exposed to UFP during rest, here the

465 increased ventilation rate could also play a role in the

466 amount of particles inhaled. To our knowledge, no other

467 studies have investigated the acute effect of a single UFP

468 exposure on BDNF expression in the brain. A few studies

469 have investigated the effect of short-term air pollution

470 exposure on BDNF expression in the brain of rodents. Bos

471 et al. [46] found a reduction of BDNF mRNA levels in the

472 olfactory bulb but no significant effect on BDNF mRNA

473 expression in the hippocampus of mice that were exposed

474 to traffic-related PM for 5 days. Win-Shwe et al. [58] found

475 higher BDNF mRNA levels in the hippocampus of mice

476 that had been exposed to nanoparticle-rich diesel exhaust

477 for 3 months, in addition to an impaired performance on a

478 spatial learning and memory task. The inconsistency of the

479 findings might be caused by differences in study design,

480 such as composition of the air mixture and exposure

481 duration. Furthermore, mRNA levels of BDNF may not

482 always represent protein levels, possibly because of regu-

483 lation at post-transcriptional level [106]. Future examina-

484 tion of hippocampal protein levels of BDNF should bring

485 more clarity to the acute and chronic effect of air pollution

486 on hippocampal BDNF expression. PM exposure also

487 affects hippocampal expression of other genes important in

488 neural plasticity and cognition, e.g. N-methyl-D-aspartate

489 receptor (NMDAR1) subunits 1, 2A and 2B, calcium/cal-

490 modulin-dependent protein kinase IV (CaMK-IV), excit-

491 atory amino-acid transporter 4 (EAAT4), glutamate

492 decarboxylase 65 (GAD65) and neuronal glutamate

493 receptor subunit 1 (GluA1) [52, 57–59]. The finding that

494 10 months of PM exposure reduces hippocampal dendritic

495 plasticity [62] suggests indeed that there is a negative effect

496 of PM exposure on the expression of BDNF and the other

497 genes involved in neural plasticity.

498 Finally, we designed a study to investigate the effect of

499 air pollution exposure during aerobic training on cognition.

500 In this study, formerly untrained subjects participated in a

501 12-week aerobic training program, one group in a rural

502 environment and another group in an urban environment.

503 At the end of the training program, performance in the

504 Stroop Color-Word test, a test to measure executive func-

505 tion, was improved in the group that had trained in the rural

506 environment but not in the group that had trained in the

507 urban environment, where UFP levels were significantly

508 higher [18]. The findings suggest that high exposure to

509 traffic-related air pollution during exercise training inhibits

510 the positive effects of exercise training on cognition. This

511 indicates that air pollution exposure might have a negative

512 effect on cognition, which is in accordance with previous

513 studies that have shown an inverse link between air

514pollution exposure and cognition [16, 44, 45]. After

51512 weeks, we did not observe a chronic effect of exercise

516or air pollution exposure on basal serum BDNF levels.

517Although it remains very speculative, the absence of an

518acute increase in BDNF level in response to exercise in

519polluted air, as described in Bos et al. [20], and the absence

520of cognitive improvements in humans in response to

521exercise training in polluted air, as described in Bos et al.

522[18], might be caused by an acute negative effect of air

523pollution exposure on the expression and/or secretion of

524BDNF in the brain. The evidence suggests that regular

525exercise in highly polluted air might not result in the same

526neurological benefits that are observed in non-polluted air.

527However, to the authors knowledge there is not enough

528evidence to suggest that regular exercise in highly polluted

529air causes more damage to the brain due to air pollution

530exposure than benefits of physical activity.

5315.1 Possible Mechanisms

532It is believed that air pollution induces adverse health

533effects mainly via induction of oxidative stress and

534inflammation, also in the brain [14, 25]. PM exposure may

535create oxidative stress and inflammation in the brain

536directly after entry of the particles into the brain, or indi-

537rectly via the stimulation of peripheral/systemic inflam-

538mation (Fig. 1) [14, 15, 135].

539There are several possible routes by which the smaller

540fraction of particles might be able to enter the brain, as

541described in the review of Oberdorster et al. (Fig. 1) [135].

542The first possible pathway involves retrograde and anter-

543ograde transport in axons and dendrites via sensory nerve

544fibers that innervate the nasopharyngeal and tracheobron-

545chial regions of the respiratory tract [135, 136]. An

546example is the nasal olfactory pathway, which is believed

547to be the most direct route to the brain. In the nasal

548olfactory pathway UFP—after deposition on the nasal

549olfactory mucosa—migrate via the olfactory nerve into the

550olfactory bulb and from there to other brain regions [136].

551Another rapid translocation route from nose to brain that

552has been described is perineural translocation [137], which

553involves extracellular transport of particles via perineural

554space into cerebrospinal fluid and from there across the

555cerebrospinal fluid brain barrier into the brain [138]. A

556third possible route is via entry into the blood circulation

557after inhalation and crossing of the alveolar-capillary bar-

558rier, or after swallowing into the gastrointestinal tract and

559crossing of the intestinal epithelium [139]. Particles that

560have entered the circulation might be able to enter the

561brain, preferably at sites where the BBB is less well

562developed or injured, for example via the circumventricu-

563lar areas, which are highly vascularized brain structures

564lacking a BBB [135]. However, the smallest particles can

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565 penetrate cell membranes and might therefore be able to

566 cross the BBB [140].

567 Alternatively, the presence of particles in the respiratory

568 system, the circulation, and the peripheral organs induces

569 oxidative stress and triggers an inflammatory response.

570 This may lead to increased levels of proinflammatory

571 cytokines. Studies in humans have reported an increase of

572 peripheral inflammatory markers in response to acute and

573 chronic exposure to traffic-related air pollution [24, 141–

574 143]. The observed effects of traffic-related air pollution

575 exposure on BDNF levels and cognition in humans were

576 associated with increased levels of peripheral inflammatory

577 markers [18, 20]. An increased fraction of blood neutro-

578 phils, a marker of inflammation, was observed after a

579 cycling test along a busy motorway, but not after a cycling

580 test in an air-filtered room [144]. Also in the training study,

581 the level of exhaled nitric oxide, a marker of respiratory

582 inflammation, and the count of blood leukocytes and neu-

583 trophils were increased in the group that had been training

584 in an urban environment but not in the group that had

585 trained in a rural environment. The changes in these

586 markers were correlated with personal exposure during the

587 training sessions [18]. A peripheral immune activation may

588 lead to neuroinflammation through multiple pathways [15,

589145]. The cytokines, for example, can enter the brain via

590diffusion or active transport, they may activate peripheral

591neuronal afferents, or they can disrupt BBB integrity,

592which may facilitate leukocyte infiltration leading to brain

593injury [14, 15, 39, 145, 146].

594An inflammatory reaction is initially activated as a

595protective mechanism in response to exposure to foreign

596substances, such as PM, to remove the foreign substance

597and to restore homeostasis. However, repeated exposure to

598PM may result in chronic inflammation, which is poten-

599tially harmful to the body, especially the brain. Chronic

600neuroinflammation is involved in the pathogenesis of sev-

601eral types of neurodegenerative diseases [147, 148]. It has

602become evident that the immune system plays an important

603role in neural plasticity and cognition [149]. In normal

604conditions, the immune system is involved in positive

605effects of environmental/psychological stimuli on neural

606plasticity and cognition, but it may also induce detrimental

607effects when it becomes strongly activated [149–151]. In

608elderly, for example, an inflammatory event such as injury

609or infection is often accompanied by a decline in cognition

610[151, 152]. Moreover, low-grade inflammation, as indi-

611cated by erythrocyte sedimentation rate, may already be

612associated with reduced cognitive ability at age 18–20

613years [150]. A mechanistic link between inflammation,

614BDNF expression and cognition has been described in the

615literature. In aged rats, an increase of IL-1b levels in the

616hippocampus 2–24 h after a peripheral injection of Esch-

617erichia coli is associated with amnesia for hippocampal-

618dependent memories [153]. BDNF might be involved in the

619mechanism since hippocampal BDNF levels, as well as

620downstream effects of BDNF action, e.g. activation of the

621TrkB receptor, are markedly reduced in aged animals fol-

622lowing infection, but not when an IL-1 receptor antagonist

623(IL-1 RA) is administered [154].

624Traffic-related air pollution exposure might also have a

625negative effect on central BDNF levels and cognition via

626induction of oxidative stress to which the brain is extre-

627mely vulnerable because of its high energy use, low levels

628of endogenous scavengers, and high metabolic demands

629[155]. A high-saturated-fat diet, for example, compromises

630cognitive function but it was shown that antioxidant sup-

631plementation reduces the free radicals and reverses the

632diet-induced reduction of BDNF, CREB and synapsin I

633(SYNI) levels and cognitive function [156]. Cellular oxi-

634dative stress in the brain might have a negative effect on

635BDNF gene expression via a reduced DNA-binding

636capacity of the transcription factor CREB, which regulates

637transcription of BDNF [157]. In contrast, regular exercise

638has an anti-neuroinflammatory effect and increases resis-

639tance against oxidative damage which might contribute to

640the pathway by which exercise enhances hippocampal

641BDNF expression and improves cognition [157–160].

Fig. 1 Schematic overview of different potential pathways through

which inhaled particles may induce adverse effects on the central

nervous system. BBB blood-brain barrier, NTS nucleus tractus

solitarius, ANS autonomic nervous system. Black dots represent

particulate matter, full arrows represent effects, dotted arrows

represent migration, ? represents induction

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642 Although it remains very speculative, opposite effects,

643 including inflammation and oxidative stress, might be

644 involved in a pathway by which air pollution might inter-

645 fere with the beneficial effects of exercise on the brain

646 (Fig. 2).

647 Another route through which inhaled PM might affect

648 the brain is via activation of peripheral neuronal afferents

649 due to interactions of the particles or inflammatory medi-

650 ators with the nerve endings [14, 15, 146, 161]. Primary

651 afferent information from the respiratory tract, for exam-

652 ple, is transported to the nucleus tractus solitarius (NTS)

653 via the vagus nerve. The NTS is known to be critical for

654 homeostasis and autonomic regulation [162]. Stimulation

655 of vagal nerves in the lungs may induce perturbation of

656 systemic autonomic nervous system balance. Short-term

657 exposure to PM has been associated with changes in

658 autonomic function, as evidenced by changes in cardiac

659 rhythm in both humans and rodents [24, 161, 163]. Ghelfi

660 et al. [161] provided evidence for a primary role of irritant

661 receptors in the lung in mediating the particle-induced

662 autonomic perturbations by showing that the changes in

663 cardio-electrophysiology and the resulting cardiac oxida-

664 tive stress could be prevented by blocking the vanilloid

665receptor 1 in the lungs. They concluded that these

666responses were unlikely to be attributable to inflammatory

667mediators since they were detectable within a few minutes

668of exposure.

669Acute vagal nerve stimulation (VNS) has been shown to

670stimulate BDNF gene expression in the hippocampus and

671cerebral cortex [164]. VNS stimulates neuronal activity

672[165] and neurotransmission [164]. Neuronal activity [166]

673and certain neurotransmitters, such as NA [167], stimulate

674the expression and secretion of BDNF. It is therefore

675suggested that effects on neuronal activity and neuro-

676transmission are involved in the mechanism through which

677VNS may affect BDNF expression [164].

678Physical exercise is also accompanied with neuronal

679activation in certain brain regions, including the hippo-

680campus, paraventricular nucleus, cortex, striatum, etc.

681[168]. Neuronal activity is suggested to play a key role in

682the mechanism through which BDNF expression and

683secretion is upregulated by exercise in brain regions such

684as the hippocampus [106].

685Gackiere et al. [162] showed that ozone challenge

686induced the activation of NTS through vagus nerves and

687promoted neuronal activation in the stress-responsive brain

688regions. They found that the brain activation pattern was

689similar to the one elicited by ‘systemic stress’ since there

690was no activation of limbic structures such as the hippo-

691campus. Systemic stress is generally induced by stressors

692that involve an immediate physiologic threat, such as

693respiratory stressors, infection, cytokines or intraperitoneal

694lipopolysaccharide administration [169]. It does not require

695cognitive processing and therefore does not activate limbic

696and cortical structures in contrast to processive stress

697which is induced by stimuli that become stressful by

698comparison with previous experience such as fear condi-

699tioning or exposure to novel environments [169]. On the

700other hand, the brain activation pattern induced by exer-

701cise, which also includes activation of the hippocampus

702and cortex, seems to be more similar to the one induced by

703processive stressors [168]. However, the absence of an

704exercise-induced upregulation of the mRNA level of

705BDNF in the rat hippocampus in response to PM exposure

706during exercise suggests that PM exposure during exercise

707might result in a brain activation pattern similar to the one

708elicited by systemic stress [19].

7096 Conclusion

7106.1 Public Health Relevance

711Our recent findings suggest that exposure to air pollution

712during exercise induces subclinical effects on inflammatory

713markers and inhibits the positive effects of exercise on

Fig. 2 Hypothetical pathways through which physical activity and

air pollution may induce opposite effects on cognition. BDNF brain-

derived neurotrophic factor, - represents inhibition, ? represents

induction

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714 executive functioning, as measured with the Stroop Color-

715 Word test [18–20].

716 The new insight is of great value to professionals who

717 give general health advice and those who exercise out-

718 doors. Our findings should encourage people to select a

719 green environment for their daily physical exercise and to

720 avoid close proximity to traffic and polluted urban envi-

721 ronments during exercise. Knowing that there is a large

722 spatial gradient in UFP levels, which exponentially

723 decreases with distance from major roadways, increasing

724 distance from traffic will lower exposure substantially.

725 Also, when exercising it is better to avoid traffic rush

726 hours, whereas weather conditions such as rain and wind

727 are known to dilute local PM levels.

728 In some circumstances, it is difficult to avoid traffic-

729 related PM exposure, for example commuting by bicycle to

730 work often occurs close to traffic. It is proposed that the

731 positive effects of physical activity are stronger than the

732 negative effects of air pollution [170, 171]. However, this is

733 suggested by studies analyzing the mortality risks and

734 benefits of commuter cycling, which do not consider aspects

735 such as morbidity, peak exposures, and susceptible popu-

736 lations; they may also underestimate ventilation rate [170–

737 172]. It should also be emphasized that all possible health

738 effects for the different organ systems and populations

739 should be taken into consideration before any accurate

740 general recommendation can be given concerning exercis-

741 ing in an environment with air pollution. The risks for

742 harmful effects on the brain, for example, might be different

743 from those on the cardiovascular system. In addition, the

744 balance between the risks and benefits may also be different

745 in diverse populations, e.g. healthy populations versus

746 populations susceptible to certain diseases [24].

747 This finding should encourage policymakers to make an

748 effort towards infrastructural changes aimed at improving

749 the air quality of the direct environment where sport is

750 practiced or active transport/commuting is performed.

751 6.2 Future Perspectives

752 The findings of our studies described in this review remain to

753 be confirmed by others. Studies in rodents should be dedi-

754 cated to examine the acute effect of PM exposure during

755 exercise (and rest) on protein levels of BDNF in the hippo-

756 campus. Most studies in rodents detect an increased protein

757 level of BDNF from 2 to 6 h after exercise [106, 107]. Time-

758 course studies should therefore investigate BDNF levels in

759 this timeframe. In case it is confirmed that air pollution

760 exposure during exercise inhibits the exercise-induced

761 increase of hippocampal BDNF levels, a next step should be

762 to explore short-term effects on hippocampal BDNF levels

763 and neural plasticity mechanisms, e.g. neurogenesis, and

764 hippocampal-dependent learning and memory.

765Future studies should also address whether air pollution

766exposure during exercise inhibits the assumed increase of

767BDNF production and/or secretion in the human brain, for

768example by monitoring the arterial to internal jugular

769venous difference in circulating BDNF level. Neuroimag-

770ing techniques may provide biological data of structural

771and functional effects of PM exposure during aerobic

772training at brain level in humans. The findings described in

773this review occurred in populations of (mainly) adults

774whose cognition is known to be relatively stable. The

775health-enhancing potential of physical activity is of par-

776ticular interest to a population at risk for cognitive decline,

777such as the elderly, as a preventive intervention. The

778consequences of a negative effect of air pollution exposure

779during exercise might therefore be especially relevant to a

780population at risk for cognitive decline. Children might

781represent another group of susceptible subjects since the

782developing brain is very plastic and thus very responsive to

783modifying stimuli [74]. The medical community should be

784aware of the potential impact on geriatric and pediatric

785populations and in pregnant women, which brings another

786important avenue for research.

7876.3 Final Comments

788In conclusion, early findings indicate that traffic-related air

789pollution exposure might have a negative effect on exer-

790cise-induced cognitive improvements. It is suggested that

791the responsible mechanism might include an inflammatory

792effect and an acute, negative effect of traffic-related air

793pollution exposure on BDNF expression and secretion in

794the brain. More research is necessary to explore possible

795interactions between the neurological effects of air pollu-

796tion and physical activity and to further unravel the neu-

797rological impact of air pollution exposure during acute and

798regular exercise.

799Acknowledgments Inge Bos was supported by a PhD fellowship of800the Flemish Institute for Technological Research (VITO). Inge Bos,801Patrick De Boever, Luc Int Panis and Romain Meeusen have no802conflicts of interest that are directly relevant to the content of this803review. All authors made substantial contributions to this manuscript804from inception to submission.

805

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