TOXICOLOGICAL SCIENCES 140(1), 160–178 2014
Advance Access publication April 1, 2014
Developmental Exposure to Concentrated Ambient Ultrafine Particulate
Matter Air Pollution in Mice Results in Persistent and Sex-Dependent
Behavioral Neurotoxicity and Glial Activation
Joshua L. Allen,*Xiufang Liu,*Douglas Weston,*Lisa Prince,*G¨ unter Oberd¨ orster,*Jacob N. Finkelstein,*,†Carl
J. Johnston,*,†and Deborah A. Cory-Slechta*,†,1
*Department of Environmental Medicine; and †Department of Pediatrics, University of Rochester School of Medicine Rochester, New York 14642
1To whom correspondence should be addressed at 601 Elmwood Avenue, Box EHSC/Room-2-6821, Rochester, NY 14642. Fax: (585) 256-2591. E-mail:
Received October 28, 2013; accepted March 6, 2014
The brain appears to be a target of air pollution. This study
aimed to further ascertain behavioral and neurobiological mech-
anisms of our previously observed preference for immediate re-
ward (Allen, J. L., Conrad, K., Oberdorster, G., Johnston, C. J.,
Sleezer, B., and Cory-Slechta, D. A. (2013). Developmental expo-
sure to concentrated ambient particles and preference for immedi-
ate reward in mice. Environ. Health Perspect. 121, 32–38), a pheno-
type consistent with impulsivity, in mice developmentally exposed
to inhaled ultrafine particles. It examined the impact of postna-
tal and/or adult concentrated ambient ultrafine particles (CAPS)
or filtered air on another behavior thought to reflect impulsiv-
ity, Fixed interval (FI) schedule-controlled performance, and ex-
tended the assessment to learning/memory (novel object recog-
nition (NOR)), and locomotor activity to assist in understand-
ing behavioral mechanisms of action. In addition, levels of brain
monoamines and amino acids, and markers of glial presence and
regions mediating these cognitive functions. This design produced
four treatment groups/sex of postnatal/adult exposure: Air/Air,
Air/CAPS, CAPS/Air, and CAPS/CAPS. FI performance was
adversely influenced by CAPS/Air in males, but by Air/CAPS
in females, effects that appeared to reflect corresponding changes
in brain mesocorticolimbic dopamine/glutamate systems that me-
diate FI performance. Both sexes showed impaired short-term
memory on the NOR. Mechanistically, cortical and hippocampal
changes in amino acids raised the potential for excitotoxicity, and
losum of both sexes. Collectively, neurodevelopment and/or adult-
hood CAPS can produce enduring and sex-dependent neurotoxic-
ity. Although mechanisms of these effects remain to be fully eluci-
dated, findings suggest that neurodevelopment and/or adulthood
air pollution exposure may represent a significant underexplored
risk factor for central nervous system diseases/disorders and thus
Associations between air pollution and adverse cardiopul-
monary heath effects are well documented. Ultrafine particles
(UFP; <100 nm in diameter), found ubiquitously in ambient in-
door and outdoor air (Oberdorster et al., 2004), are considered
2000). Increasing evidence suggests that air pollutants may also
adversely affect the central nervous system (CNS). Epidemio-
logical studies have identified associations between exposure to
diverse ambient air pollutants such as particulate matter (PM),
ozone, carbon monoxide, and nitrogen dioxide with ischemic
Lokken et al., 2009), with one of the first studies reporting in-
creased risk of stroke due to exposure to indoor coal fumes
(Zhang et al., 1988).
Behavioral function also appears to be a target of the toxic ef-
fects of ambient air pollutants. A positive association between
diagnosed attention deficit hyperactivity disorder (ADHD) and
ambient particulate matter level was reported in school-aged
tial confounders (Siddique et al., 2011). Correspondingly, we
reported that postnatal exposures of mice to concentrated am-
bient ultrafine particles (CAPS) increased preference for imme-
diate reward, a type of impulsivity using a fixed-ratio waiting-
a marker of traffic-generated PM, was associated with reduced
neurocognitive function in urban school-aged children (Suglia
also associated with neurocognitive decline in a cohort of men
with deficits in short-term memory in male rats (Zanchi et al.,
monary tissue (Alessandrini et al., 2009; Delfino et al., 2009;
Fujii et al., 2001; Ishii et al., 2004; Nemmar et al., 2009; van
Eeden et al., 2001) with similar effects seen in the CNS (Camp-
bell et al., 2009; Gerlofs-Nijland et al., 2010; Kleinman et al.,
2008). In vitro, brain microglia were found to be primed in re-
sponse to diesel exhaust exposure when later challenged with
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DEVELOPMENTAL AIR POLLUTION NEUROTOXICITY
lipopolysaccharide (Levesque et al., 2011). In vivo studies in
rats indicated that subchronic diesel exhaust exposure caused
neuroinflammation and elevated early markers of neurodegen-
erative disease (Levesque et al., 2011). Although experimental
data suggests that UFP can directly translocate into the CNS
(Oberdorster et al., 2002, 2004), it would not be necessary for
this to occur to produce neurotoxicity, because peripheral in-
flammation itself can adversely affect the CNS (Banks et al.,
2002; Delfino et al., 2009; Hagberg and Mallard, 2005; Kons-
man et al., 2002; Perry, 2004).
To further understand the nature of behavioral deficits pro-
duced by ambient air pollutants and their corresponding behav-
ioral and neurobiological mechanisms, this study further exam-
ined our previously reported CAPS-induced preference for im-
mediate reward (Allen et al., 2013). To do so, it used a fixed
interval (FI) 60 and 120 s (FI60 and FI120, respectively) sched-
ule of food reward, as performance on this schedule has been
demonstrated to be a surrogate for impulsivity in both infants
and children (Darcheville et al., 1992, 1993). Impulsivity is a
component of attention deficit disorder and consistent with a
preference for immediate reward. On the FI schedule, delivery
of a reinforcer follows the first occurrence of a response (here,
a lever press) after an FI of time (in this case, 60 s) has elapsed
because the previous reinforcement delivery. The “scalloped”
pattern of FI behavior, characterized by periods of little or no
responding early in the interval followed by a gradual increase
in rate of responding as the opportunity for reinforcer delivery
approaches (Ferster and Skinner, 1957), has been observed over
a wide range of species, which attests to the generality of these
underlying behavioral processes (Kelleher and Morse, 1968).
Our studies in rats have confirmed a critical role of mesocor-
ticolimbic dopamine systems in the mediation of FI behavior
(Cory-Slechta et al., 1997, 1998, 2002).
Because changes in FI response rate might reflect altered ac-
tivity rather than impulsive-like behavior, changes in locomo-
tor activity were also examined. As an additional assessment
of CAPS behavioral toxicity, a measure of learning/short-term
memory, a novel object recognition (NOR) paradigm was uti-
lized. Levels of brain neurotransmitters and markers of neuro-
toxicity in brain regions known to mediate cognition and at-
tention, as well as neuroinflammation were measured as po-
tential mechanisms of behavioral toxicity. Based on known
mechanisms of air pollution and of regions/neurotransmitters
mediating these behaviors, we hypothesized that early post-
natal CAPS exposure and/or adult CAPS would induce be-
havioral toxicity mediated by changes in mesocorticolim-
bic monoamines/glutamate, brain glial activation, and brain
MATERIALS AND METHODS
Animals/experimental design/exposure. Young adult male
and female C57BL/6J mice obtained from Jackson Laborato-
ries (Bar Harbor, ME) were bred using a monogamous pairing
scheme. Male and female (n = 35 pairs) mice were paired for
3 days, after which males were removed from the home cage.
Pregnant dams (n = 24) remained singly housed throughout
weaning. On average, litters contained (mean ± SD) 5.91 ±
1.56 pups with (mean ± SD) ∼45 ± 22% males. Litter sizes
ranged from four to eight pups. Litters were not culled as al-
location of pups into treatment groups was counter-balanced
against litter size. Pups were randomly assigned to treatment
groups with no more than a single pup per litter per sex being
allocated to a given treatment group, with one pup per sex be-
ing allocated for each of the four treatment groups when possi-
ble. Upon weaning at postnatal day (PND) 25, male and female
progeny were housed in same sex pairs under a 12-h light/dark
cycle and temperature maintained at 72◦F.
The experimental design is shown in Figure 1. Offspring
(n = 8–12/treatment group/sex) were exposed to CAPS or
HEPA-filtered (99.99% effective) room air in compartmental-
ized whole body inhalation chambers over PNDs 4–7 and 10–
13 for 4 h/day between 0700 h–1300 h. Pups were removed
dling) from impacting behavior. No gross differences in mater-
nalcare bytreatmentwere observed after cessationof exposure.
These hours correspond to high levels of vehicular traffic near
the ambient air intake valve. Exposures were carried out using
the Harvard University Concentrated Ambient Particle System
(HUCAPS) as described elsewhere (Allen et al., 2013). Briefly,
the HUCAPS system concentrates ambient ultrafine particles
from a nearby highly trafficked roadway ∼10 times that of am-
bient air (see Fig. 2) and delivers them to compartmentalized
whole-body inhalation chambers. The variability in these expo-
sures represents the real-world nature of the exposure paradigm
and the natural variability in ambient, urban, and outdoor air.
Filtered air and CAPS-treated mice experienced similar exper-
imental manipulations. Particle counts were obtained using a
condensation particle counter (model 3022A; TSI, Shoreview,
ticle density of 1.5 g/cm3. Both CAPS and control mouse expo-
humidity. At PND56, mice received a secondary challenge with
CAPS or filtered air for an additional 4 days to assess cumula-
tive toxicity, generating four treatment groups per sex: postna-
tal air with (n = 9 males; n = 8 females) and without (n = 9
and Air/CAPS, respectively) and postnatal CAPS with (n = 12
males; n = 11 females) and without (n = 12 males and females)
particles/cm3that were concentrated 3–21-fold giving rise to
CAPS exposure particle count concentrations ranging from
centrations in Erfurt, Germany (Wichmann and Peters, 2010)
and Atlanta, GA, USA (Woo et al., 2010) ranged from 10,000
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ALLEN ET AL.
Spontaneous locomotor (SLA) activity was collected every other day for three sessions from PNDs 71–78. Starting on PND93, animals were autoshaped and
subsequently placed under the FI schedule of reinforcement until PND240. Novel object recognition (NOR) was carried out at ∼6 months of age. Blood was
collected (represented by arrows) on PND60, 6 months of age, and upon sacrifice at approximately PND270 .
Experimental design. Mice were exposed in the postnatal period from PNDs 4–7 and 10–13, with adult re-exposure occurring at PNDs 57–59.
number of particles × 105/cm3± SDs. Concentration factor (left) was calculated as [CAPS]/[UFP]. Mean particle mass (right) is reported as ?g/m3± SDs.
Daily diameter of CAPS (right) is reported in nm ± SDs.
Ambient outdoor UFP and CAPS characterization. Daily outdoor ambient UFP and CAPS counts across all exposure days (left) are reported as
to 20,000 particles/cm3, similar to ambient UFP concentrations
CA, USA and Minneapolis, MN, USA have been reported at
200,000–400,000/cm3, respectively, near highways, with peak
episodic counts reaching as high as 2,000,000 particles/cm3in
Minneapolis (Kittelson, 2004; Westerdahl et al., 2005). Diam-
eter of the particles remained <100 nm (i.e., ultrafine) over all
exposure days. Thus, particle exposures in this study are rela-
tively low and clearly within human-relevant ranges.
10 days prior to commencing behavioral testing on PND71. On
g for males and 19.6 g for females and there were no treatment-
related differences in body weight. Four weeks after the con-
clusion of operant behavior testing (at ∼9 months of age), mice
were sacrificed by cervical dislocation without the use of seda-
immersion-fixed in4%paraformaldehyde for48 hand cryopro-
tected in 30% sucrose until it sunk. Fixed frozen brains were
sectioned on a sliding microtome at 40 ?m for immunohisto-
chemical analysis. Tissue was collected in cryoprotectant (30%
sucrose; 30% ethylene glycol in 0.1M PB) into a six-series,
with every sixth section being collected into a single well for
immunohistochemical analysis. The right hemisphere was dis-
Whole blood was collected by submandibular bleed at
PND60 (24 h after final adult exposure) and again at ∼6 months
of age. Upon sacrifice, trunk blood was collected. Whole blood
was collected into prechilled centrifuge tubes and centrifuged
for 20 min at 3500 × g for 20 min to obtain serum.
Spontaneous locomotor activity. Automated locomotor ac-
tivity chambers equipped with infrared photobeams (Opto-
Varimex Minor, Columbus Instruments, Columbus, OH) were
used to assess spontaneous locomotor activity (SLA). SLA was
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ALLEN ET AL.
of a CAPS-induced inflammatory event in the CNS or else-
where. It will be important to determine whether the HPA axis
represents a direct toxicological target of CAPS, or perhaps a
response to alterations in excitatory amino acid function in un-
derstanding CNS mechanisms of CAPS.
An additional notable finding was the persistent glial activa-
tion observed in corpus callosum and cortex of CAPS-exposed
mice, observed months posttermination of exposure consistent,
with a sustained neuroinflammatory state. IBA-1, a marker of
brain microglia and macrophages was increased in the cor-
tex of males receiving postnatal CAPS and in corpus callosum
of Air/CAPS and CAPS/Air males, consistent with a CAPS-
induced increased macrophage (i.e., microglial) presence in
the brain. In females, postnatal CAPS increased frontal cortex
GFAP, and adult CAPS increased corpus callosum GFAP lev-
els. Such neuroinflammation, in addition to being present in
neurodevelopmental disorders such as autism (Morgan et al.,
2010; Rodriguez and Kern, 2011) and schizophrenia (Cropley
neurodegenerative diseases, including Alzheimer’s and Parkin-
son’ disease, multiple sclerosis, Huntington’s disease and amy-
otrophic lateral sclerosis (Frank-Cannon et al., 2009; Hirsch
et al., 2012; Li et al., 2011). Thus, the current findings raise the
question as to the extent that developmental CAPS exposures
may also contribute to the subsequent onset of neurodegener-
ative diseases. The glial changes in the corpus callosum were
discovered incidentally while examining the mesocorticolimbic
structures of the brain. The corpus callosum is a central white
munication. Neuropathology or dysfunction in the corpus cal-
losum has been implicated in a number of neurological condi-
tions including both schizophrenia and autism (Newbury and
in connectivity in the central nervous system such that typical
neurotransmission is disrupted, is one putative mechanism by
which corpus callosum pathology is thought to elict neurologi-
cal dysfunction. Interestingly, CAPS induces both corpus callo-
sum glial changes and widespread, multi-brain system changes
in both monoamine and amino acid neurotransmitters which is
consistent with functional disconnection; however, further and
more in depth study into this question is required.
Collectively, these data demonstrate persistent neurotoxic
changes in response to CAPS during the early postnatal period,
young adulthood, or the combination. CAPS produced changes
in a sex-specific manner, underscoring the necessity of exam-
ining the effects of toxicants in both males and females. Al-
though the molecular mechanism of CAPS-induced neurobe-
havioral toxicity remains to be fully elucidated, our evidence,
coupled with that of others, suggests that exposure to ambient
air pollutants in the context of neurodevelopment and/or adult-
hood may represent a significant and as yet underexplored risk
factor for CNS diseases/disorders. If so, air pollution may con-
stitute a significant public health threat even beyond current ap-
(NIH P30ES01247 to T.G.); PI (NIH T32ES007026 to B.P.L.).
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