Table S3: Other Neurological Effects of (Sub)Chronic PM Exposure in Rodents

Table S3: Other neurological effects of (sub)chronic PM exposure in rodents

Reference / Species, sex, age/weight, (treatment) / Study design: exposure groups (size), exposure type & pollutant / Exposure duration / Outcome measures / Results
Bos et al. [46] / Male, 6wk-old, C57BL6 mice / 4 groups (n=5/group): without filter in highway tunnel (test group), with enforced filtercap in highway tunnel (control A), with normal filter in indoor location near tunnel (control B); stayed in animal house (control animal facility) / 5-days / Endothelial dysfunction in hippocampus and olfactory bulb: mRNA levels of endothelial mediator eNOS / ↑ mRNA levels of eNOS in test group versus control A in hippocampus; no sign effects on eNOS levels in olfactory bulb
Oxidative stress in hippocampus and olfactory bulb: mNRA levels of the transcription factor, Nrf2, that activates the anti-oxidant response / ↑ mRNA levels of NFE2L2 in test group versus control B in hippocampus; ↓ mRNA levels of Nrf2 in test group versus control A in olfactory bulb
Messenger RNA levels of the neurotrophin BDNF transcript 1, 2, 3, 4 in hippocampus and olfactory bulb / ↓ mRNA levels of BDNF in test group versus control A in olfactory bulb; no sign effects on BDNF mRNA levels in hippocampus
Farina et al. [47] / Male, 7-8 wk-old, BALB/c mice / 2 groups (n=6/group): it instillation of 100µg/100µL PM10 or 100µL saline (control) on day 0, 3 and 6 / 6 days (3 instillations) / Protein level of endothelial mediator ET-1, oxidative stress marker HO-1, markers of apoptose (Caspase8-p18 and Caspase3-p17), Hsp70, and Cyp1B1 in brain homogenates / ↑ ET-1 and HO-1 level in PM10 instilled mice compared to controls, no differences in other protein levels between PM10 instilled mice and controls
Guo et al. [49] / Male, 190-210g, Wistar rats / 6 groups (n=6/group): it instillation of PM10 at concentrations 0.3, 1, 3 or 10 mg/kg bw or saline (normal control) or vehicle (special control) / 15-day exposure (5 x 3 days) / Endothelial dysfunction in the cortex: mRNA and protein levels of endothelial mediators ET-1 and eNOS / ↑ mRNA and protein levels of ET-1 at dose 1 mg/kg bw PM10 and all doses PM10 respectively; ↓ mRNA and protein levels of eNOS at doses 3 and 10 mg/kg bw PM10 and 1, 3 and 10 mg/kg bw PM10 compared to normal control
Apoptosis in the cortex: mRNA and protein levels of bax, bcl-2 and p53; and histopathological assessment of apoptosis (TUNEL assay) / ↑mRNA and protein levels of bax at dose 1, 3 and 1, 3, 10 mg/kg bw PM10 respectively;
No sign effects on bcl-2 expression; ↑ mRNA and protein level of bax/bcl-2 ratio at all doses; ↑ mRNA and protein levels of p53 at dose 3 and 10 mg/kg bw PM10 respectively compared to normal control;
no. TUNEL-positive neurons increased in a concentration-dependent manner (10.6 ± 0.51%, 17.2 ± 0.92% and 22.4 ± 1.29% immune-reactive neurons at1, 3 and 10 mg/kg bw,respectively) compared to normal control
Zanchi et al. [65] / Male, 45-dayold, Wistar rats / 4 groups (n=10/group): in instillation of 10 µl saline (control) or 20 µg ROFA and ip injection of 150 mg/kg NAC or 1ml/kg saline / 30 days (every day) / Oxidative damage in striatum and cerebellum: lipid peroxidation (TBARS test) / ↑ lipid peroxidation level in ROFA/saline mice compared to other groups
Zanchi et al. [66] / Male, 45-dayold, Wistar rats / 4 groups (n=10/group): in instillation of 10 µl saline or 20 µg ROFA and ip injection of 150 mg/kg NAC or 1ml/kg saline / 30 days (every day) / Oxidative damage in the hippocampus: lipid peroxidation (TBARS test) / ↑ lipid peroxidation in ROFA + saline ip treated mice compared to other groups
Win-Shwe et al. [52] / Male, 6 wk-old, BALB/c mice / 4 groups (n=6/group): inhalation exposure to clean air (particle concentration, 4.58 µg/m3) or NRDE (148.86 µg/m3), with weekly ip injection of LTA or saline / 4 wks (5h/day, 5 days/wk) / Messenger RNA level of oxidative stress marker HO-1 in the hippocampus / No effects of NRDE or LTA exposure on HO-1 mRNA levels
Messenger RNA levels of memory function-related genes (NMDA receptor subunits NR1, NR2A, NR2B) in the hippocampus / ↑ mRNA levels of NR1, NR2A, and NR2B in NRDE/LTA (+) mice compared to clean air/LTA (-) mice
Win-Shwe et al. [68] / Male, 6wk-old, BALB/c mice / 4 groups (n=6/group): inhalation exposure to clean air (particle concentration, 4.58 µg/m3) or NRDE (148.86 µg/m3) with or without weekly ip injection of LTA / 4 wks (5h/day, 5 days/wk) / Extracellular glutamate levels in olfactory bulb (in vivo microdialysis and high-performance liquid chromatography assay); Messenger RNA levels of memory function-related genes (NMDA receptor subunits NR1, NR2A, and NR2B; and CaMK-IV and CREB1) in olfactory bulb / ↑ extracellular glutamate levels in all 3 treatment groups compared to clean air/LTA(-) (NRDE and/or LTA ↑ extracellular glutamate level);
↑ mRNA level of NR1, NR2A, NR2B, CREB1 and CaMK-IV in NRDE/LTA(+) compared to clean air/LTA(-); ↑ mRNA level of NR1 and CaMK-IV in NRDE/LTA(-) compared to clean air/LTA(-); ↑ mRNA level of NR2B in clean air/LTA(+) compared to clean air/LTA(-) (NRDE ↑ NR1, NR2A, NR2B, and CaMK-IV mRNA level, while LTA ↑ only NR2B and CREB1 mRNA level)
Yokota et al. [67] / 50 infant (2 wk-old), male, Sprague Dawley rats / 4 groups (n=3-5/group): in instillation of air (sham), vehicle, 10 µg or 50 µg NRDEP once a week / 4 wks / Histopathological examination / ↑ number of corpuscles in glomerulus of olfactory bulb in group treated with 50µg NRDEP; electron dense lamellar bodies in the microglial cells of the glomerulus; accumulation of electron dense granules in axonal cytosole; large granules containing phosphorus
Levels of the neurotransmitters NA, DA, DOPAC, HVA, 5-HT, 5-HIAA in lateral hypothalamus, medial amygdaloid nucleus, ventromedial hypothalamic nucleus, medial mammillary nucleus / No significant effect on neurotransmitter levels in the brains of NRDEP treated animals compared to vehicle control, but ↓ DA level (trend), ↓DOPAC level (trend), ↓ HVA level (trend), and ↓ 5-HT level (trend) in the medial mammillary nucleus of NRDEP treated animals compared to vehicle control
Levesque et al. [53] / Male, 12-14 wk-old Wistar Kyoto rats / 3 groups (n=3-4/group): inhalation exposure to 0 (air, control), 0.5 or 2 mg/m3 DEP / 1 month (4hr/day), 5 days/wk) / Level of protein nitration, a common marker of oxidative stress, in whole-brain homogenate / ↑ level of protein nitration in rats exposed to DEP compared to control
DA level in the midbrain / No difference in DA level between DEP and control
Level of the preclinical marker of neurodegenerative disease α-synuclein in whole brain homogenate / No difference in α-synuclein level between DEP and control
Guerra et al. [56] / Male, 6wk-old Sprague Dawley rats / 4 groups (n=6/group): inhalation exposure to coarse (32 µg/m3), fine (178 µg/m3) or ultrafine (107 µg/m3) concentrated PM or FA (control) / 8 wks (5h/day, 4 days/wk) / Activation level of transcription factor Nrf2 associated with antioxidant processes in brain tissue nuclear fractions; Messenger RNA levels of pro-oxidant markers (SOD-2 and HO-1), apoptotic markers (caspase 3), unfolded response markers (XBP-1S, BiP) in olfactory bulb, corpus striatum, frontal cortex and hippocampus / ↑ mRNA levels of HO-1 in olfactory bulb and striatum of all particle exposed groups compared to control; ↑ mRNA levels in frontal cortex and hippocampus of the groups exposed to fine and ultrafine particles compared to control; ↑ mRNA level of Nrf2 and SOD-2 in striatum and hippocampus of rats exposed to ultrafine particles compared to control; ↑ mRNA levels of SOD-2 in striatum of all particle exposed groups compared to control; ↑ mRNA level of BiP and XBP-1S in striatum of rats exposed to coarse particles and ↑ mRNA level of BiP in rats exposed to ultrafine particles compared to control
Morgan et al. [57] / Male, 3 month-old, C57BL/6J mice / 2 groups (n=7/group): inhalation exposure to re-aerosolized urban nPM (< 200 nm) collected near urban freeway or ambient air (control) / 10 wks (5 hr/day, 3 days/wk, 150 h total) / Protein levels of neuronal glutamate receptor subunits GluA1 and GluA2, and the synaptic proteins synaptophysin and PSD95 in hippocampus / ↓ (35 %) protein levels of GluA1; no effects on protein levels GluA2, synaptophysin, and PSD95
Zhang et al. [69] / Male, 3 and 18 month-old, C57BL/6J mice / 4 groups (n=6/group): inhalation exposure to re-aerosolized nPM or ambient room air (control) in young or old mice / 10 wks (5h/day, 3 days/wk, 150 h total) / Messenger RNA level of Nrf2-regulated phase II detoxifying enzymes (GCLC, GCLM, NQO1, HO-1), and transcription factor Nrf2 in cerebellum of young and old mice; protein level of the transcription factor Nrf2 in (cell and nucleus), of Nrf2-regulate phase II detoxifying enzymes (GCLC, GCLM), and of co-transcription factors that interact with Nrf2 (Bach 1 and c-myc) in cerebellum of young and old mice / ↑ mRNA level of GCLC, GCLM, NQO1 and HO-1 in nPM exposed young mice compared to control; ↓ mRNA level of GCLC and GCLM in nPM exposed old mice compared to control; no difference in mRNA level of NQO1 and HO-1 in old mice exposed to nPM compared to control;
↑ protein level of GCLC and GCLM in nPM exposed young mice compared to control; no difference in protein level of GCLC and GCLM in nPM exposed old mice compared to same age control;
↑Nrf2 mRNA and protein level in nPM exposed young mice compared to same age control; ↓ mRNA level and ↑ protein level of Nrf2 in nPM exposed old mice compared to same age control; ↑ nuclear Nrf2 level in young mice exposed to nPM compared to same age control; no difference in nuclear Nrf2 level in old mice exposed to nPM compared to same age control;
↑ c-Myc level and no difference in Bach1 level in nPM exposed young mice compared to same age control; ↑Bach1 level and no difference in c-Myc level in old nPM exposed mice compared to same age control
Win-Shwe et al. [58] / Female, 7 wk-old BALB/c mice / 4 groups (n=6/group): inhalation exposure to FA (control, 6.02 μg/m3), M-NRDE (35.48 μg/m3), H-NRDE (122.08 μg/m3), or F-DE (5.50 μg/m3) / 3 months(5 h/day, 5 days/wk) / Messenger RNA levels of memory function-related gene expression (the NMDA receptor subunits NR1, NR2A, NR2B, the protein kinase CaMK-IV, the transcription factor CREB1 and the neurotrophins NGF and BDNF) in the hippocampus / ↑ mRNA levels of NR2A and BDNF in mice exposed to H-NRDE compared to the control; ↑ mRNA levels of BDNF in F-NRDE compared to control; no difference in mRNA levels of NR1, NR2B, CaMK-IV, CREB1, and NGF between NRDE-exposed groups and control
Win-Shwe et al. [59] / Female, 7 wk-old, BALB/c mice / 4 groups (n=6/group): inhalation exposure to FA (control), M-NRDE (47 μg/m3), H-NRDE (129 μg/m3), or F-DE (8.52 μg/m3) / 3 months (5 h/day, 5 days/wk) / Hippocampal mRNA levels of NMDA receptor subunits NR1, NR2A, and NR2B, of the protein kinase CaMK-IV, which is involved in the NMDA receptor signaling pathway, and of CREB1, GLT1, EAAT4, and GAD65 and GAD67, which are genes related to glutamate metabolism / No difference in mRNA levels of NMDA receptor subunits between control and NRDE groups, ↓ mRNA level of CaMK-IV and EAAT4 in H-NRDE compared to control; ↑ mRNA levels of GAD65 in H-NRDE compared to other groups
Veronesi et al. [60] / ApoE-/- and C57BL/6 mice / 4 groups (n=5-9/group): inhalation exposure to air (control) or NY CAPs in ApoE-/- or C57BL/6 mice / 4 months / Degeneration of DA neurons in substantia nigral nucleus compacta / 29% ↓ of DA-containing neurons in CAPS exposed Apoe-/- compared to air exposed Apoe-/- mice; no difference in number of DA-containing neurons in CAPs- and air-exposed C57BL/6 mice
Levesque et al. [61] / Male, 10-12 wk-old, Fischer 344 rats / 5 groups (n=8/group): inhalation exposure to FA (control) or DE (992, 311, 100, 35 μg PM/m3) / 6 months (6hr/day; 7 days/wk) / Levels of preclinical markers of neurodegenerative disease (α-synuclein in midbrain, Tau [pS199] in temporal and frontal lobe; and Aβ42 in frontal lobe) / ↑ Tau [pS199] levels in temporal lobe of rats exposed to 311 and 992 μg PM/m3 DE compared to control; ↑ Tau [pS199] levels in frontal lobe of rats exposed to 992 μg PM/m3 DE compared to control; ↑ α-synuclein levels in midbrain of rats exposed to 992 μg PM/m3 DE compared to control; ↑ Aβ42 levels in the frontal lobe of rats exposed to 992 μg PM/m3 DE compared to control
Fonken et al. [62] / Male, 4 wk-old, C57BL/6 mice / 2 groups: FA (control) or ambient concentrated PM2.5 / 10 months (6h/day; 5day/wk) / Hippocampal cell morphology and spine density in 3 hippocampal subfields CA1 region, CA3 region and dendategyrus / ↓ Apical dendritic spine density in CA1 region; and ↓ dendritic branching (apical dendritic length and cell complexity) in CA3 region in PM2.5 mice compared to control
Messenger RNA level of oxidative stress marker HO-1 in the hippocampus / ↑ HO-1 mRNA level in PM2.5 mice compared to control
Ljubimova et al. [70] / Male, 3-7 wk-old, Fisher 344 rats / 4 groups (n = 104): inhalation exposure to coarse, fine and ultrafine particles or FA (control) in Riverside, CA nearby (~500m) heavily trafficked major freeway interchange / 0.5, 1, 3, 10 month (5h/day, 4 days/wk) / Messenger RNA levels of Arc, Rac1, calmodulin 3, placenta-specific 8/onzin in brain tissue; Arc and Rac staining in brain tissue / ↑ Arc mRNA levels in rats exposed to coarse particles for 2 wks, 1 month, and 3 months compared to control; ↓ Arc mRNA levels in rats exposed to coarse particles for 10 months compared to control; no significant effects of ultrafine and fine particles on Arc mRNA level; ↑ mRNA level of Rac1 and calmodulin 3 in rats exposed to coarse particles for 10 months compared to control; ↑ mRNA level placenta-specific 8/onzin in rats exposed to fine and rats exposed to coarse particles for 10 months compared to control; visually strong Arc staining in rats exposed to coarse particles for 2 weeks compared to control which decreased in later phases and was similar to control at 10 months of exposure; no effects of fine and ultrafine particles on Arc staining; Rac1 staining was rather weak at 2 months and stronger at 10 months in rats exposed to coarse particles

eNOS endothelial NO synthase, Nrf2 nuclear factor (erythroid-derived 2)-like 2, BDNF brain-derived neurotrophic factor, itintratracheal, ET-1endothelin 1, HO-1hemeoxygenase 1, hsp70 heat shock protein 70, bw body weight, Cyp1B1 cytochrome P450 family 1, subfamily b, polypeptide 1, bax bcl2-associated X protein, bcl-2 B-cell lymphoma 2, p53 tumor protein 53, in intranasal, ROFA residual oil fly ash, ip intraperitoneal, NAC N-acetylcysteine, TBARSthiobarbituric acid-reactive substances test, NRDE nanoparticle-rich diesel exhaust, ip intraperitoneal, LTAlipoteichoic acid, glutamate, NMDA receptor N-methyl-D-aspartatereceptor , CaMK-IV calcium/calmodulin-dependent protein kinase IV, CREB1 cyclic AMP responsive element binding protein 1, NRDEP nanoparticle-rich diesel exhaust particles, NA noradrenaline, DA dopamine, DOPAC 3,4-dihydroxyphenylacetic acid, HVA homovanillic acid, 5-HT serotonin, 5-HIAA5-hydroxyindoleacetic acid, DEP diesel exhaust particles, FA filtered air, SOD-2 superoxide dismutase 2, XBP-1SX-box binding protein 1 spliced form, BiP heat shock 70kDa protein 5, nPMnanoscale PM, GluA1 glutamate receptor 1, GluA2 glutamate receptor 2, PSD95 postsynaptic density protein 95, GCLC glutamate cysteine ligase catalytic subunit, GCLM glutamate cysteine ligase modifier subunit, NQO1 NAD(P)H: quinoneoxidoreductase 1, Bach1 BTB and CNC homology 1, basic leucine zipper transcription factor 1, c-myc V-mycmyelocytomatosis viral oncogene homolog (avian), NGF nerve growth factor,M-NRDE moderate dose nanoparticle-rich diesel exhaust, H-NRDE high dose nanoparticle-rich diesel exhaust, F-DE filtered high dose nanoparticle-rich diesel exhaust, GLT1 glutamate transporter 1, EAAT4 excitatory amino acid transporter 4, GAD65 glutamate decarboxylase 65, GAD67 glutamate decarboxylase 67, CAPs concentrated ambient particles, apoe-/-apolipoprotein E knockout, DE diesel exhaust, Tau[pS199] phosphorylation of the microtubule binding protein Tau at the serine 199 residue, Aβ42 amyloid β42, Arcactivity-regulatedcytoskeleton-associated protein, Rac1Ras-related C3 botulinum toxin substrate 1