Toxicity of urban air pollution particulate matter in developing and adult mouse brain: Comparison of total and filter-eluted nanoparticles

Haghani, Amin; Johnson, Richard G.; Safi, Nikoo; Zhang, Hongqiao; Thorwald, Max; Mousavi, Amirhosein; Woodward, Nick; Shirmohammadi, Farimah; Coussa, Valerio; Wise, John Pierce; Sioutas, Constantinos; Allayee, Hooman; Morgan, Todd E.; Finch, Caleb E.

doi:10.1016/j.envint.2020.105510

Cited by 70 publications

(43 citation statements)

References 71 publications

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“…Air pollution is closely associated with the development of several adverse effects on the human body throughout life, having been linked to decrease in function of several organs including the brain, where it has been associated with an increased risk of developing neurodevelopment disorders including autism spectrum disorder and neurodegenerative disorders such as dementia [ 25 , 26 , 27 , 28 ]. Recently, studies evaluating the extensive toxicity mediated by air pollution, especially particulate matter (PM2.5), have shown that these particles via several different routes, including a direct way by inhalation or ingestion and indirect routes by systemic responses in the human body, reach the brain and then damage the parenchyma of the CNS through the blood–brain barrier (BBB) [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, studies evaluating the extensive toxicity mediated by air pollution, especially particulate matter (PM2.5), have shown that these particles via several different routes, including a direct way by inhalation or ingestion and indirect routes by systemic responses in the human body, reach the brain and then damage the parenchyma of the CNS through the blood–brain barrier (BBB) [ 29 , 30 ]. In the adult brain, PM2.5 passes through the BBB, inducing the inflammatory responses via (1) glial activation [ 31 , 32 , 33 ], (2) amyloid toxicity [ 34 , 35 ], and (3) altered expression of the glutamatergic pathway genes [ 25 , 36 ]. Many studies on air pollution have focused on the effects of inhaled pollution in the respiratory systems, especially on the nose and lungs.…”

Section: Discussionmentioning

confidence: 99%

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Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Kim

Shin

Han

et al. 2020

IJMS

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Air pollution has become one of the most serious issues for human health and has been shown to be particularly concerning for neural and cognitive health. Recent studies suggest that fine particulate matter of less than 2.5 (PM2.5), common in air pollution, can reach the brain, potentially resulting in the development and acceleration of various neurological disorders including Alzheimer’s disease, Parkinson’s disease, and other forms of dementia, but the underlying pathological mechanisms are not clear. Astaxanthin is a red-colored phytonutrient carotenoid that has been known for anti-inflammatory and neuroprotective effects. In this study, we demonstrated that exposure to PM2.5 increases the neuroinflammation, the expression of proinflammatory M1, and disease-associated microglia (DAM) signature markers in microglial cells, and that treatment with astaxanthin can prevent the neurotoxic effects of this exposure through anti-inflammatory properties. Diesel particulate matter (Sigma-Aldrich) was used as a fine particulate matter 2.5 in the present study. Cultured rat glial cells and BV-2 microglial cells were treated with various concentrations of PM2.5, and then the expression of various inflammatory mediators and signaling pathways were measured using qRT-PCR and Western blot. Astaxanthin was then added and assayed as above to evaluate its effects on microglial changes, inflammation, and toxicity induced by PM2.5. PM2.5 increased the production of nitric oxide and reactive oxygen species and upregulated the transcription of various proinflammatory markers including Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), triggering receptor expressed on myeloid cells 2 (TREM2), Toll-like receptor 2/4 (TLR2/4), and cyclooxygenase-2 (COX-2) in BV-2 microglial cells. However, the mRNA expression of IL-10 and arginase-1 decreased following PM2.5 treatment. PM2.5 treatment increased c-Jun N-terminal kinases (JNK) phosphorylation and decreased Akt phosphorylation. Astaxanthin attenuated these PM2.5-induced responses, reducing transcription of the proinflammatory markers iNOS and heme oxygenase-1 (HO-1), which prevented neuronal cell death. Our results indicate that PM2.5 exposure reformulates microglia via proinflammatory M1 and DAM phenotype, leading to neurotoxicity, and the fact that astaxanthin treatment can prevent neurotoxicity by inhibiting transition to the proinflammatory M1 and DAM phenotypes. These results demonstrate that PM2.5 exposure can induce brain damage through the change of proinflammatory M1 and DAM signatures in the microglial cells, as well as the fact that astaxanthin can have a potential beneficial effect on PM2.5 exposure of the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Kim

Shin

Han

et al. 2020

IJMS

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“…By examining chromatin accessibility, we gained insights into possible mechanisms of DPM exposure on development. DPM exposure has been previously linked to alterations in oxidative stress [ 72 ], brain development [ 73 ], and inflammation [ 74 ]. We have shown here that gene enhancers that regulate ASD related genes are also altered following DPM exposure.…”

Section: Discussionmentioning

confidence: 99%

Environmental Epigenetics of Diesel Particulate Matter Toxicogenomics

Bilinovich

Lewis

Thompson

et al. 2020

IJERPH

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disruptions in social communication and behavioral flexibility. Both genetic and environmental factors contribute to ASD risk. Epidemiologic studies indicate that roadway vehicle exhaust and in utero exposure to diesel particulate matter (DPM) are associated with ASD. Using the Comparative Toxicogenomics Database (CTD), we identified genes connected to DPM exposure and ASD, extracted the known enhancers/promoters of the identified genes, and integrated this with Assay for Transposase Accessible Chromatin (ATAC-seq) data from DPM-exposed human neural progenitor cells. Enhancer/promoter elements with significantly different chromosome accessibility revealed enriched DNA sequence motifs with transcription factor binding sites for EGR1. Variant extraction for linkage disequilibrium blocks of these regions followed by analysis through Genome Wide Association Studies (GWAS) revealed multiple neurological trait associations including exploratory eye movement and brain volume measurement. This approach highlights the effects of pollution on the regulatory regions of genes implicated in ASD by genetic studies, indicating convergence of genetic and environmental factors on molecular networks that contribute to ASD. Integration of publicly available data from the CTD, cell culture exposure studies, and phenotypic genetics synergize extensive evidence of chemical exposures on gene regulation for altered brain development.

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“…The aqueous suspension was aerosolized to 300 μg/m 3 throughout exposure. The re-aerosolized nPM in animal exposure chambers were collected on filters for chemical characterization by high resolution mass spectrometry (SF-ICPMS) and Sievers 900 total organic carbon analyzer 27 . Endotoxin content of the nPM suspension was assessed by a Limulus assay (Pierce LAL chromogenic endotoxin, ThermoFisher).…”

Section: Methods Npm Collectionmentioning

confidence: 99%

“…Based on the documented male behavioral bias in gestational response to nPM 13,27 , we chose to examine neurogenesis in male offspring only. Male mice were injected i.p.…”

Section: Edu Injectionsmentioning

confidence: 99%

Adult mouse hippocampal transcriptome changes associated with long-term behavioral and metabolic effects of gestational air pollution toxicity

et al. 2020

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Gestational exposure to air pollution increases the risk of autism spectrum disorder and cognitive impairments with unresolved molecular mechanisms. This study exposed C57BL/6J mice throughout gestation to urban-derived nanosized particulate matter (nPM). Young adult male and female offspring were studied for behavioral and metabolic changes using forced swim test, fat gain, glucose tolerance, and hippocampal transcriptome. Gestational nPM exposure caused increased depressive behaviors, decreased neurogenesis in the dentate gyrus, and increased glucose tolerance in adult male offspring. Both sexes gained fat and body weight. Gestational nPM exposure induced 29 differentially expressed genes (DEGs) in adult hippocampus related to cytokine production, IL17a signaling, and dopamine degradation in both sexes. Stratification by sex showed twofold more DEGs in males than females (69 vs 37), as well as male-specific enrichment of DEGs mediating serotonin signaling, endocytosis, Gαi, and cAMP signaling. Gene co-expression analysis (WCGNA) identified a module of 43 genes with divergent responses to nPM between the sexes. Chronic changes in 14 DEGs (e.g., microRNA9-1) were associated with depressive behaviors, adiposity and glucose intolerance. These genes enriched neuroimmune pathways such as HMGB1 and TLR4. Based on cerebral cortex transcriptome data of neonates, we traced the initial nPM responses of HMGB1 pathway. In vitro, mixed glia responded to 24 h nPM with lower HMGB1 protein and increased proinflammatory cytokines. This response was ameliorated by TLR4 knockdown. In sum, we identified transcriptional changes that could be associated with air pollution-mediated behavioral and phenotypic changes. These identified genes merit further mechanistic studies for therapeutic intervention development.

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Toxicity of urban air pollution particulate matter in developing and adult mouse brain: Comparison of total and filter-eluted nanoparticles

Cited by 70 publications

References 71 publications

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Astaxanthin Suppresses PM2.5-Induced Neuroinflammation by Regulating Akt Phosphorylation in BV-2 Microglial Cells

Environmental Epigenetics of Diesel Particulate Matter Toxicogenomics

Adult mouse hippocampal transcriptome changes associated with long-term behavioral and metabolic effects of gestational air pollution toxicity

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