Mouse brain transcriptome responses to inhaled nanoparticulate matter differed by sex and APOE in Nrf2-Nfkb interactions.
Amin HaghaniMafalda CacciottoloKevin R DotyCarla D'AgostinoMax ThorwaldNikoo SafiMorgan E LevineConstantinos SioutasTerrence C TownHenry Jay FormanHongqiao ZhangTodd E MorganCaleb E FinchPublished in: eLife (2020)
The neurotoxicity of air pollution is undefined for sex and APOE alleles. These major risk factors of Alzheimer's disease (AD) were examined in mice given chronic exposure to nPM, a nano-sized subfraction of urban air pollution. In the cerebral cortex, female mice had two-fold more genes responding to nPM than males. Transcriptomic responses to nPM had sex-APOE interactions in AD-relevant pathways. Only APOE3 mice responded to nPM in genes related to Abeta deposition and clearance (Vav2, Vav3, S1009a). Other responding genes included axonal guidance, inflammation (AMPK, NFKB, APK/JNK signaling), and antioxidant signaling (NRF2, HIF1A). Genes downstream of NFKB and NRF2 responded in opposite directions to nPM. Nrf2 knockdown in microglia augmented NFKB responses to nPM, suggesting a critical role of NRF2 in air pollution neurotoxicity. These findings give a rationale for epidemiologic studies of air pollution to consider sex interactions with APOE alleles and other AD-risk genes.
Keyphrases
- air pollution
- acute myeloid leukemia
- oxidative stress
- cognitive decline
- genome wide
- high fat diet
- particulate matter
- risk factors
- genome wide identification
- bioinformatics analysis
- lung function
- high fat diet induced
- single cell
- mild cognitive impairment
- genome wide analysis
- clinical trial
- dna methylation
- type diabetes
- cell death
- rna seq
- subarachnoid hemorrhage
- adipose tissue
- cystic fibrosis
- spinal cord injury
- signaling pathway
- chronic obstructive pulmonary disease
- brain injury
- insulin resistance
- metabolic syndrome
- functional connectivity
- peripheral nerve
- optical coherence tomography
- cerebral ischemia
- endoplasmic reticulum stress