Mouse brain transcriptome responses to inhaled nanoparticulate matter differed by sex and APOE in Nrf2-Nfkb interactions

Elife. 2020 Jun 24:9:e54822. doi: 10.7554/eLife.54822.

Abstract

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.

Keywords: APOE; Nrf2; air pollution; computational biology; mouse; neuroscience; nf-kb; sex; systems biology; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Air Pollutants / toxicity
  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Brain / drug effects*
  • Brain / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nanoparticles / toxicity*
  • Transcriptome

Substances

  • Air Pollutants
  • Apoe protein, mouse
  • Apolipoproteins E
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, mouse

Associated data

  • GEO/GSE142066