4.7 Article

Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin primes cortical microglia to tissue injury

期刊

BRAIN BEHAVIOR AND IMMUNITY
卷 101, 期 -, 页码 288-303

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2022.01.013

关键词

Aryl hydrocarbon receptor; Dioxin; Two-photon microscopy; Microglia; Visual cortex; RNA-sequencing; Gene expression

资金

  1. National Institutes of Health [EY019277, NS114480, AA02711, T32 ES007026]
  2. National Institute of Medical Sciences [K12 GM106997]
  3. National Institute of Environmental Health Sciences [P30ES001247]
  4. National Institute of Child Health and Human Development [P50HD103536-02]

向作者/读者索取更多资源

Recent studies have shown that exposure to AhR ligands during gestational and lactational periods can lead to subtle but durable changes in the transcription of microglial cells in the brain, resulting in a heightened response towards tissue injury. However, this effect can be rectified through depletion and repopulation of microglia cells.
Recent studies have shown that the aryl hydrocarbon receptor (AhR) is expressed in the brain's native immune cells, known as microglia. However, while the impact of exposure to AhR ligands is well studied in the peripheral immune system, the impact of such exposure on immune function in the brain is less well defined. Microglia serve dual roles in providing synaptic and immunological support for neighboring neurons and in mediating responses to environmental stimuli, including exposure to environmental chemicals. Because of their dual roles in regulating physiological and pathological processes, cortical microglia are well positioned to translate toxic stimuli into defects in cortical function via aberrant synaptic and immunological functioning, mediated either through direct microglial AhR activation or in response to AhR activation in neighboring cells. Here, we use gene expression studies, histology, and two-photon in vivo imaging to investigate how developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high-affinity and persistent AhR agonist, modulates microglial characteristics and function in the intact brain. Whole cortical RT-qPCR analysis and RNA-sequencing of isolated microglia revealed that gestational and lactational TCDD exposure produced subtle, but durable, changes in microglia transcripts. Histological examination and two-photon in vivo imaging revealed that while microglia density, distribution, morphology, and motility were unaffected by TCDD exposure, exposure resulted in microglia that responded more robustly to focal tissue injury. However, this effect was rectified with depletion and repopulation of microglia. These results suggest that gestational and lactational exposure to AhR ligands can result in long-term priming of microglia to produce heightened responses towards tissue injury which can be restored to normal function through microglial repopulation.

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