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Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN
BACKGROUND: Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children. METHODS: You...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562069/ https://www.ncbi.nlm.nih.gov/pubmed/31060905 http://dx.doi.org/10.1016/j.ebiom.2019.04.048 |
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author | Zhang, Lei Xue, Zhenyu Liu, Qidong Liu, Yunbo Xi, Siwei Cheng, Yanyong Li, Jingjie Yan, Jia Shen, Yuan Xiao, Chong Xie, Zhongcong Qiu, Zilong Jiang, Hong |
author_facet | Zhang, Lei Xue, Zhenyu Liu, Qidong Liu, Yunbo Xi, Siwei Cheng, Yanyong Li, Jingjie Yan, Jia Shen, Yuan Xiao, Chong Xie, Zhongcong Qiu, Zilong Jiang, Hong |
author_sort | Zhang, Lei |
collection | PubMed |
description | BACKGROUND: Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children. METHODS: Young rhesus macaque and mice received 2.5 to 3% sevoflurane daily for three days. DNA and RNA sequencing and immunohistochemistry among others were used in the studies. We performed unbiased transcriptome profiling in prefrontal cortex of rhesus macaques and mice after the sevoflurane anesthesia. We constructed a brain blood barrier-crossing AAV-PHP.EB vector to harbor ERMN expression in rescue studies. We measured blood folate levels in children after anesthesia and surgery. FINDINGS: We found that thymidylate synthase (TYMS) gene was downregulated after the sevoflurane anesthesia in both rhesus macaque and mice. There was a reduction in blood folate levels in children after the anesthesia and surgery. Combined with transcriptome and genome-wide DNA methylation analysis, we identified that ERMN was the primary target of the disrupted folate metabolism. Myelination was compromised by the anesthesia in the young mice, which was rescued by systematic administration of folic acid or expression of ERMN in the brain through brain-specific delivery of the adeno-associated virus. Moreover, folic acid and expression of ERMN alleviated the cognitive impairment caused by the sevoflurane anesthesia in the mice. INTERPRETATION: General anesthesia leads to disrupted folate metabolism and subsequently defects in myelination in the developmental brain, and ERMN is the important target affected by the anesthesia via epigenetic mechanisms. |
format | Online Article Text |
id | pubmed-6562069 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-65620692019-06-17 Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN Zhang, Lei Xue, Zhenyu Liu, Qidong Liu, Yunbo Xi, Siwei Cheng, Yanyong Li, Jingjie Yan, Jia Shen, Yuan Xiao, Chong Xie, Zhongcong Qiu, Zilong Jiang, Hong EBioMedicine Research paper BACKGROUND: Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children. METHODS: Young rhesus macaque and mice received 2.5 to 3% sevoflurane daily for three days. DNA and RNA sequencing and immunohistochemistry among others were used in the studies. We performed unbiased transcriptome profiling in prefrontal cortex of rhesus macaques and mice after the sevoflurane anesthesia. We constructed a brain blood barrier-crossing AAV-PHP.EB vector to harbor ERMN expression in rescue studies. We measured blood folate levels in children after anesthesia and surgery. FINDINGS: We found that thymidylate synthase (TYMS) gene was downregulated after the sevoflurane anesthesia in both rhesus macaque and mice. There was a reduction in blood folate levels in children after the anesthesia and surgery. Combined with transcriptome and genome-wide DNA methylation analysis, we identified that ERMN was the primary target of the disrupted folate metabolism. Myelination was compromised by the anesthesia in the young mice, which was rescued by systematic administration of folic acid or expression of ERMN in the brain through brain-specific delivery of the adeno-associated virus. Moreover, folic acid and expression of ERMN alleviated the cognitive impairment caused by the sevoflurane anesthesia in the mice. INTERPRETATION: General anesthesia leads to disrupted folate metabolism and subsequently defects in myelination in the developmental brain, and ERMN is the important target affected by the anesthesia via epigenetic mechanisms. Elsevier 2019-05-03 /pmc/articles/PMC6562069/ /pubmed/31060905 http://dx.doi.org/10.1016/j.ebiom.2019.04.048 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Zhang, Lei Xue, Zhenyu Liu, Qidong Liu, Yunbo Xi, Siwei Cheng, Yanyong Li, Jingjie Yan, Jia Shen, Yuan Xiao, Chong Xie, Zhongcong Qiu, Zilong Jiang, Hong Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN |
title | Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN |
title_full | Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN |
title_fullStr | Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN |
title_full_unstemmed | Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN |
title_short | Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN |
title_sort | disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ermn |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562069/ https://www.ncbi.nlm.nih.gov/pubmed/31060905 http://dx.doi.org/10.1016/j.ebiom.2019.04.048 |
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