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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
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.
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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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