L-S Ju1, J-J Yang1, T E Morey1, N Gravenstein2, C N Seubert1, J L Resnick3, J-Q Zhang4, A E Martynyuk5. 1. Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA. 2. Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA. 3. Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA. 4. Department of Anesthesiology, Zhengzhou University, Zhengzhou, China. 5. Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA. Electronic address: amartynyuk@anest.ufl.edu.
Abstract
BACKGROUND: Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl- Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. METHODS: Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. RESULTS: Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. CONCLUSIONS: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.
BACKGROUND: Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl- Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. METHODS: Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. RESULTS: Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. CONCLUSIONS: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.
Authors: Caleb Ing; Ming Sun; Mark Olfson; Charles J DiMaggio; Lena S Sun; Melanie M Wall; Guohua Li Journal: Anesth Analg Date: 2017-12 Impact factor: 5.108
Authors: Gregory A Chinn; Matthew L Pearn; Laszlo Vutskits; Cyrus D Mintz; Andreas W Loepke; Jennifer J Lee; Jerri Chen; Zeljko J Bosnjak; Ansgar M Brambrink; Vesna Jevtovic-Todorovic; Lena S Sun; Jeffrey W Sall Journal: Br J Anaesth Date: 2020-03-04 Impact factor: 9.166
Authors: Ling-Sha Ju; Jiao-Jiao Yang; Ning Xu; Jia Li; Timothy E Morey; Nikolaus Gravenstein; Christoph N Seubert; Barry Setlow; Anatoly E Martynyuk Journal: Anesthesiology Date: 2019-11 Impact factor: 7.892
Authors: Gregory A Chinn; Jennifer M Sasaki Russell; Nicole A Yabut; Deenu Maharjan; Jeffrey W Sall Journal: Anesthesiology Date: 2020-10-01 Impact factor: 7.892
Authors: Yunan Lin; Lei Lei; Ling-Sha Ju; Ning Xu; Timothy E Morey; Nikolaus Gravenstein; Jianjun Yang; Anatoly E Martynyuk Journal: Neurosci Lett Date: 2020-07-07 Impact factor: 3.046