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Barton K, Yellowman RD, Holm T, Beaulieu F, Zuckerberg G, Gwal K, Setty BN, Janitz E, Hwang M. Pre-clinical and clinical trials for anesthesia in neonates: gaps and future directions. Pediatr Radiol 2024; 54:2143-2156. [PMID: 39349661 DOI: 10.1007/s00247-024-06066-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 09/17/2024] [Accepted: 09/21/2024] [Indexed: 12/13/2024]
Abstract
Literature examining possible deleterious effects of anesthesia exposure on the developing brain has increased substantially over the past 30 years. Initial concerning findings in animal models, both rodents and non-human primates, prompted increasingly thorough examinations in humans, including randomized controlled trials. This review will provide a concise overview of what we know about anesthesia and the developing brain: the background in animal studies, the most robust results we have in humans, and the work yet to be done. This is particularly relevant to a pediatric radiology audience because we have the unique opportunity to modify anesthesia exposure during imaging through innovation.
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Affiliation(s)
- Katherine Barton
- Department of Radiology, Oregon Health & Science University, Portland, OR, USA.
- Department of Diagnostic Radiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code L340, Portland, OR, 97239, USA.
| | | | - Tara Holm
- Department of Radiology, University of Minnesota, Masonic Children's Hospital, Minneapolis, MN, USA
| | - Forrest Beaulieu
- Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gabriel Zuckerberg
- Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kriti Gwal
- Department of Radiology, Nemours Children's Hospital, Wilmington, DE, USA
| | - Bindu N Setty
- Department of Radiology, Boston University, Boston, MA, USA
| | - Emily Janitz
- Department of Radiology, Akron Children's Hospital, Akron, OH, USA
| | - Misun Hwang
- Department of Radiology, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Ju LS, Morey T, Gravenstein N, Setlow B, Seubert CN, Martynyuk AE. Effects of Cohabitation on Neurodevelopmental Outcomes in Rats Discordant for Neonatal Exposure to Sevoflurane. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100359. [PMID: 39282654 PMCID: PMC11400603 DOI: 10.1016/j.bpsgos.2024.100359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 06/03/2024] [Accepted: 07/02/2024] [Indexed: 09/19/2024] Open
Abstract
Background Having a sibling with autism spectrum disorder is a risk factor for autism spectrum disorder. We used a rat model in which the general anesthetic sevoflurane (SEVO) induces autism spectrum disorder-like neurodevelopmental abnormalities to test whether they can be transmitted via cohabitation. Methods Male rat pups from several litters were mixed and randomized to 3 new litter types: SEVO-exposed (SEVO), SEVO-unexposed (control), and equal numbers of SEVO-exposed and SEVO-unexposed (MIXED). After weaning, rats in experiment 1 were housed with littermates in SEVO, control, and MIXED (MIXED-exposed and MIXED-unexposed) pairs. In experiment 2, MIXED-exposed and MIXED-unexposed rats were paired with an unfamiliar naïve cagemate. Corticosterone levels, gene expression, central inflammatory markers (experiment 1), and behavior and corticosterone levels (experiment 2) were assessed in adulthood. Results In experiment 1, compared with control rats, SEVO rats exhibited abnormalities in the hypothalamic-pituitary-adrenal axis, inflammatory markers, oxytocin, arginine vasopressin, and DNA methylation systems. Almost all these measures in MIXED-exposed and MIXED-unexposed rats were statistically indistinguishable from and similar to those in SEVO or control rats, with most measures in MIXED rats being similar to those in SEVO rats. Experiment 2 showed that pairing with unfamiliar, naïve rats after weaning caused MIXED-unexposed and MIXED-exposed rats' behavior to be no different from that of control and SEVO rats, respectively; however, the 2 groups of MIXED rats also did not differ from each other. Conclusions These findings suggest that neurodevelopmental abnormalities can be transmitted to otherwise healthy individuals through interactions during cohabitation; however, subsequent pairing with unfamiliar, naïve cohabitants may weaken this interaction effect.
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Timothy Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Barry Setlow
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
- Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
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Gholamalizadeh H, Amiri-Shahri M, Rasouli F, Ansari A, Baradaran Rahimi V, Reza Askari V. DNA Methylation in Autism Spectrum Disorders: Biomarker or Pharmacological Target? Brain Sci 2024; 14:737. [PMID: 39199432 PMCID: PMC11352561 DOI: 10.3390/brainsci14080737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/20/2024] [Accepted: 07/21/2024] [Indexed: 09/01/2024] Open
Abstract
Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental disabilities with persistent impairments in cognition, communication, and social behavior. Although environmental factors play a role in ASD etiopathogenesis, a growing body of evidence indicates that ASD is highly inherited. In the last two decades, the dramatic rise in the prevalence of ASD has interested researchers to explore the etiologic role of epigenetic marking and incredibly abnormal DNA methylation. This review aimed to explain the current understanding of the association between changes in DNA methylation signatures and ASD in patients or animal models. We reviewed studies reporting alterations in DNA methylation at specific genes as well as epigenome-wide association studies (EWASs). Finally, we hypothesized that specific changes in DNA methylation patterns could be considered a potential biomarker for ASD diagnosis and prognosis and even a target for pharmacological intervention.
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Affiliation(s)
- Hanieh Gholamalizadeh
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad 13131-99137, Iran;
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Maedeh Amiri-Shahri
- Student Research Committee, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran; (M.A.-S.); (F.R.); (A.A.)
- Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Fatemeh Rasouli
- Student Research Committee, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran; (M.A.-S.); (F.R.); (A.A.)
- Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Arina Ansari
- Student Research Committee, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran; (M.A.-S.); (F.R.); (A.A.)
- Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran;
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
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Zhu S, Shi J, Zhang Y, Chen X, Shi T, Li L. Combination administration of alprazolam and N-Ethylmaleimide synergistically enhances sleep behaviors in mice with no potential CNS side effects. PeerJ 2024; 12:e17342. [PMID: 38737745 PMCID: PMC11086308 DOI: 10.7717/peerj.17342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 04/15/2024] [Indexed: 05/14/2024] Open
Abstract
Background N-Ethylmaleimide (NEM), an agonist of the potassium chloride cotransporters 2 (KCC2) receptor, has been correlated with neurosuppressive outcomes, including decreased pain perception and the prevention of epileptic seizures. Nevertheless, its relationship with sleep-inducing effects remains unreported. Objective The present study aimed to investigate the potential enhancement of NEM on the sleep-inducing properties of alprazolam (Alp). Methods The test of the righting reflex was used to identify the appropriate concentrations of Alp and NEM for inducing sleep-promoting effects in mice. Total sleep duration and sleep quality were evaluated through EEG/EMG analysis. The neural mechanism underlying the sleep-promoting effect was examined through c-fos immunoreactivity in the brain using immunofluorescence. Furthermore, potential CNS-side effects of the combination Alp and NEM were assessed using LABORAS automated home-cage behavioral phenotyping. Results Combination administration of Alp (1.84 mg/kg) and NEM (1.0 mg/kg) significantly decreased sleep latency and increased sleep duration in comparison to administering 1.84 mg/kg Alp alone. This effect was characterized by a notable increase in REM duration. The findings from c-fos immunoreactivity indicated that NEM significantly suppressed neuron activation in brain regions associated with wakefulness. Additionally, combination administration of Alp and NEM showed no effects on mouse neural behaviors during automated home cage monitoring. Conclusions This study is the first to propose and demonstrate a combination therapy involving Alp and NEM that not only enhances the hypnotic effect but also mitigates potential CNS side effects, suggesting its potential application in treating insomnia.
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Affiliation(s)
- Siqing Zhu
- State Key Laboratory of NBC Protection for Civilian, Beijing, China
| | - Jingjing Shi
- State Key Laboratory of NBC Protection for Civilian, Beijing, China
| | - Yi Zhang
- State Key Laboratory of NBC Protection for Civilian, Beijing, China
| | - Xuejun Chen
- State Key Laboratory of NBC Protection for Civilian, Beijing, China
| | - Tong Shi
- State Key Laboratory of NBC Protection for Civilian, Beijing, China
| | - Liqin Li
- State Key Laboratory of NBC Protection for Civilian, Beijing, China
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Alharbi KS, Almalki WH, Alzarea SI, Kazmi I, Al-Abbasi FA, Afzal O, Altamimi ASA, Albratty M, Najmi A, Gupta G. Anaesthesia-induced Changes in Genomic Expression Leading to Neurodegeneration. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:411-419. [PMID: 37157197 DOI: 10.2174/1871527322666230508123558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 05/10/2023]
Abstract
General anaesthetics (GA) have been in continuous clinical use for more than 170 years, with millions of young and elderly populations exposed to GA to relieve perioperative discomfort and carry out invasive examinations. Preclinical studies have shown that neonatal rodents with acute and chronic exposure to GA suffer from memory and learning deficits, likely due to an imbalance between excitatory and inhibitory neurotransmitters, which has been linked to neurodevelopmental disorders. However, the mechanisms behind anaesthesia-induced alterations in late postnatal mice have yet to be established. In this narrative review, we present the current state of knowledge on early life anaesthesia exposure-mediated alterations of genetic expression, focusing on insights gathered on propofol, ketamine, and isoflurane, as well as the relationship between network effects and subsequent biochemical changes that lead to long-term neurocognitive abnormalities. Our review provides strong evidence and a clear picture of anaesthetic agents' pathological events and associated transcriptional changes, which will provide new insights for researchers to elucidate the core ideas and gain an in-depth understanding of molecular and genetic mechanisms. These findings are also helpful in generating more evidence for understanding the exacerbated neuropathology, impaired cognition, and LTP due to acute and chronic exposure to anaesthetics, which will be beneficial for the prevention and treatment of many diseases, such as Alzheimer's disease. Given the many procedures in medical practice that require continuous or multiple exposures to anaesthetics, our review will provide great insight into the possible adverse impact of these substances on the human brain and cognition.
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Affiliation(s)
- Khalid Saad Alharbi
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
| | | | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box. 114, Jazan 45142, Saudi Arabia
| | - Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box. 114, Jazan 45142, Saudi Arabia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, 302017, Jaipur, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
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Oğuz SŞ, Kutman GHK, Oğuz K. The Anesthetic Modality but Not the Mode of Delivery Seem to Modulate the Methylation Status of Cyclooxygenase-2 Promoter of the Newborns. Am J Perinatol 2023; 40:1292-1299. [PMID: 34587635 DOI: 10.1055/s-0041-1735898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Cesarean section (CS) rates are high. Epidemiological data supports increased risk of inflammatory conditions in the offspring born by CS. Epigenetic alterations occurring during the perinatal period may account for this risk. Cyclooxygenase-2 (COX2) has strong implications for inflammatory diseases. The methylation of COX2 of newborn infants was compared with respect to their mode of delivery. STUDY DESIGN Ninety healthy term infants born by vaginal delivery (VD), planned cesarean section (PCS), or emergency CS (ECS) were recruited (30 infants in each group). For obstetric anesthesia, local (LA), regional (RA), or general (GA) anesthesia were used. Carefully selected exclusion criteria were implemented to eliminate any confounders with potential epigenetic effects. Umbilical artery blood samples were collected. Demographic and clinical characteristics, folate and CRP levels, and mean methylation levels of the COX2 gene promoter were determined. RESULTS Except the birth weight and maternal age parameters, VD, PCS, and ECS were similar. The methylation percentage of COX2 was higher in ECS (16.9 ± 5.1) than VD (14.5 ± 4.1) and PCS (14.8 ± 2.9), albeit p was 0.064. Because of the dual anesthetic modality populations (RA and GA) in PCS and ECS and the recent literature on anesthetics and epigenetics, the anesthetic modality groups were also analyzed. The methylation percentage of COX2 was significantly different between LA, RA, and GA groups (14.5 ± 4.1, 13.9 ± 2.8, and 17.0 ± 4.6, respectively, p = 0.012). CONCLUSION When the mode of delivery is the question of debate, the anesthetic modality should be remembered as an important epigenetic modulator. KEY POINTS · Perinatal period is a vulnerable time period for epigenetic modulations.. · The mode of delivery is influential in any potential epigenetic alterations occurring perinatally.. · The obstetric anesthetic modality should be remembered as an important epigenetic modulator..
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Affiliation(s)
- Suna Şerife Oğuz
- Deparments of Pediatrics, Division of Neonatology, Neonatology Unit, Ankara City Hospital, Ankara, Turkey
| | | | - Kemal Oğuz
- Department of Internal Medicine, Başkent University Faculty of Medicine, Ankara, Turkey
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Zhang X, Zuo Y, Zhang J, Zhang D, Naeem M, Chang Y, Shi Z. Sevoflurane inhibited reproductive function in male mice by reducing oxidative phosphorylation through inducing iron deficiency. Front Cell Dev Biol 2023; 11:1184632. [PMID: 37346174 PMCID: PMC10279888 DOI: 10.3389/fcell.2023.1184632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 05/25/2023] [Indexed: 06/23/2023] Open
Abstract
Sevoflurane (Sev) is one of the commonly used inhalation anesthetic chemicals in clinics. It has great impact on spermatogenesis and fertilization in male animals. The underlying mechanism remains largely unexplored. Based on our previous research, we hypothesized that Sev induced iron metabolism disturbance in the testis and epididymis and inhibited the spermatogenesis. In this study, two-month-old C57BL/6 male mice were treated with 3% Sev for 6 h, and their fertility (including sperm concentration, sperm mobility, and the number of offspring) was evaluated. Mice testis, epididymis, and sperm were harvested and subjected to Western blot analysis and immunofluorescence analysis. Iron levels were reflected by the gene expression of iron metabolism-related proteins (including ferritin, TfR1, and FpN1) and ICP-MS and Perl's iron staining. Electron transport and oxidative phosphorylation levels were measured by Oxygraph-2k and ATP contents. The activity of ribonucleotide reductase was evaluated by assay kit. DNA synthesis status in testis and/or epididymis was marked with BrdU. Cell proliferation was evaluated by double immunofluorescence staining of specific protein marker expression. Our results revealed that the mice exposed to Sev showed damaged testicular and epididymis structure and significantly reduced the sperm concentration, sperm motility, and fertility. Sev decreases the iron levels through down-regulating the expression of H-ferritin, L-ferritin, and FpN1, and up-regulating the expression of TfR1 in the testis and epididymis. Iron levels also significantly reduced in germ cells which decrease the number of germ cells, including sperm, Sertoli cells, and primary spermatocyte. Iron deficiency not only decreases electron transport, oxidative phosphorylation level, and ATP production but also suppresses the activity of ribonucleotide reductase and the expression of Ki67, DDX4, GATA1, and SCP3, indicating that Sev affects the spermatogenesis and development. Meanwhile, Sev impaired the blood-testis barrier by decreasing the ZO1 expression in the testis and epididymis. The damage effect induced by Sev can be significantly ameliorated by iron supplementation. In conclusion, our study illustrates a new mechanism by which Sev inhibits spermatogenesis and fertility through an oxidative phosphorylation pathway due to iron deficiency of epididymis and testis or sperm. Furthermore, the damaging effects could be ameliorated by iron supplementation.
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Affiliation(s)
| | | | | | | | | | | | - Zhenhua Shi
- *Correspondence: Jianhua Zhang, ; Zhenhua Shi,
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Ju LS, Morey TE, Gravenstein N, Seubert CN, Setlow B, Martynyuk AE. Cohabitation of Neonatally Sevoflurane-exposed and -unexposed Male Rats Affects Their Respective Behavioral Phenotypes: Research Letter. Anesthesiology 2023; 138:658-661. [PMID: 37017655 PMCID: PMC10375299 DOI: 10.1097/aln.0000000000004546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023]
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Ju LS, Morey TE, Seubert CN, Martynyuk AE. Intergenerational Perioperative Neurocognitive Disorder. BIOLOGY 2023; 12:biology12040567. [PMID: 37106766 PMCID: PMC10135810 DOI: 10.3390/biology12040567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023]
Abstract
Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Timothy E Morey
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Christoph N Seubert
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
| | - Anatoly E Martynyuk
- Department of Anesthesiology, College of Medicine, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA
- Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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Ju LS, Zhu J, Brant JO, Morey TE, Gravenstein N, Seubert CN, Vasilopoulos T, Setlow B, Martynyuk AE. Intergenerational Perioperative Neurocognitive Disorder in Young Adult Male Rats with Traumatic Brain Injury. Anesthesiology 2023; 138:388-402. [PMID: 36637480 PMCID: PMC10411496 DOI: 10.1097/aln.0000000000004496] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND The authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder). METHODS Sprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1). RESULTS Acutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1β and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1β and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus. CONCLUSIONS These findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida
| | - Jiepei Zhu
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida
| | - Jason O Brant
- Department of Biostatistics, University of Florida, College of Medicine, Gainesville, Florida
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida
| | - Terrie Vasilopoulos
- Departments of Anesthesiology, Orthopedic Surgery and Sports Medicine, University of Florida, College of Medicine, Gainesville, Florida
| | - Barry Setlow
- Department of Psychiatry and the McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, Florida
| | - Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, Florida
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Associations between maternal exposure to surgery or pregnancy exposure to fluorinated anesthetics and children's cognitive development and educational outcomes. J Dev Orig Health Dis 2023; 14:199-208. [PMID: 35968856 DOI: 10.1017/s2040174422000472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
A transgenerational, epigenetic effect of anesthesia, particularly fluorinated agents, has been examined in rat models, but translation to humans is unclear. This study examined associations of maternal lifetime exposure to anesthesia and pregnancy exposure to fluorinated anesthetics with child cognitive and educational outcomes. Women in the US Collaborative Perinatal Project (1959-1963) reported lifetime history of surgeries, and the obstetric record captured pregnancy exposure to anesthetics. Children were followed to age 7 for global cognitive ability and educational outcomes (n=47,977). Logistic and linear regressions were adjusted for maternal and child birth years, race and ethnicity, smoking, education, parity, study site. Many outcomes were not associated with exposure to maternal surgery that occurred at various life stages. However, maternal surgery in early childhood was associated both with being in a special school or not in school (adj OR=1.42; 95% CI 1.02, 1.98) and with slightly better cognitive ability across childhood (e.g., WISC IQ (adj β=0.59; CI 0.13, 1.04) (especially among boys)). Maternal surgery in puberty was associated with slightly lower IQ (adj β = -0.42; CI -0.79, -0.05) and poorer spelling at age 7. Children's prenatal exposure to fluorinated anesthetics was associated with slightly better spelling ability (adj β = 1.20; CI 0.02, 2.38) but lower performance IQ at age 7 (only among boys, adj β = -1.97; CI -3.88, -0.06). This study shows inconsistent evidence of effects of maternal exposure to surgery or prenatal exposure to fluorinated agents on child developmental and educational outcomes Residual confounding by indication and socioeconomic status may explain observed associations.
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Jiang Y, Zhou Y, Tan S, Xu C, Ma J. Role of posttranslational modifications in memory and cognitive impairments caused by neonatal sevoflurane exposure. Front Pharmacol 2023; 14:1113345. [PMID: 36992831 PMCID: PMC10040769 DOI: 10.3389/fphar.2023.1113345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/23/2023] [Indexed: 03/18/2023] Open
Abstract
With the advancement of technology, increasingly many newborns are receiving general anesthesia at a young age for surgery, other interventions, or clinical assessment. Anesthetics cause neurotoxicity and apoptosis of nerve cells, leading to memory and cognitive impairments. The most frequently used anesthetic in infants is sevoflurane; however, it has the potential to be neurotoxic. A single, short bout of sevoflurane exposure has little impact on cognitive function, but prolonged or recurrent exposure to general anesthetics can impair memory and cognitive function. However, the mechanisms underlying this association remain unknown. Posttranslational modifications (PTMs), which can be described roughly as the regulation of gene expression, protein activity, and protein function, have sparked enormous interest in neuroscience. Posttranslational modifications are a critical mechanism mediating anesthesia-induced long-term modifications in gene transcription and protein functional deficits in memory and cognition in children, according to a growing body of studies in recent years. Based on these recent findings, our paper reviews the effects of sevoflurane on memory loss and cognitive impairment, discusses how posttranslational modifications mechanisms can contribute to sevoflurane-induced neurotoxicity, and provides new insights into the prevention of sevoflurane-induced memory and cognitive impairments.
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Affiliation(s)
- Yongliang Jiang
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yue Zhou
- Department of Pharmacy, Xindu District People’s Hospital of Chengdu, Chengdu, China
| | - Siwen Tan
- Outpatient Department, West China Hospital of Sichuan University, Chengdu, China
| | - Chongxi Xu
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
| | - Junpeng Ma
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Junpeng Ma,
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Zhou X, Xu X, Lu D, Chen K, Wu Y, Yang X, Xiong W, Chen X, Lan L, Li W, Shen S, He W, Feng X. Repeated early-life exposure to anaesthesia and surgery causes subsequent anxiety-like behaviour and gut microbiota dysbiosis in juvenile rats. Br J Anaesth 2023; 130:191-201. [PMID: 36088134 PMCID: PMC11541082 DOI: 10.1016/j.bja.2022.06.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/19/2022] [Accepted: 06/10/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Early exposure to general anaesthetics for multiple surgeries or procedures might negatively affect brain development. Recent studies indicate the importance of microbiota in the development of stress-related behaviours. We determined whether repeated anaesthesia and surgery in early life cause gut microbiota dysbiosis and anxiety-like behaviours in rats. METHODS Sprague Dawley rats received skin incisions under sevoflurane 2.3 vol% three times during the first week of life. After 4 weeks, gut microbiota, anxiety-related behaviours, hippocampal serotonergic activity, and plasma stress hormones were tested. Subsequently, we explored the effect of faecal microbiota transplantation from multiple anaesthesia/surgery exposed rats after administration of a cocktail of antibiotics on anxiety-related behaviours. RESULTS Anxiety-like behaviours were observed in rats with repeated anaesthesia/surgery exposures: In the OF test, multiple anaesthesia/surgery exposures induced a decrease in the time spent in the centre compared to the Control group (P<0.05, t=3.05, df=16, Cohen's d=1.44, effect size=0.58). In the EPM test, rats in Multiple AS group travelled less (P<0.05, t=5.09, df=16, Cohen's d=2.40, effective size=0.77) and spent less time (P<0.05, t=3.58, df=16, Cohen's d=1.69, effect size=0.65) in the open arms when compared to the Control group. Repeated exposure caused severe gut microbiota dysbiosis, with exaggerated stress response (P<0.01, t=4.048, df=16, Cohen's d=-1.91, effect size=-0.69), a significant increase in the hippocampal concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) (P<0.05; for 5-HT: t=3.33, df=18, Cohen's d=-1.49, effect size=-0.60; for 5-HIAA: t=3.12, df=18, Cohen's d=-1.40, effect size=-0.57), and changes in gene expression of serotonergic receptors later in life (for Htr1a: P<0.001, t=4.49, df=16, Cohen's d=2.24, effect size=0.75; for Htr2c: P<0.01, t=3.72, df=16, Cohen's d=1.86, effect size=0.68; for Htr6: P<0.001, t=7.76, df=16, Cohen's d=3.88, effect size=0.89). Faecal microbiota transplantation led to similar anxiety-like behaviours and changes in the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. CONCLUSIONS Gut microbiota dysbiosis caused by early repeated exposure to anaesthesia and surgery affects long-term anxiety emotion behaviours in rats.
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Affiliation(s)
- Xue Zhou
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- MGH Centre for Translational Pain Research, Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Xuanxian Xu
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Dihan Lu
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Keyu Chen
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Yan Wu
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Xiaoyu Yang
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Wei Xiong
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Xi Chen
- Department of Anaesthesiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Liangtian Lan
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Wenda Li
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Shiqian Shen
- MGH Centre for Translational Pain Research, Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Wen He
- Department of Geriatrics, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Xia Feng
- Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
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Escher J, Yan W, Rissman EF, Wang HLV, Hernandez A, Corces VG. Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders. J Autism Dev Disord 2022; 52:4608-4624. [PMID: 34596807 PMCID: PMC9035896 DOI: 10.1007/s10803-021-05304-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 01/31/2023]
Abstract
Investigations into the etiology of autism spectrum disorders have been largely confined to two realms: variations in DNA sequence and somatic developmental exposures. Here we suggest a third route-disruption of the germline epigenome induced by exogenous toxicants during a parent's gamete development. Similar to cases of germline mutation, these molecular perturbations may produce dysregulated transcription of brain-related genes during fetal and early development, resulting in abnormal neurobehavioral phenotypes in offspring. Many types of exposures may have these impacts, and here we discuss examples of anesthetic gases, tobacco components, synthetic steroids, and valproic acid. Alterations in parental germline could help explain some unsolved phenomena of autism, including increased prevalence, missing heritability, skewed sex ratio, and heterogeneity of neurobiology and behavior.
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Affiliation(s)
- Jill Escher
- Escher Fund for Autism, 1590 Calaveras Avenue, San Jose, CA, USA.
| | - Wei Yan
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Emilie F Rissman
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Hsiao-Lin V Wang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Arturo Hernandez
- Maine Medical Center Research Institute, MaineHealth, Scarborough, ME, USA
- Tufts University School of Medicine, Boston, MA, USA
| | - Victor G Corces
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
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Yang Z, Tong Y, Brant JO, Li N, Ju LS, Morey TE, Gravenstein N, Setlow B, Zhang J, Martynyuk AE. Dexmedetomidine Diminishes, but Does Not Prevent, Developmental Effects of Sevoflurane in Neonatal Rats. Anesth Analg 2022; 135:877-887. [PMID: 35759382 PMCID: PMC9481710 DOI: 10.1213/ane.0000000000006125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Sevoflurane (SEVO) increases neuronal excitation in neonatal rodent brains through alteration of gamma aminobutyric acid (GABA)(A) receptor signaling and increases corticosterone release. These actions may contribute to mechanisms that initiate the anesthetic's long-term neuroendocrine and neurobehavioral effects. Dexmedetomidine (DEX), a non-GABAergic α2-adrenergic receptor agonist, is likely to counteract SEVO-induced neuronal excitation. We investigated how DEX pretreatment may alter the neurodevelopmental effects induced by SEVO in neonatal rats. METHODS Postnatal day (P) 5 Sprague-Dawley male rats received DEX (25 µg/kg, intraperitoneal) or vehicle before exposure to 2.1% SEVO for 6 hours (the DEX + SEVO and SEVO groups, respectively). Rats in the DEX-only group received DEX without exposure to SEVO. A subcohort of P5 rats was used for electroencephalographic and serum corticosterone measurements. The remaining rats were sequentially evaluated in the elevated plus maze on P80, prepulse inhibition of the acoustic startle response on P90, Morris water maze (MWM) starting on P100, and for corticosterone responses to physical restraint for 30 minutes on P120, followed by assessment of epigenomic DNA methylation patterns in the hippocampus. RESULTS Acutely, DEX depressed SEVO-induced electroencephalogram-detectable seizure-like activity (mean ± SEM, SEVO versus DEX + SEVO, 33.1 ± 5.3 vs 3.9 ± 5.3 seconds, P < .001), but it exacerbated corticosterone release (SEVO versus DEX + SEVO, 169.935 ± 20.995 versus 280.853 ± 40.963 ng/mL, P = .043). DEX diminished, but did not fully abolish, SEVO-induced corticosterone responses to restraint (control: 11625.230 ± 877.513, SEVO: 19363.555 ± 751.325, DEX + SEVO: 15012.216 ± 901.706, DEX-only: 12497.051 ± 999.816; F[3,31] = 16.878, P < .001) and behavioral deficiencies (time spent in the target quadrant of the MWM: control: 31.283% ± 1.722%, SEVO: 21.888% ± 2.187%, DEX + SEVO: 28.617% ± 1.501%, DEX-only: 31.339% ± 3.087%; F[3,67] = 3.944, P = .012) in adulthood. Of the 391 differentially methylated genes in the SEVO group, 303 genes in the DEX + SEVO group had DNA methylation patterns that were not different from those in the control group (ie, they were normal). DEX alone did not cause acute or long-term functional abnormalities. CONCLUSIONS This study suggests that the ability of DEX to depress SEVO-induced neuronal excitation, despite increasing corticosterone release, is sufficient to weaken mechanisms leading to long-term neuroendocrine/neurobehavioral abnormalities. DEX may prevent changes in DNA methylation in the majority of genes affected by SEVO, epigenetic modifications that could predict abnormalities in a wide range of functions.
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Affiliation(s)
- Zhengbo Yang
- From the Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Yuanyuan Tong
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | | | - Ningtao Li
- From the Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute
| | - Barry Setlow
- Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida
| | - Jiaqiang Zhang
- From the Department of Anesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute
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16
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Changes in Stereotypies: Effects over Time and over Generations. Animals (Basel) 2022; 12:ani12192504. [PMID: 36230246 PMCID: PMC9559266 DOI: 10.3390/ani12192504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/06/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022] Open
Abstract
Simple Summary Herein, we propose that there should be discussion about the function and effects of stereotypies in relation to the time during which they are shown. In the first stages, stereotypies may help animals deal with challenges. However, behavior can potentially alter the brain, impairing its function due the absence of a diverse repertory, and change brain connections, neurophysiology and later neuroanatomy. The neuroanatomical changes in individuals showing stereotypies could be an effect rather than a cause of the stereotypy. As a consequence, studies showing different outcomes for animal welfare from stereotypy expression could be due to variation in a timeline of expression. Stereotypies are widely used as an animal welfare indicator, and their expression can tell us about psychological states. However, there are questions about the longer-term consequences if animals express stereotypies: do the stereotypies help in coping? During the prenatal period, stereotypic behavior expressed by the mother can change the phenotype of the offspring, especially regarding emotionality, one mechanism acting via methylation in the limbic system in the brain. Are individuals that show stereotypies for shorter or longer periods all better adjusted, and hence have better welfare, or is the later welfare of some worse than that of individuals that do not show the behavior? Abstract Stereotypies comprise a wide range of repeated and apparently functionless behaviors that develop in individuals whose neural condition or environment results in poor welfare. While stereotypies are an indicator of poor welfare at the time of occurrence, they may have various consequences. Environmental enrichment modifies causal factors and reduces the occurrence of stereotypies, providing evidence that stereotypies are an indicator of poor welfare. However, stereotypy occurrence and consequences change over time. Furthermore, there are complex direct and epigenetic effects when mother mammals that are kept in negative conditions do or do not show stereotypies. It is proposed that, when trying to deal with challenging situations, stereotypies might initially help animals to cope. After further time in the conditions, the performance of the stereotypy may impair brain function and change brain connections, neurophysiology and eventually neuroanatomy. It is possible that reported neuroanatomical changes are an effect of the stereotypy rather than a cause.
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Repeated Sevoflurane Exposures in Neonatal Rats Increased the Brain Vulnerability to Future Stress Exposure and Resulted in Fear Extinction Deficit. Neurotox Res 2022; 40:1405-1414. [PMID: 35917085 DOI: 10.1007/s12640-022-00529-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/29/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023]
Abstract
Sevoflurane anesthesia during neonatal period was reported to sensitize the rodent animals to stress later in life. The authors tested the hypothesis that repeated sevoflurane exposures in neonatal rats increased the brain vulnerability to future stress exposure and resulted in fear extinction deficit and investigated whether the neonatal brain depolarizing γ-aminobutyric acid type A receptor (GABAAR) is involved in mediating these abnormalities. Neonatal Sprague-Dawley male rats, pretreated with vehicle or the NKCC1 inhibitor, bumetanide, received sequential exposures to 3% sevoflurane for 2 h on postnatal days (P) 5, P6, and P7 and then were exposed to electric foot shock stress in fear conditioning training at P14. Juvenile rats at different developmental brain stage receiving identical sevoflurane exposures on P25, P26, and P27 were also studied. The results showed repeated sevoflurane exposures in neonatal rats and increased the cation-chloride cotransporters NKCC1/KCC2 ratio in the PFC at P14. Repeated exposures to sevoflurane in neonatal rather than juvenile rats enhanced the stress response and exacerbated neuroapoptosis in the PFC after exposed to electric foot shock in fear conditioning training. Neonatal rather than juvenile sevoflurane-exposed rats exhibited deficits in fear extinction training and recall. Pretreatment of neonatal rats prior to sevoflurane exposures with bumetanide reduced the NKCC1/KCC2 ratio at P14 and ameliorated most of the subsequent adverse effects. Our study indicates that repeated sevoflurane exposures in neonatal rats might increase the brain vulnerability to future stress exposure and resulted in fear extinction deficit, which might be associated with the neonatal enhanced brain depolarizing GABAAR activity.
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18
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Yang Y, Liang F, Gao J, Dong Y, Zhang Y, Yang G, Soriano SG, Feng HJ, Xie Z. Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Br J Anaesth 2021; 127:929-941. [PMID: 34686310 DOI: 10.1016/j.bja.2021.08.028] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/14/2021] [Accepted: 08/26/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sevoflurane anaesthesia induces phosphorylation of the microtubule-associated protein tau and cognitive impairment in neonatal, but not adult, mice. The underlying mechanisms remain largely to be determined. Sex hormones can be neuroprotective, but little is known about the influence of testosterone on age-dependent anaesthesia effects. METHODS Six- and 60-day-old male mice received anaesthesia with sevoflurane 3% for 2 h daily for 3 days. Morris water maze, immunoassay, immunoblotting, co-immunoprecipitation, nanobeam technology, and electrophysiology were used to assess cognition; testosterone concentrations; tau phosphorylation; glycogen synthase kinase-3β (GSK3β) activation; binding or interaction between tau and GSK3β; and neuronal activation in mice, cells, and neurones. RESULTS Compared with 60-day-old male mice, 6-day-old male mice had lower testosterone concentrations (3.03 [0.29] vs 0.44 [0.12] ng ml-1; P<0.01), higher sevoflurane-induced tau phosphorylation in brain (133 [20]% vs 100 [6]% in 6-day-old mice, P<0.01; 103 [8]% vs 100 [13]% in 60-day-old mice, P=0.77), and sevoflurane-induced cognitive impairment. Testosterone treatment increased brain testosterone concentrations (1.76 [0.10] vs 0.39 [0.05] ng ml-1; P<0.01) and attenuated the sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Testosterone inhibited the interaction between tau and GSK3β, and attenuated sevoflurane-induced inhibition of excitatory postsynaptic currents in hippocampal neurones. CONCLUSIONS Lower brain testosterone concentrations in neonatal compared with adult male mice contributed to age-dependent tau phosphorylation and cognitive impairment after sevoflurane anaesthesia. Testosterone might attenuate the sevoflurane-induced tau phosphorylation and cognitive impairment by inhibiting the interaction between tau and GSK3β.
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Affiliation(s)
- Yongyan Yang
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, People's Republic of China; Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Feng Liang
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Jie Gao
- Department of Anesthesiology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Yuanlin Dong
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Yiying Zhang
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Guang Yang
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA
| | - Sulpicio G Soriano
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Hua-Jun Feng
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhongcong Xie
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
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Cabrera OH, Useinovic N, Jevtovic-Todorovic V. Neonatal Anesthesia and dysregulation of the Epigenome. Biol Reprod 2021; 105:720-734. [PMID: 34258621 DOI: 10.1093/biolre/ioab136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 11/14/2022] Open
Abstract
Each year, millions of infants and children are anesthetized for medical and surgical procedures. Yet, a substantial body of preclinical evidence suggests that anesthetics are neurotoxins that cause rapid and widespread apoptotic cell death in the brains of infant rodents and non-human primates. These animals have persistent impairments in cognition and behavior many weeks or months after anesthesia exposure, leading us to hypothesize that anesthetics do more than simply kill brain cells. Indeed, anesthetics cause chronic neuropathology in neurons that survive the insult, which then interferes with major aspects of brain development, synaptic plasticity, and neuronal function. Understanding the phenomenon of anesthesia-induced developmental neurotoxicity is of critical public health importance because clinical studies now report that anesthesia in human infancy is associated with cognitive and behavioral deficits. In our search for mechanistic explanations for why a young and pliable brain cannot fully recover from a relatively brief period of anesthesia, we have accumulated evidence that neonatal anesthesia can dysregulate epigenetic tags that influence gene transcription such as histone acetylation and DNA methylation. In this review, we briefly summarize the phenomenon of anesthesia-induced developmental neurotoxicity. We then discuss chronic neuropathology caused by neonatal anesthesia, including disturbances in cognition, socio-affective behavior, neuronal morphology, and synaptic plasticity. Finally, we present evidence of anesthesia-induced genetic and epigenetic dysregulation within the developing brain that may be transmitted intergenerationally to anesthesia-naïve offspring.
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Affiliation(s)
- Omar Hoseá Cabrera
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Nemanja Useinovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
| | - Vesna Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States of America
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20
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Martynyuk AE, Ju LS, Morey TE. The potential role of stress and sex steroids in heritable effects of sevoflurane. Biol Reprod 2021; 105:735-746. [PMID: 34192761 DOI: 10.1093/biolre/ioab129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/17/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.,McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA
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21
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Wang HLV, Forestier S, Corces VG. Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism. Biol Reprod 2021; 105:705-719. [PMID: 33982067 DOI: 10.1093/biolre/ioab097] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 11/13/2022] Open
Abstract
One in 54 children in the U.S. is diagnosed with Autism Spectrum Disorder (ASD). De novo germline and somatic mutations cannot account for all cases of ASD, suggesting that epigenetic alterations triggered by environmental exposures may be responsible for a subset of ASD cases. Human and animal studies have shown that exposure of the developing brain to general anesthetic (GA) agents can trigger neurodegeneration and neurobehavioral abnormalities but the effects of general anesthetics on the germ line have not been explored in detail. We exposed pregnant mice to sevoflurane during the time of embryonic development when the germ cells undergo epigenetic reprogramming and found that more than 38% of the directly exposed F1 animals exhibit impairments in anxiety and social interactions. Strikingly, 44-47% of the F2 and F3 animals, which were not directly exposed to sevoflurane, show the same behavioral problems. We performed ATAC-seq and identified more than 1200 differentially accessible sites in the sperm of F1 animals, 69 of which are also present in the sperm of F2 animals. These sites are located in regulatory regions of genes strongly associated with ASD, including Arid1b, Ntrk2, and Stmn2. These findings suggest that epimutations caused by exposing germ cells to sevoflurane can lead to ASD in the offspring, and this effect can be transmitted through the male germline inter and trans-generationally.
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Affiliation(s)
- Hsiao-Lin V Wang
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Atlanta, GA 30322, USA
| | - Samantha Forestier
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Atlanta, GA 30322, USA
| | - Victor G Corces
- Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Atlanta, GA 30322, USA
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22
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Escher J. How Family Histories Can Inform Research About Germ Cell Exposures: The Example of Autism. Biol Reprod 2021; 105:767-773. [PMID: 33959752 DOI: 10.1093/biolre/ioab092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/08/2021] [Accepted: 04/30/2021] [Indexed: 12/19/2022] Open
Abstract
Throughout the scientific literature, heritable traits are routinely presumed to be genetic in origin. However, as emerging evidence from the realms of genetic toxicology and epigenomics demonstrate, heritability may be better understood as encompassing not only DNA sequence passed down through generations, but also disruptions to the parental germ cells causing de novo mutations or epigenetic alterations, with subsequent shifts in gene expression and functions in offspring. The Beyond Genes conference highlighted advances in understanding these aspects at molecular, experimental and epidemiological levels. In this commentary I suggest that future research on this topic could be inspired by collecting parents' germ cell exposure histories, with particular attention to cases of families with multiple children suffering idiopathic disorders. In so doing I focus on the endpoint of autism spectrum disorders (ASD). Rates of this serious neurodevelopment disability have climbed around the world, a growing crisis that cannot be explained by diagnostic shifts. ASD's strong heritability has prompted a research program largely focused on DNA sequencing to locate rare and common variants, but decades of this gene-focused research have revealed surprisingly little about the molecular origins of the disorder. Based on my experience as the mother of two children with idiopathic autism, and as a research philanthropist and autism advocate, I suggest ways researchers might probe parental germ cell exposure histories to develop new hypotheses that may ultimately reveal sources of non-genetic heritability in a subset of idiopathic heritable pathologies.
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Fan XY, Shi G, Zhao P. Neonatal Sevoflurane Exposure Impairs Learning and Memory by the Hypermethylation of Hippocampal Synaptic Genes. Mol Neurobiol 2021; 58:895-904. [PMID: 33052583 DOI: 10.1007/s12035-020-02161-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/04/2020] [Indexed: 12/20/2022]
Abstract
Sevoflurane anesthesia is widely used in pediatric patients. Clinical studies report memory impairment in those exposed to general anesthesia early in life. DNA methylation is essential for the modulation of synaptic plasticity through regulating the transcription of synaptic genes. Therefore, we tested whether neonatal sevoflurane exposure affects learning and memory underlying the hippocampal DNA methylation of synaptic genes. Male Sprague-Dawley rats were exposed to 3% sevoflurane or air for 2 h daily from postnatal day 7 (P7) to P9. 5-aza-2-deoxycytidine (5-AZA), an inhibitor of DNA methyltransferases (DNMTs), was intraperitoneally injected 30 min before sevoflurane or air exposure on P7-9. The rats were euthanized 6, 12, 24 h, and 28 days after the last sevoflurane exposure, followed by the determination of global and gene-specific DNA methylation. The expression of synaptic proteins and synaptic density and the transcription of Dnmts and ten eleven translocations (Tets) in the hippocampus were measured. The ability of learning and memory was assessed using Morris water maze, novel object recognition, and intruder tests. Repeated neonatal sevoflurane exposure impaired cognitive, social, and spatial memory. The memory impairment was associated with the increased Dnmt1, Dnmt3a, and 5-methylcytosine level and the decreased Tet1 and 5-hydromethylcytosine level. Sevoflurane subsequently induced hypermethylation of Shank2, Psd95, Syn1, and Syp gene and down-regulated the expression of synaptic proteins, which finally led to the decrease of synaptic density in a time-dependent manner. Notably, 5-AZA pretreatment ameliorated learning and memory in sevoflurane-treated rats. In conclusion, neonatal exposure to sevoflurane can impair learning and memory through DNA methylation of synaptic genes.
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Affiliation(s)
- Xin-Yu Fan
- Department of Anesthesiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Guang Shi
- Department of Neurology, Liaoning Provincial People's Hospital, Shenyang, China
| | - Ping Zhao
- Department of Anesthesiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China.
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Neuroanesthesiology Update. J Neurosurg Anesthesiol 2021; 33:107-136. [PMID: 33480638 DOI: 10.1097/ana.0000000000000757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 12/18/2020] [Indexed: 11/27/2022]
Abstract
This review summarizes the literature published in 2020 that is relevant to the perioperative care of neurosurgical patients and patients with neurological diseases as well as critically ill patients with neurological diseases. Broad topics include general perioperative neuroscientific considerations, stroke, traumatic brain injury, monitoring, anesthetic neurotoxicity, and perioperative disorders of cognitive function.
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Rutkowska J, Lagisz M, Bonduriansky R, Nakagawa S. Mapping the past, present and future research landscape of paternal effects. BMC Biol 2020; 18:183. [PMID: 33246472 PMCID: PMC7694421 DOI: 10.1186/s12915-020-00892-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/08/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Although in all sexually reproducing organisms an individual has a mother and a father, non-genetic inheritance has been predominantly studied in mothers. Paternal effects have been far less frequently studied, until recently. In the last 5 years, research on environmentally induced paternal effects has grown rapidly in the number of publications and diversity of topics. Here, we provide an overview of this field using synthesis of evidence (systematic map) and influence (bibliometric analyses). RESULTS We find that motivations for studies into paternal effects are diverse. For example, from the ecological and evolutionary perspective, paternal effects are of interest as facilitators of response to environmental change and mediators of extended heredity. Medical researchers track how paternal pre-fertilization exposures to factors, such as diet or trauma, influence offspring health. Toxicologists look at the effects of toxins. We compare how these three research guilds design experiments in relation to objects of their studies: fathers, mothers and offspring. We highlight examples of research gaps, which, in turn, lead to future avenues of research. CONCLUSIONS The literature on paternal effects is large and disparate. Our study helps in fostering connections between areas of knowledge that develop in parallel, but which could benefit from the lateral transfer of concepts and methods.
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Affiliation(s)
- Joanna Rutkowska
- Institute of Environmental Sciences, Faculty of Biology, Jagiellonian University, Kraków, Poland
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
| | - Malgorzata Lagisz
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
| | - Russell Bonduriansky
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
| | - Shinichi Nakagawa
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
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Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats. Anesthesiology 2020; 133:852-866. [PMID: 32930727 DOI: 10.1097/aln.0000000000003437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats. METHODS Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30). RESULTS Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s). CONCLUSIONS Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Richard K Barnes
- From the Anesthetic Department, Monash Medical Centre, Melbourne, Australia
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Xu N, Lei L, Lin Y, Ju LS, Morey TE, Gravenstein N, Yang J, Martynyuk AE. A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane. Anesth Analg 2020; 131:1291-1299. [PMID: 32925350 PMCID: PMC7593836 DOI: 10.1213/ane.0000000000005097] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Neonatal exposure to sevoflurane induces neurobehavioral and neuroendocrine abnormalities in exposed male rats (generation F0) and neurobehavioral, but not neuroendocrine, abnormalities in their male, but not female, offspring (generation F1). These effects of sevoflurane are accompanied by a hypermethylated neuron-specific K-2Cl (Kcc2) Cl exporter gene in the F0 spermatozoa and the F1 male hypothalamus, while the gene's expression is reduced in the F0 and F1 hypothalamus. We investigated whether inhibition of deoxyribonucleic acid methyltransferases (DNMTs) before paternal sevoflurane exposure could alleviate the anesthetic's F0 and F1 effects. METHODS Sprague-Dawley male rats were anesthetized with 2.1% sevoflurane for 5 hours on postnatal day (P) 5 and mated with control females on P90 to generate offspring. The nonselective DNMT inhibitor decitabine (0.5 mg/kg, intraperitoneally) was administered 30 minutes before sevoflurane exposure. The F0 and F1 male rats were evaluated in in vivo and in vitro tests in adulthood. RESULTS Paternal exposure to sevoflurane induced impaired prepulse inhibition of the acoustic startle response and exacerbated corticosterone responses to stress in F0 males and impaired prepulse inhibition of the startle responses in F1 males. These effects were accompanied in both generations by reduced and increased expressions of hypothalamic Kcc2 and Dnmt3a/b, respectively. Decitabine deterred the effects of paternal exposure to sevoflurane in F0 and F1 males. CONCLUSIONS These results suggest that similar decitabine-sensitive mechanisms regulating expression of multiple genes are involved in the mediation of neurobehavioral abnormalities in sires neonatally exposed to sevoflurane and in their future unexposed male offspring.
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Affiliation(s)
- Ning Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Lei Lei
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Timothy E. Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
| | - Jianjun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Anatoly E. Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida
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Wang J, Yang B, Ju L, Yang J, Allen A, Zhang J, Martynyuk AE. The Estradiol Synthesis Inhibitor Formestane Diminishes the Ability of Sevoflurane to Induce Neurodevelopmental Abnormalities in Male Rats. Front Syst Neurosci 2020; 14:546531. [PMID: 33013333 PMCID: PMC7498728 DOI: 10.3389/fnsys.2020.546531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/14/2020] [Indexed: 01/14/2023] Open
Abstract
Background In rodents, the period of increased vulnerability to the developmental effects of general anesthetics coincides with the period of age-specific organizing (masculinizing) effects of the major female sex hormone 17β-estradiol (E2) in the male brain and excitatory GABA type A receptor (GABAAR) signaling. We studied whether E2 synthesis and excitatory GABAAR signaling are involved in the mediation of the developmental effects of sevoflurane in male rats. Methods Male Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na+-K+-2Cl– (NKCC1) Cl– importer, bumetanide, prior to sevoflurane exposure for 6 h on postnatal (P) day 4, P5, or P6. We tested whether a subsequent exposure of these rats to sevoflurane on P∼10 would cause electroencephalography (EEG)-detectable seizures. We also evaluated their behavior during the elevated plus maze (EPM) test on P∼60, prepulse inhibition (PPI) of acoustic startle responses on P∼70, and corticosterone secretion to physical restraint on P∼80. Results The rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures (F(3,24) = 7.445, P = 0.001) and exhibited deficiencies during the EPM (F(3,55) = 4.397, P = 0.008) and PPI (F(3,110) = 5.222, P = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone (F(3,16) = 11.906, P < 0.001). These parameters in the sevoflurane-exposed rats that were pretreated with formestane or bumetanide were not different from those in the control rats. Conclusion These results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABAAR signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.
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Affiliation(s)
- Jie Wang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China.,Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Baofeng Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States.,Department of Anesthesiology and Perioperative Medicine, Affiliated, Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Lingsha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiaojiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Andrea Allen
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States.,The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
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Yu Y, Yang Y, Tan H, Boukhali M, Khatri A, Yu Y, Hua F, Liu L, Li M, Yang G, Dong Y, Zhang Y, Haas W, Xie Z. Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice. Anesthesiology 2020; 133:595-610. [PMID: 32701572 PMCID: PMC7429299 DOI: 10.1097/aln.0000000000003452] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Sevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria-adenosine triphosphate (ATP)-Nuak1-Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function. METHODS 6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice. RESULTS Under baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2. CONCLUSIONS Higher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage-dependent cognitive dysfunction after sevoflurane anesthesia.
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Affiliation(s)
- Yang Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, P.R. China, 300052
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Yongyan Yang
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, P.R. China, 300052
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Hong Tan
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Department of Anesthesia, Xinhua Hospital of Shanghai Jiaotong University, Shanghai, P. R. China, 200092
| | - Myriam Boukhali
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 02114
| | - Ashok Khatri
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 02114
| | - Yonghao Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, P.R. China, 300052
| | - Fuzhou Hua
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Department of Anesthesia, Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China, 330006
| | - Ling Liu
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P.R. China, 510120
| | - Mengzhu Li
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, P.R. China, 200092
| | - Guang Yang
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA, 10032
| | - Yuanlin Dong
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Yiying Zhang
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
| | - Wilhelm Haas
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 02114
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA, 02129-2060
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Lin Y, Lei L, Ju LS, Xu N, Morey TE, Gravenstein N, Yang J, Martynyuk AE. Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms. Neurosci Lett 2020; 735:135240. [PMID: 32650051 DOI: 10.1016/j.neulet.2020.135240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/09/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Deficiencies in neurocognitive function have been found in late childhood or adolescence in patients who had prolonged and/or repeated early-life general anesthesia. Animal studies suggest that anesthetic-induced impairment in the neuron-specific K+-2Cl- (Kcc2) Cl- exporter expression, which regulates developmental maturation of GABA type A receptor (GABAAR) signaling from excitatory to inhibitory, may play a mediating role. We tested whether the DNA methyltransferase (DNMT) inhibitor decitabine ameliorates the anesthetic's adverse effects. METHODS Sprague-Dawley male rats were injected with vehicle or decitabine 30 min before 2.1 % sevoflurane exposure for 5 h on postnatal day 5 (P5). On P19, P20, or P21, electroencephalography-detectable seizures were measured during 1 h of sevoflurane exposure, followed by collection of the trunk blood and brain tissue samples. Other rats were evaluated for changes in hippocampal CA1 dendrite morphology and gene expressions on ≥ P120. RESULTS Rats in the vehicle plus sevoflurane group responded to sevoflurane exposure on P19, P20 or P21 with electroencephalography-detectable seizures and stress-like corticosterone secretion and had altered hippocampal dendrite morphology in adulthood. These rats had expressions of Kcc2 and Dnmt genes downregulated and upregulated, respectively, in the P19 - P21 cortex and hypothalamus and the ≥ P120 hippocampus. All measured parameters in the sevoflurane-exposed rats that were pretreated with decitabine were not different from those in the control group. CONCLUSIONS Neonatal exposure to sevoflurane sensitizes rats to adverse effects of repeated exposure to the anesthetic. The anesthetic-caused changes in the decitabine-sensitive mechanisms may play a mediating role in the developmental effects of early-life anesthesia.
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Affiliation(s)
- Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lei Lei
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ning Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jianjun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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Li T, Huang Z, Wang X, Zou J, Tan S. Role of the GABAA receptors in the long-term cognitive impairments caused by neonatal sevoflurane exposure. Rev Neurosci 2020; 30:869-879. [PMID: 31145696 DOI: 10.1515/revneuro-2019-0003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 03/29/2019] [Indexed: 02/06/2023]
Abstract
Sevoflurane is a widely used inhalational anesthetic in pediatric surgeries, which is considered reasonably safe and reversible upon withdrawal. However, recent preclinical studies suggested that peri-neonatal sevoflurane exposure may cause developmental abnormalities in the brain. The present review aimed to present and discuss the accumulating experimental data regarding the undesirable effects of sevoflurane on brain development as revealed by the laboratory studies. First, we summarized the long-lasting side effects of neonatal sevoflurane exposure on cognitive functions. Subsequently, we presented the structural changes, namely, neuroapoptosis, neurogenesis and synaptogenesis, following sevoflurane exposure in the immature brain. Finally, we also discussed the potential mechanisms underlying subsequent cognitive impairments later in life, which are induced by neonatal sevoflurane exposure and pointed out potential strategies for mitigating sevoflurane-induced long-term cognitive impairments. The type A gamma-amino butyric acid (GABAA) receptor, the main targets of sevoflurane, is excitatory rather than inhibitory in the immature neurons. The excitatory effects of the GABAA receptors have been linked to increased neuroapoptosis, elevated serum corticosterone levels and epigenetic modifications following neonatal sevoflurane exposure in rodents, which might contribute to sevoflurane-induced long-term cognitive abnormalities. We proposed that the excitatory GABAA receptor-mediated HPA axis activity might be a novel mechanism underlying sevoflurane-induced long-term cognitive impairments. More studies are needed to investigate the effectiveness and mechanisms by targeting the excitatory GABAA receptor as a prevention strategy to alleviate cognitive deficits induced by neonatal sevoflurane exposure in future.
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Affiliation(s)
- Tao Li
- Grade 2015 of Clinical Medicine, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Zeyi Huang
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Xianwen Wang
- Grade 2015 of Clinical Medicine, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Ju Zou
- Department of Parasitology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Sijie Tan
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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Chinn GA, Pearn ML, Vutskits L, Mintz CD, Loepke AW, Lee JJ, Chen J, Bosnjak ZJ, Brambrink AM, Jevtovic-Todorovic V, Sun LS, Sall JW. Standards for preclinical research and publications in developmental anaesthetic neurotoxicity: expert opinion statement from the SmartTots preclinical working group. Br J Anaesth 2020; 124:585-593. [PMID: 32145876 PMCID: PMC7424895 DOI: 10.1016/j.bja.2020.01.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 01/06/2020] [Accepted: 01/24/2020] [Indexed: 12/16/2022] Open
Abstract
In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work.
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Affiliation(s)
- Gregory A Chinn
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA
| | - Matthew L Pearn
- Department of Anesthesiology, University of California, San Diego, CA, USA
| | - Laszlo Vutskits
- Department of Anesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, University Hospitals of Geneva, Geneva, Switzerland
| | - Cyrus D Mintz
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Andreas W Loepke
- Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jennifer J Lee
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Jerri Chen
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Zeljko J Bosnjak
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | | | - Lena S Sun
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Jeffrey W Sall
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
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Abstract
BACKGROUND Sevoflurane administered to neonatal rats induces neurobehavioral abnormalities and epigenetic reprogramming of their germ cells; the latter can pass adverse effects of sevoflurane to future offspring. As germ cells are susceptible to reprogramming by environmental factors across the lifespan, the authors hypothesized that sevoflurane administered to adult rats could induce neurobehavioral abnormalities in future offspring, but not in the exposed rats themselves. METHODS Sprague-Dawley rats were anesthetized with 2.1% sevoflurane for 3 h every other day between postnatal days 56 and 60. Twenty-five days later, exposed rats and nonexposed controls were mated to produce offspring. RESULTS Adult male but not female offspring of exposed parents of either sex exhibited deficiencies in elevated plus maze (mean ± SD, offspring of both exposed parents vs. offspring of control parents, 35 ± 12 vs. 15 ± 15 s, P < 0.001) and prepulse inhibition of acoustic startle (offspring of both exposed parents vs. offspring of control parents, 46.504 ± 13.448 vs. 25.838 ± 22.866%, P = 0.009), and increased methylation and reduced expression of the potassium ion-chloride ion cotransporter KCC2 gene (Kcc2) in the hypothalamus. Kcc2 was also hypermethylated in sperm and ovary of the exposed rats. Surprisingly, exposed male rats also exhibited long-term abnormalities in functioning of the hypothalamic-pituitary-gonadal and -adrenal axes, reduced expression of hypothalamic and hippocampal Kcc2, and deficiencies in elevated plus maze (sevoflurane vs. control, 40 ± 24 vs. 25 ± 12 s, P = 0.038) and prepulse inhibition of startle (sevoflurane vs. control, 39.905 ± 21.507 vs. 29.193 ± 24.263%, P < 0.050). CONCLUSIONS Adult sevoflurane exposure affects brain development in male offspring by epigenetically reprogramming both parental germ cells, while it induces neuroendocrine and behavioral abnormalities only in exposed males. Sex steroids may be required for mediation of the adverse effects of adult sevoflurane in exposed males.
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Abstract
This review is intended to provide a summary of the literature pertaining to the perioperative care of neurosurgical patients and patients with neurological diseases. General topics addressed in this review include general neurosurgical considerations, stroke, neurological monitoring, and perioperative disorders of cognitive function.
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Cabrera OH, Gulvezan T, Symmes B, Quillinan N, Jevtovic-Todorovic V. Sex differences in neurodevelopmental abnormalities caused by early-life anaesthesia exposure: a narrative review. Br J Anaesth 2020; 124:e81-e91. [PMID: 31980157 DOI: 10.1016/j.bja.2019.12.032] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 12/15/2019] [Accepted: 12/23/2019] [Indexed: 01/12/2023] Open
Abstract
Exposure to anaesthetic drugs during the fetal or neonatal period induces widespread neuronal apoptosis in the brains of rodents and non-human primates. Hundreds of published preclinical studies and nearly 20 clinical studies have documented cognitive and behavioural deficits many months or years later, raising the spectre that early life anaesthesia exposure is a long-term, perhaps permanent, insult that might affect the quality of life of millions of humans. Although the phenomenon of anaesthesia-induced developmental neurotoxicity is well characterised, there are important and lingering questions pertaining to sex differences and neurodevelopmental sequelae that might occur differentially in females and males. We review the relevant literature on sex differences in the field of anaesthesia-induced developmental neurotoxicity, and present an emerging pattern of potential sex-dependent neurodevelopmental abnormalities in rodent models of human infant anaesthesia exposure.
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Affiliation(s)
- Omar H Cabrera
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Thomas Gulvezan
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Breanna Symmes
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Nidia Quillinan
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Luo A, Tang X, Zhao Y, Zhou Z, Yan J, Li S. General Anesthetic-Induced Neurotoxicity in the Immature Brain: Reevaluating the Confounding Factors in the Preclinical Studies. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7380172. [PMID: 31998797 PMCID: PMC6970503 DOI: 10.1155/2020/7380172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/17/2019] [Indexed: 01/30/2023]
Abstract
General anesthetic (GA) is used clinically to millions of young children each year to facilitate surgical procedures, relieve perioperative stress, and provide analgesia and amnesia. During recent years, there is a growing concern regarding a causal association between early life GA exposure and subsequently long-term neurocognitive abnormalities. To address the increasing concern, mounting preclinical studies and clinical trials have been undergoing. Until now, nearly all of the preclinical findings show that neonatal exposure to GA causally leads to acute neural cell injury and delayed cognitive impairment. Unexpectedly, several influential clinical findings suggest that early life GA exposure, especially brief and single exposure, does not cause adverse neurodevelopmental outcome, which is not fully in line with the experimental findings and data from several previous cohort trials. As the clinical data have been critically discussed in previous reviews, in the present review, we try to analyze the potential factors of the experimental studies that may overestimate the adverse effect of GA on the developing brain. Meanwhile, we briefly summarized the advance in experimental research. Generally, our purpose is to provide some useful suggestions for forthcoming preclinical studies and strengthen the powerfulness of preclinical data.
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Affiliation(s)
- Ailin Luo
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Xiaole Tang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Yilin Zhao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Zhiqiang Zhou
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Jing Yan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Shiyong Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
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Cabrera OH, Tesic V, Tat QL, Chastain S, Quillinan N, Jevtovic-Todorovic V. Sevoflurane-Induced Dysregulation of Cation-Chloride Cotransporters NKCC1 and KCC2 in Neonatal Mouse Brain. Mol Neurobiol 2020; 57:1-10. [PMID: 31493242 PMCID: PMC6980440 DOI: 10.1007/s12035-019-01751-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 08/29/2019] [Indexed: 11/26/2022]
Abstract
The cation-chloride cotransporters Na+-K+-2Cl--1 (NKCC1) and K+-2Cl--2 (KCC2) critically regulate neuronal responses to gamma-aminobutyric acid (GABA). NKCC1 renders GABA excitatory in immature neurons while expression of KCC2 signals GABA maturation to its inhibitory role. Imbalances in NKCC1/KCC2 alter GABA neurotransmission, which may contribute to hyperexcitability and blunted inhibition in neurocircuitry after neonatal exposure to anesthesia. Thus, we hypothesized that anesthetics may dysregulate NKCC1 and/or KCC2 in developing brain. We exposed postnatal day (PND) 7 mice to sevoflurane or carrier gases and assessed NKCC1 and KCC2 expression across three brain regions 6 h and 24 h after initial exposure. To test differences in behavior, we challenged pups receiving sevoflurane or carrier gases on PND7 with propofol on PND8 and recorded parameters of anesthesia induction and maintenance. Sevoflurane exposure increased cortical NKCC1 at 6 h (p = 0.03) and decreased cortical and hippocampal KCC2 at 24 h (p = 0.009 and p = 0.007, respectively). NKCC1/KCC2 ratio was significantly increased at both 6 h (p = 0.02) and 24 h (p = 0.03) in cortex and at 24 h (p = 0.02) in hippocampus. After propofol challenge on PND8, pups previously exposed to sevoflurane on PND7 regained righting reflex significantly faster than their non-exposed cohort (p < 0.001). Disturbing NKCC1/KCC2 balance may underlie circuit hyperexcitability and contribute to neurodevelopmental impairments we have observed in previous studies of neonatal anesthesia exposure. Human infants previously exposed to anesthesia may require higher concentrations of anesthetic drugs, potentially compounding their susceptibility for neurodevelopmental sequalae.
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Affiliation(s)
- O H Cabrera
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl., Aurora, CO, 80045, USA.
| | - V Tesic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - Q L Tat
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - S Chastain
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - N Quillinan
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - V Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, 13001 E. 17th Pl., Aurora, CO, 80045, USA
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Li N, Xu N, Lin Y, Lei L, Ju LS, Morey TE, Gravenstein N, Zhang J, Martynyuk AE. Roles of Testosterone and Estradiol in Mediation of Acute Neuroendocrine and Electroencephalographic Effects of Sevoflurane During the Sensitive Period in Rats. Front Endocrinol (Lausanne) 2020; 11:545973. [PMID: 33101193 PMCID: PMC7556268 DOI: 10.3389/fendo.2020.545973] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 09/10/2020] [Indexed: 01/14/2023] Open
Abstract
Testosterone (T), predominantly acting through its derivative 17β-estradiol (E2), regulates the brain's sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia's adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane's acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor α (Erα) [not estrogen receptor β (Erβ)], Na+-K+-Cl- cotransporter (Nkcc1)/K+-Cl- cotransporter (Kcc2) mRNA ratio, electroencephalography-detectable seizures, and stress-like corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERα antagonist MPP, but not the ERβ antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABAAR-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development.
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Affiliation(s)
- Ningtao Li
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ning Xu
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Yunan Lin
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Lei Lei
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E. Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Jiaqiang Zhang, ; Anatoly E. Martynyuk,
| | - Anatoly E. Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
- *Correspondence: Jiaqiang Zhang, ; Anatoly E. Martynyuk,
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Chastain-Potts SE, Tesic V, Tat QL, Cabrera OH, Quillinan N, Jevtovic-Todorovic V. Sevoflurane Exposure Results in Sex-Specific Transgenerational Upregulation of Target IEGs in the Subiculum. Mol Neurobiol 2020; 57:11-22. [PMID: 31512116 PMCID: PMC6980510 DOI: 10.1007/s12035-019-01752-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 08/29/2019] [Indexed: 12/22/2022]
Abstract
Large body of animal work and emerging clinical findings have suggested that early exposure to anesthetics may result in increased risk of learning disabilities and behavioral impairments. Recent studies have begun to investigate anesthesia-induced epigenetic modifications to elucidate their role in behavioral and neurodevelopmental abnormalities. Here we examine sevoflurane-induced transgenerational modifications of subicular neuronal DNA methylation and expression of immediate early genes (IEGs), arc and junB, crucial to synaptic plasticity and normal neuronal development. We show that 6 h sevoflurane exposure in postnatal day 7 rat pups resulted in decreased neuronal 5-methycytosine, indicating reduced DNA methylation. This effect is transgenerationally expressed in offspring born to exposed mothers which is of importance considering that decreased DNA methylation in the brain has been linked with functional decline in learning and memory. We further show that sevoflurane exposure induces upregulation of Arc and JunB mRNA expression, 42.7% and 35.2%, respectively. Transgenerational changes in Arc and JunB mRNA were sexually dimorphic only occurring in males born to exposed females, expressed as upregulation of Arc and JunB mRNA, 71.6% and 74.0%, respectively. We further investigated correlation between altered arc promoter methylation and observed upregulation of Arc mRNA and observed that sevoflurane reduced methylation in the 5-upstream promoter region of females exposed to sevoflurane. Transgenerational hypomethylation and modifications to IEGs crucial to synaptic plasticity, observed following neonatal sevoflurane exposure could contribute to morphological and cognitive deficits known to occur with neonatal sevoflurane exposure.
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Affiliation(s)
- Shelby E Chastain-Potts
- Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - Vesna Tesic
- Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - Quy L Tat
- Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - Omar H Cabrera
- Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - Nidia Quillinan
- Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA
| | - Vesna Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado School of Medicine, 13001 E. 17th Pl., Aurora, CO, 80045, USA.
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Escher J, Ford LD. General anesthesia, germ cells and the missing heritability of autism: an urgent need for research. ENVIRONMENTAL EPIGENETICS 2020; 6:dvaa007. [PMID: 32704384 PMCID: PMC7368377 DOI: 10.1093/eep/dvaa007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/31/2020] [Accepted: 04/14/2020] [Indexed: 05/08/2023]
Abstract
Agents of general anesthesia (GA) are commonly employed in surgical, dental and diagnostic procedures to effectuate global suppression of the nervous system, but in addition to somatic targets, the subject's germ cells-from the embryonic primordial stage to the mature gametes-may likewise be exposed. Although GA is generally considered safe for most patients, evidence has accumulated that various compounds, in particular the synthetic volatile anesthetic gases (SVAGs) such as sevoflurane, can exert neurotoxic, genotoxic and epigenotoxic effects, with adverse consequences for cellular and genomic function in both somatic and germline cells. The purpose of this paper is to review the evidence demonstrating that GA, and in particular, SVAGs, may in some circumstances adversely impact the molecular program of germ cells, resulting in brain and behavioral pathology in the progeny born of the exposed cells. Further, we exhort the medical and scientific communities to undertake comprehensive experimental and epidemiological research programs to address this critical gap in risk assessment.
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Affiliation(s)
- Jill Escher
- Correspondence address. Escher Fund for Autism, 1590 Calaveras Avenue, San Jose, CA 95126, USA. E-mail:
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Abstract
General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.
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Affiliation(s)
- Mary Ellen McCann
- Department of Anesthesia, Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Sulpicio G Soriano
- Department of Anesthesia, Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
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Syimir Fizal AN, Sohrab Hossain M, Alkarkhi AF, Oyekanmi AA, Hashim SRM, Khalil NA, Zulkifli M, Ahmad Yahaya AN. Assessment of the chemical hazard awareness of petrol tanker driver: A case study. Heliyon 2019; 5:e02368. [PMID: 31485542 PMCID: PMC6717159 DOI: 10.1016/j.heliyon.2019.e02368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 06/06/2019] [Accepted: 08/21/2019] [Indexed: 10/29/2022] Open
Abstract
Understanding the tanker driver hazard awareness on chemical exposure is important to ensure that they are fortified with the appropriate information regarding the risk of their occupation. This present study was conducted to determine the awareness of the petrol tanker driver on the chemical exposure during transportation petroleum product. The assessment on hazardous awareness of the petrol tank driver was conducted through questionnaire survey. Wherein, the questionnaire was designed with considering the variables of age of the driver, working experience, working hours in a day and knowledge on chemical hazard presence in the petroleum oil. A reliability test of Cronbach's Alpha was performed to validate the questionnaire and the Chi-Square test was conducted to determine the correlation among the studied variables. The findings of the present study revealed that the drivers who are frequently come into direct contact with petrol cannot identify the spillage had occurred during working. The study identified that there is an urgency to conduct training on safe handling of petroleum oil in order to eliminate the risk of chemical hazards exposure to the tanker driver.
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Affiliation(s)
- Ahmad Noor Syimir Fizal
- Malaysian Institute of Chemical and Bioengineering Technology, Universiti Kuala Lumpur (UniKL), Melaka, Malaysia
| | - Md. Sohrab Hossain
- Division of Environmental Technology, School of Industrial Technology, Universiti Sains Malaysia (USM), Penang, Malaysia
| | - Abbas F.M. Alkarkhi
- Malaysian Institute of Chemical and Bioengineering Technology, Universiti Kuala Lumpur (UniKL), Melaka, Malaysia
| | - Adeleke Abdulrahman Oyekanmi
- Division of Environmental Technology, School of Industrial Technology, Universiti Sains Malaysia (USM), Penang, Malaysia
| | | | - Nor Afifah Khalil
- Malaysian Institute of Chemical and Bioengineering Technology, Universiti Kuala Lumpur (UniKL), Melaka, Malaysia
| | - Muzafar Zulkifli
- Malaysian Institute of Chemical and Bioengineering Technology, Universiti Kuala Lumpur (UniKL), Melaka, Malaysia
| | - Ahmad Naim Ahmad Yahaya
- Malaysian Institute of Chemical and Bioengineering Technology, Universiti Kuala Lumpur (UniKL), Melaka, Malaysia
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Escher J, Robotti S. Pregnancy drugs, fetal germline epigenome, and risks for next-generation pathology: A call to action. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2019; 60:445-454. [PMID: 30891817 DOI: 10.1002/em.22288] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/09/2019] [Accepted: 03/16/2019] [Indexed: 06/09/2023]
Abstract
Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long-term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the "missing heritability" of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445-454, 2019. © 2019 Wiley Periodicals, Inc.
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Affiliation(s)
- Jill Escher
- Escher Fund for Autism, San Jose, California
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Zhang L, Xue Z, Liu Q, Liu Y, Xi S, Cheng Y, Li J, Yan J, Shen Y, Xiao C, Xie Z, Qiu Z, Jiang H. Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN. EBioMedicine 2019; 43:473-486. [PMID: 31060905 PMCID: PMC6562069 DOI: 10.1016/j.ebiom.2019.04.048] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 11/22/2022] Open
Abstract
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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Affiliation(s)
- Lei Zhang
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Zhenyu Xue
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Qidong Liu
- Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, PR China
| | - Yunbo Liu
- The Institute of Laboratory Animal Science, CAMS & PUMC. Beijing, PR China
| | - Siwei Xi
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Yanyong Cheng
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Jingjie Li
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Jia Yan
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China
| | - Yuan Shen
- Department of Psychiatry, Anesthesia and Brain Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, PR China
| | - Chong Xiao
- The Institute of Laboratory Animal Science, CAMS & PUMC. Beijing, PR China
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
| | - Zilong Qiu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
| | - Hong Jiang
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai, PR China.
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Abstract
This review provides a summary of the literature pertaining to the perioperative care of neurosurgical patients and patients with neurological diseases. General topics addressed in this review include general neurosurgical considerations, stroke, traumatic brain injury, neuromonitoring, neurotoxicity, and perioperative disorders of cognitive function.
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Yang J, Ju L, Yang C, Xue J, Setlow B, Morey TE, Gravenstein N, Seubert CN, Vasilopoulos T, Martynyuk AE. Effects of combined brief etomidate anesthesia and postnatal stress on amygdala expression of Cl - cotransporters and corticotropin-releasing hormone and alcohol intake in adult rats. Neurosci Lett 2018; 685:83-89. [PMID: 30125644 DOI: 10.1016/j.neulet.2018.08.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/09/2018] [Accepted: 08/16/2018] [Indexed: 01/18/2023]
Abstract
Early life stressors, including general anesthesia, can have adverse effects on adult neural and behavioral outcomes, such as disruptions in inhibitory signaling, stress responsivity and increased risk of psychiatric disorders. Here we used a rat model to determine the effects of combined exposure to etomidate (ET) neonatal anesthesia and maternal separation on adult amygdala expression of genes for corticotropin-releasing hormone (Crh) and the chloride co-transporters Nkcc1 and Kcc2, as well as ethanol intake. Male and female Sprague-Dawley rats were subjected to 2 h of ET anesthesia on postnatal days (P) 4, 5, or 6 followed by maternal separation for 3 h on P10 (ET + SEP). During the P91-P120 period rats had daily 2 h access to three 0.05% saccharin solutions containing 0%, 5%, or 10% ethanol, followed by gene expression analyses. The ET + SEP group had increased Crh mRNA levels and Nkcc1/Kcc2 mRNA ratios in the amygdala, with greater increases in Nkcc1/Kcc2 mRNA ratios in males. A moderate increase in 5% ethanol intake was evident in the ET + SEP males, but not females, after calculation of the ratio of alcohol intake between the last week and first week of exposure. In contrast, control males tended to decrease alcohol consumption during the same period. A brief exposure to ET combined with a subsequent episode of stress early in life induced significant alterations in expression of amygdala Crh, Nkcc1 and Kcc2 with greater changes in the Cl- transporter expression in males. The possibility of increased alcohol intake in the exposed males requires further confirmation using different alcohol intake paradigms.
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Affiliation(s)
- Jiaojiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Lingsha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Chunyao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jinhu Xue
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Barry Setlow
- The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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Vutskits L, Sall J, Jevtovic-Todorovic V. A poisoned chalice: the heritage of parental anaesthesia exposure. Br J Anaesth 2018; 121:337-339. [DOI: 10.1016/j.bja.2018.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 05/14/2018] [Indexed: 10/14/2022] Open
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