scholarly journals Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism

2021 ◽  
Author(s):  
Hsiao-Lin V Wang ◽  
Samantha Forestier ◽  
Victor G Corces
Keyword(s):  
Germ Cells ◽  
Behavioral Problems ◽  
Animal Studies ◽  
De Novo ◽  
Germ Line ◽  
Autism Spectrum ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Male Germline ◽  
Pregnant Mice

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.

scholarly journals Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism

2021 ◽  
Author(s):  
Hsiao-Lin V. Wang ◽  
Samantha Forestier ◽  
Victor G. Corces
Keyword(s):  
Transcription Factor ◽  
Germ Cells ◽  
Behavioral Problems ◽  
De Novo ◽  
Germ Line ◽  
Pregnant Mouse ◽  
Autism Spectrum ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Transcription Factor Occupancy

ABSTRACTOne 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 1,200 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.Summary sentencePregnant mouse F0 females exposed to sevoflurane give rise to F1 males with sociability and anxiety defects. These behaviors are transmitted to F2 and F3 males. Their sperm show changes in transcription factor occupancy in genes implicated in autism.

scholarly journals MORC1 represses transposable elements in the mouse male germline

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
William A. Pastor ◽  
Hume Stroud ◽  
Kevin Nee ◽  
Wanlu Liu ◽  
Dubravka Pezic ◽  
...  
Keyword(s):  
Germ Cells ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Cell Loss ◽  
Genetic Screens ◽  
Male Germline ◽  
Silent Genes ◽  
Localized Defects ◽  
Eukaryotic Organisms ◽  
Male Specific

Abstract The Microrchidia (Morc) family of GHKL ATPases are present in a wide variety of prokaryotic and eukaryotic organisms but are of largely unknown function. Genetic screens in Arabidopsis thaliana have identified Morc genes as important repressors of transposons and other DNA-methylated and silent genes. MORC1-deficient mice were previously found to display male-specific germ cell loss and infertility. Here we show that MORC1 is responsible for transposon repression in the male germline in a pattern that is similar to that observed for germ cells deficient for the DNA methyltransferase homologue DNMT3L. Morc1 mutants show highly localized defects in the establishment of DNA methylation at specific classes of transposons, and this is associated with failed transposon silencing at these sites. Our results identify MORC1 as an important new regulator of the epigenetic landscape of male germ cells during the period of global de novo methylation.

scholarly journals Oxidative Stress in the Male Germline: A Review of Novel Strategies to Reduce 4-Hydroxynonenal Production

Antioxidants ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 132 ◽  
Author(s):  
Jessica Walters ◽  
Geoffry De Iuliis ◽  
Brett Nixon ◽  
Elizabeth Bromfield
Keyword(s):  
Oxidative Stress ◽  
Germ Cells ◽  
Cell Function ◽  
De Novo ◽  
Protein Translation ◽  
Egg Recognition ◽  
Male Germline ◽  
New Strategy ◽  
Artery Disease ◽  
The Stability

Germline oxidative stress is intimately linked to several reproductive pathologies including a failure of sperm-egg recognition. The lipid aldehyde 4-hydroxynonenal (4HNE) is particularly damaging to the process of sperm-egg recognition as it compromises the function and the stability of several germline proteins. Considering mature spermatozoa do not have the capacity for de novo protein translation, 4HNE modification of proteins in the mature gametes has uniquely severe consequences for protein homeostasis, cell function and cell survival. In somatic cells, 4HNE overproduction has been attributed to the action of lipoxygenase enzymes that facilitate the oxygenation and degradation of ω-6 polyunsaturated fatty acids (PUFAs). Accordingly, the arachidonate 15-lipoxygenase (ALOX15) enzyme has been intrinsically linked with 4HNE production, and resultant pathophysiology in various complex conditions such as coronary artery disease and multiple sclerosis. While ALOX15 has not been well characterized in germ cells, we postulate that ALOX15 inhibition may pose a new strategy to prevent 4HNE-induced protein modifications in the male germline. In this light, this review focuses on (i) 4HNE-induced protein damage in the male germline and its implications for fertility; and (ii) new methods for the prevention of lipid peroxidation in germ cells.

scholarly journals Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families

2021 ◽  
Vol 22 (4) ◽  
pp. 1660
Author(s):  
Isaac Baldwin ◽  
Robin L. Shafer ◽  
Waheeda A. Hossain ◽  
Sumedha Gunewardena ◽  
Olivia J. Veatch ◽  
...  
Keyword(s):  
Behavioral Problems ◽  
De Novo ◽  
Clinical Laboratory ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Genomic Variation ◽  
Future Research ◽  
Symptom Presentation ◽  
Clinical Genetic ◽  
Genetic Evaluations

The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

scholarly journals Reproductive Isolation and Morphogenetic Evolution in Drosophila Analyzed by Breakage of Ethological Barriers

Genetics ◽  
1997 ◽  
Vol 147 (1) ◽  
pp. 231-242 ◽  
Author(s):  
Lucas Sánchez ◽  
Pedro Santamaria
Keyword(s):  
Reproductive Isolation ◽  
Germ Cells ◽  
Morphological Analysis ◽  
Seminal Fluid ◽  
Germ Line ◽  
Regulatory Gene ◽  
Motile Sperm ◽  
Male And Female ◽  
Drosophila Yakuba

Abstract This article reports the breaking of ethological barriers through the constitution of soma-germ line chimeras between species of the melanogaster subgroup of Drosophila, which are ethologically isolated. Female Drosophila yakuba and D. teissieri germ cells in a D. melanogaster ovary produced functional oocytes that, when fertilized by D. melanogaster sperm, gave rise to sterile yakuba-melanogaster andteissieri-melanogaster male and female hybrids. However, the erecta-melanogaster and orena-melanogaster hybrids were lethal, since female D. erecta and D. orena germ cells in a D. melanogaster ovary failed to form oocytes with the capacity to develop normally. This failure appears to be caused by an altered interaction between the melanogaster soma and the erecta and orena germ lines. Germ cells of D. teissieri and D. orena in a D. melanogaster testis produced motile sperm that was not stored in D. melanogaster females. This might be due to incompatibility between the teissieri and orena sperm and the melanogaster seminal fluid. A morphological analysis of the terminalia of yakuba-melanogaster and teissieri-melanogaster hybrids was performed. The effect on the terminalia of teissieri-melanogaster hybrids of a mutation in doublesex, a regulatory gene that controls the development of the terminalia, was also investigated.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals The Impact of COVID-19 on the Adaptive Functioning, Behavioral Problems, and Repetitive Behaviors of Italian Children with Autism Spectrum Disorder: An Observational Study

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 96
Author(s):  
Martina Siracusano ◽  
Eugenia Segatori ◽  
Assia Riccioni ◽  
Leonardo Emberti Gialloreti ◽  
Paolo Curatolo ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Behavioral Problems ◽  
Adaptive Functioning ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Assessment System ◽  
Spectrum Disorder ◽  
Adaptive Skills ◽  
The Impact

Children with autism spectrum disorder (ASD) and their families have represented a fragile population on which the extreme circumstances of the COVID-19 outbreak may have doubly impaired. Interruption of therapeutical interventions delivered in-person and routine disruption constituted some of the main challenges they had to face. This study investigated the impact of the COVID-19 lockdown on adaptive functioning, behavioral problems, and repetitive behaviors of children with ASD. In a sample of 85 Italian ASD children (mean age 7 years old; 68 males, 17 females), through a comparison with a baseline evaluation performed during the months preceding COVID-19, we evaluated whether after the compulsory home confinement any improvement or worsening was reported by parents of ASD individuals using standardized instruments (Adaptive Behavior Assessment System (Second Edition), Achenbach Child Behavior Checklist, Repetitive Behavior Scale-Revised). No significant worsening in the adaptive functioning, problematic, and repetitive behaviors emerged after the compulsory home confinement. Within the schooler children, clinical stability was found in reference to both adaptive skills and behavioral aspects, whereas within preschoolers, a significant improvement in adaptive skills emerged and was related to the subsistence of web-delivered intervention, parental work continuance, and online support during the lockdown.

scholarly journals A Bibliometric Insight of Genetic Factors in ASD: Emerging Trends and New Developments

2020 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Kang Wang ◽  
Weicheng Duan ◽  
Yijie Duan ◽  
Yuxin Yu ◽  
Xiuyi Chen ◽  
...  
Keyword(s):  
Genetic Factors ◽  
De Novo ◽  
Rapid Development ◽  
The United States ◽  
Research Area ◽  
Scientific Output ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Emerging Trends ◽  
Genetic Abnormalities

Autism spectrum disorder (ASD) cases have increased rapidly in recent decades, which is associated with various genetic abnormalities. To provide a better understanding of the genetic factors in ASD, we assessed the global scientific output of the related studies. A total of 2944 studies published between 1997 and 2018 were included by systematic retrieval from the Web of Science (WoS) database, whose scientific landscapes were drawn and the tendencies and research frontiers were explored through bibliometric methods. The United States has been acting as a leading explorer of the field worldwide in recent years. The rapid development of high-throughput technologies and bioinformatics transferred the research method from the traditional classic method to a big data-based pipeline. As a consequence, the focused research area and tendency were also changed, as the contribution of de novo mutations in ASD has been a research hotspot in the past several years and probably will remain one into the near future, which is consistent with the current opinions of the major etiology of ASD. Therefore, more attention and financial support should be paid to the deciphering of the de novo mutations in ASD. Meanwhile, the effective cooperation of multi-research centers and scientists in different fields should be advocated in the next step of scientific research undertaken.

scholarly journals Chromatin Remodeler CHD8 in Autism and Brain Development

2021 ◽  
Vol 10 (2) ◽  
pp. 366
Author(s):  
Anke Hoffmann ◽  
Dietmar Spengler
Keyword(s):  
Animal Studies ◽  
Mental Disease ◽  
Transgenic Animal ◽  
Autism Spectrum ◽  
Homeostatic Plasticity ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Facial Dysmorphism ◽  
Transcriptional Level ◽  
Level Function

Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including ‘humanized’ mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.

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