Understanding environmental contributions to autism: Causal concepts and the state of science

Hertz‐Picciotto, Irva; Schmidt, Rebecca Jean; Krakowiak, Paula

doi:10.1002/aur.1938

Cited by 144 publications

(103 citation statements)

References 309 publications

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“…Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social and communicative impairments and excessive repetitive behaviors (American Psychiatric Association, 2013). Although the pathogenesis of ASD is not fully understood, several factors have been identified as possible contributors such as genetic (Sebat et al, 2007;Klei et al, 2012;De Rubeis et al, 2014) or environmental factors (Brown, 2012;Hertz-Picciotto et al, 2018). Hallmarks of autistic-like symptoms in rodents can be measured with several behavioral assays such as the three-chamber social interaction, self-grooming, ultrasonic vocalization, tube dominance or social playtests.…”

Section: Introductionmentioning

confidence: 99%

Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats

Pelsőczi

Kelemen

Csölle

et al. 2020

Front. Behav. Neurosci.

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Autism spectrum disorder (ASD) is characterized by impaired socio-communicational function, repetitive and restricted behaviors. Valproic acid (VPA) was reported to increase the prevalence of ASD in humans as a consequence of its use during pregnancy. VPA treatment also induces autistic-like behaviors in the offspring of rats after prenatal exposure; hence it is a preclinical disease model with high translational value. In the present study, our aim was to characterize ASD relevant behaviors of socially housed, individually identified male rats in automated home cages. The natural behavior of rats was assessed by monitoring their visits to drinking bottles in an environment without human influence aiming at reducing interventional stress. Although rodents normally tend to explore their new environment, prenatally VPA-treated rats showed a drastic impairment in initial and long-term exploratory behavior throughout their stay in the automated cage. Furthermore, VPA rats displayed psychogenic polydipsia (PPD) as well as altered circadian activity. In the competitive situation of strict water deprivation controls switched to an uneven resource sharing and only a few dominant animals had access to water. In VPA animals similar hierarchy-related changes were completely absent. While the control rats secured their chance to drink with frequent reentering visits, thereby "guarding" the water resource, VPA animals did not switch to uneven sharing and displayed no evidence of guarding behavior.

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Section: Introductionmentioning

confidence: 99%

Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats

Pelsőczi

Kelemen

Csölle

et al. 2020

Front. Behav. Neurosci.

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“…During gestation, when rapid cellular proliferation and differentiation is occurring, environmental stressors can have long-lasting effects on behavior [9]. Maternal factors shown to modify ASD risk include environmental toxicants, nutritional factors, fever, pre-eclampsia, gestational diabetes, and medications [10]. ASD etiology is thought to begin early in development through interactions between genetic and environmental factors that alter neurodevelopmental trajectories [11,12].…”

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confidence: 99%

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Mordaunt

Jianu

Laufer

et al. 2019

Preprint

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Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Results:We identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in postmortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain 3 development. Conclusions:At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sexbiased etiology of ASD, and provides novel insights for early diagnosis and therapy. Keywordsautism spectrum disorder, neurodevelopment, umbilical cord blood, prospective study, epigenome wide association study, epigenetics, epigenome, DNA methylation, whole genome bisulfite sequencing, x chromosome Background Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that affects 1 in 59 children in the United States [1]. ASD presents as persistent difficulties in social communication and interaction, restricted and repetitive behaviors and interests, as well as sensory sensitivities. Communication deficits can include delayed and monotonous speech, echolalia, poor verbal comprehension, difficulty understanding body language cues, and making eye contact, while behavioral deficits can include stereotyped movements, insistence on routine, fixated interests, and altered sensitivity to sensory input. ASD is currently diagnosed in childhood by one of several standardized scales that include interviews, behavioral observation, and clinical assessment, such as the gold standard Autism Diagnostic Observation Schedule (ADOS) [2,3]. Clinical management of ASD symptoms consists of both behavioral interventions and pharmacological treatments. Intensive behavioral interventions have been associated with better outcomes in children with ASD, especially for those diagnosed withi...

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“…Furthermore, our findings offer mechanistic evidence linking intrapartum hypoxia, oxidative stress, and persistent abnormalities in functional connectivity as the possible drivers of neurodevelopmental disorders observed after acute obstetric complications. [1][2][3][4][5][30][31][32][33][34] Disruption to the OXT-OXTR system could possibly play a role in the observed biochemical and behavioral abnormalities. We minimized this possibility by choosing a dose of OXT that was not associated with significant placental transfer in our model.…”

Section: Discussionmentioning

confidence: 99%

Transient uterine hypercontractility causes fetal cerebral oxidative stress and enduring mitochondrial and behavioral abnormalities in adolescent male rat offspring

Palanisamy¹,

Giri²,

Jiang³

et al. 2019

Preprint

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The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI imaging, we confirmed that oxytocininduced aberrant uterine hypercontractility significantly compromised uteroplacental perfusion.This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 h after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring.Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed malespecific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders. 8.2.1; GraphPad Software Inc.), behavioral data with SYSTAT12 (Chicago, IL), and fcOISI data with MATLAB. Study approval:All experiments reported here were approved by the Institutional Animal Care and Use Committee at Washington University in St. Louis (#20170010) and comply with the ARRIVE guidelines. Author contributionsAP conceived the study design, planned the experiments, and wrote the manuscript with help from all co-authors. AP, TG and JJ developed the OXT dosing paradigm and conducted the molecular biology experiments. JDQ and JRG performed the placental imaging experiments, analyzed the data, and helped draft the manuscript. SBC performed the behavioral experiments, and SEM and DFW conducted the analysis and helped with interpretation and drafting of the manuscript. AB and AQB collected, analyzed, and interpreted the fcOISI data, and helped write the manuscript.

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Understanding environmental contributions to autism: Causal concepts and the state of science

Cited by 144 publications

References 309 publications

Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats

Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

Transient uterine hypercontractility causes fetal cerebral oxidative stress and enduring mitochondrial and behavioral abnormalities in adolescent male rat offspring

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