Propionic Acid Induces Gliosis and Neuro-inflammation through Modulation of PTEN/AKT Pathway in Autism Spectrum Disorder
With the number of children diagnosed with autism on the rise, the need to find what causes the disorder becomes more urgent every day.
UCF researchers are now a step closer to showing the link between the food pregnant women consume and the effects on a fetus’ developing brain.
2019 Study Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by glia over-proliferation, neuro-inflammation, perturbed neural circuitry, and gastrointestinal symptoms. The role of gut dys-biosis in ASD is intriguing and should be elucidated.
We investigated the effect of Propionic acid (PPA), a short-chain fatty acid (SCFA) and a product of dys-biotic ASD gut, on human neural stem cells (hNSCs) proliferation, differentiation and inflammation.
hNSCs proliferated to 66 neuropsheres when exposed to PPA versus 45 in control. The neurosphere diameter also increased at day 10 post PPA treatment to (Mean: 193.47 um ± SEM: 6.673 um) versus (154.16 um ± 9.95 um) in control, p < 0.001. Pre-treatment with β-HB, SCFA receptor inhibitor, hindered neurosphere expansion (p < 0.001). While hNSCs spontaneously differentiated to (48.38% ± 6.08%) neurons (Tubulin-IIIβ positive) and (46.63% ± 2.5%) glia (GFAP positive), PPA treatment drastically shifted differentiation to 80% GFAP cells (p < 0.05). Following 2 mM PPA exposure, TNF-α transcription increased 4.98 fold and the cytokine increased 3.29 fold compared to control (P < 0.001). Likewise, GPR41 (PPA receptor) and pro-survival p-Akt protein were elevated (p < 0.001). PTEN (Akt inhibitor) level decreased to (0.42 ug/ul ± 0.04 ug/ul) at 2 mM PPA compared to (0.83 ug/ul ± 0.09 ug/ul) in control (p < 0.001). PPA at 2 mM decreased neurite outgrowth to (80.70 um ± 5.5 um) compared to (194.93 um ± 19.7 um) in control.
Clearly, the data supports a significant role for PPA in modulating hNSC patterning leading to gliosis, disturbed neuro-circuitry, and inflammatory response as seen in ASD.
Reduced Amygdala–Prefrontal Functional Connectivity in Children With Autism Spectrum Disorder and Co-occurring Disruptive Behavior
Reduced connectivity between the amygdala and ventrolateral prefrontal cortex has been identified in children on the autism spectrum who exhibit disruptive behaviors, compared to those on the spectrum who do not. Findings suggest this distinct brain network could be independent of core autism symptoms.
More than a quarter of children with autism spectrum disorder are also diagnosed with disruptive behavior disorders. For the first time, Yale researchers have identified a possible biological cause: a key mechanism that regulates emotion functions differently in the brains of the children who exhibit disruptive behavior.
Neuroscience News reports, 21/04/2019.
2019 Study Abstract
Disruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity.
This cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age: 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control participants matched for age, gender, and IQ. During functional magnetic resonance imaging, participants completed an emotion perception task of fearful versus calm faces. Task-specific changes in amygdala reactivity and connectivity were examined using whole-brain, psychophysiological interaction, and multiple regression analyses.
Children with ASD and disruptive behavior showed reduced amygdala–vlPFC connectivity compared with children with ASD without disruptive behavior. Externalizing behaviors and callous-unemotional traits were associated with amygdala reactivity to fearful faces in children with ASD after controlling for suppressor effects.
Reduced amygdala–vlPFC connectivity during fear processing may differentiate children with ASD and disruptive behavior from children with ASD without disruptive behavior. The presence of callous-unemotional traits may have implications for identifying differential patterns of amygdala activity associated with increased risk of aggression in ASD. These findings suggest a neural mechanism of emotion dysregulation associated with disruptive behavior in children with ASD.
Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort
New research published in the American Journal of Psychiatry says that exposure to the notorious pesticide dichlorodiphenyltrichloroethane (DDT) during pregnancy could raise the risk of a child developing autism, ScienceAlert reports.
Autism is a complex neurodevelopmental disorder with a largely unknown etiology. To date, few studies have investigated prenatal exposure to toxins and risk of autism by using maternal biomarkers of exposure. Persistent organic pollutants are lipophilic halogenated organic compounds and include the insecticide dichlorodiphenyltrichloroethane (DDT), as well as its metabolite p,p′-dichlorodiphenyl dichloroethylene (p,p′-DDE), and polychlorinated biphenyls (PCBs). The objective of this study was to test whether elevated maternal levels of persistent organic pollutants are associated with autism among offspring.
The investigation was derived from the Finnish Prenatal Study of Autism, a national birth cohort study based on a nested case-control design. Cases of autism among children born between 1987 and 2005 were ascertained by national registry linkages. In cases of childhood autism and matched control subjects (778 matched case-control pairs), maternal serum specimens from early pregnancy were assayed for levels of p,p′-DDE and total levels of PCBs.
The odds of autism among offspring were significantly increased with maternal p,p′-DDE levels that were in the highest 75th percentile, with adjustment for maternal age, parity, and history of psychiatric disorders (odds ratio=1.32, 95% CI=1.02, 1.71). The odds of autism with intellectual disability were increased by greater than twofold with maternal p,p′-DDE levels above this threshold (odds ratio=2.21, 95% CI=1.32, 3.69). There was no association between total levels of maternal PCBs and autism.
These findings provide the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring. Although further research is necessary to replicate this finding, this study has implications for the prevention of autism and may provide a better understanding of its pathogenesis.
Exposure to polybrominated diphenyl ethers (PBDEs) and child behavior: Current findings and future directions
2018 Study Highlights
- Prenatal PBDEs are associated with executive function impairments and inattention.
- Prenatal and postnatal PBDE exposures increase externalizing problems in children.
- PBDEs’ association with internalizing, adaptive, and social behaviors is not clear.
- PBDE exposure adversely affects behavioral development in children.
Polybrominated diphenyl ethers (PBDEs) are recognized neurotoxicants, but the extent to which PBDEs influence various domains of behavior in children is not fully understood.
As such, we reviewed epidemiologic studies published to date to provide an overview of the current state of knowledge on PBDEs’ potential role in behavioral development.
We identified 19 epidemiologic studies reporting on associations of prenatal and childhood concentrations of PBDEs with behaviors assessed in children from 1 to 12 years, including executive function, attention, externalizing and internalizing behaviors, adaptive skills, and social behaviors/Autism Spectrum Disorder (ASD).
While the mechanisms of PBDE neurotoxicity in humans are still not clearly elucidated, findings from this review indicate that PBDE exposure during fetal development is associated with impairments in executive function and poorer attentional control in children. Results from large prospective cohorts demonstrate that prenatal and postnatal PBDE exposure adversely impacts externalizing behavior (e.g., hyperactivity and conduct problems). Additional studies are needed to determine whether PBDEs are associated with internalizing problems, adaptive skills, and social behaviors/ASD in children.
Future studies will help better understand the potential neurotoxic effects of PBDE exposures during adolescence, possible sex-dependent effects, and the impact of exposure to BDE-209 and alternative flame retardants. Future studies should also examine chemical mixtures to capture real-world exposures when examining PBDEs and their impact on various behavioral domains in the context of multiple chemical exposures.
Danish nationwide register based cohort study, 2017
What is already known on this topic
- Several studies have linked selective serotonin reuptake inhibitor use during pregnancy to autism spectrum disorder in offspring, although results have been conflicting
- The potential explanation for this association is that selective serotonin reuptake inhibitors cross the placental barrier and affect the development of the fetal brain
- If this holds true, in utero exposure to selective serotonin reuptake inhibitor and other classes of antidepressants may increase risk for various psychiatric disorders besides autism spectrum disorder
What this study adds
- Antidepressant use during pregnancy was associated with increased risk for various diagnostic groups of psychiatric disorders in offspring
- The observed associations may be attributable to the severity of underlying maternal psychiatric disorders in combination with in utero antidepressant exposure
To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders.
Population based cohort study.
Danish national registers.
905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk.
Exposures for observational studies
Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).
Main outcome measure
First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models.
Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.
In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.
- Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study, BMJ 2017;358:j3668, 06 September 2017.
- Characteristics of study population according to maternal antidepressant use before and during pregnancy. Values are numbers (percentages) unless stated otherwise, featured image credit bmj.
Anxiety Disorders Interview Schedule–Autism Addendum: Reliability and Validity in Children With Autism Spectrum Disorder
In children on the spectrum, anxiety is often masked by the symptoms of autism. But a new variant to a standard anxiety screening method has now proven effective in separating the two and it is leading to important diagnoses.
Assessing anxiety in autism spectrum disorder (ASD) is inherently challenging due to overlapping (e.g., social avoidance) and ambiguous symptoms (e.g., fears of change).
An ASD addendum to the Anxiety Disorders Interview Schedule–Child/Parent, Parent Version (ADIS/ASA) was developed to provide a systematic approach for differentiating traditional anxiety disorders from symptoms of ASD and more ambiguous, ASD-related anxiety symptoms.
Interrater reliability and convergent and discriminant validity were examined in a sample of 69 youth with ASD (8–13 years, 75% male, IQ = 68–143) seeking treatment for anxiety. The parents of participants completed the ADIS/ASA and a battery of behavioral measures. A second rater independently observed and scored recordings of the original interviews.
Treating anxiety is important in autism spectrum disorder because anxiety is associated with significantly more impairment for the child and their family.
Findings suggest reliable measurement of comorbid (intraclass correlation = 0.85–0.98, κ = 0.67–0.91) as well as ambiguous anxiety-like symptoms (intraclass correlation = 0.87–95, κ = 0.77–0.90) in children with ASD. Convergent and discriminant validity were supported for the traditional anxiety symptoms on the ADIS/ASA, whereas convergent and discriminant validity were partially supported for the ambiguous anxiety-like symptoms. Results provide evidence for the reliability and validity of the ADIS/ASA as a measure of traditional anxiety categories in youth with ASD, with partial support for the validity of the ambiguous anxiety-like categories. Unlike other measures, the ADIS/ASA differentiates comorbid anxiety disorders from overlapping and ambiguous anxiety-like symptoms in ASD, allowing for more precise measurement and clinical conceptualization. Ambiguous anxiety-like symptoms appear phenomenologically distinct from comorbid anxiety disorders and may reflect either symptoms of ASD or a novel variant of anxiety in ASD.
Study and Press Release
- Anxiety Disorders Interview Schedule–Autism Addendum: Reliability and Validity in Children With Autism Spectrum Disorder, Journal of Clinical Child & Adolescent Psychology, doi/full/10.1080/15374416.2016.1233501, 07 December 2016.
- Anxiety measure for children with autism proven reliable, Drexel University, December 8, 2016.
Help Fund Research into Neurodevelopment and Behavioral Impacts of DES
” My name is Jill Escher. I’m a science philanthropist who kickstarts pioneering research projects investigating the generational toxicity of certain potent exposures, including DES, tobacco and other drugs. While I’m not a DES daughter, I was exposed to a multitude of other synthetic steroid hormones in utero as part of a then-popular, if ineffective, “anti-miscarriage” practice. You can read my story here. You can see my science website at GermlineExposures.org.
Based on human, animal, and in vitro studies, as well as family interviews, I hypothesize that diethylstilbestrol DES, along with several other toxic substances, can damage the genomic information in early fetal-stage gametes. For a variety of reasons, the early gamete is probably the single most vulnerable stage of the human lifecycle. Damage during that phase, which could be genetic or epigenetic in nature, can manifest as abnormal development in the subsequent offspring.
For example, I hypothesize that the intensive synthetic steroid hormone drug regimen to which I was subjected as a fetus subtly deranged the molecular programming of my early eggs. This derangement I believe resulted in the starkly abnormal neurodevelopment — autism — of my children. I have met many other families with the same story.
Support Research into the Far-Reaching Generational Toxicity of DES, germline exposures, 10/10/2016.
Autism by pycik.
I am pleased to announce that I am funding the world’s first research study into the grandchild effects of DES (3d gen), looking specifically at neurodevelopment and behavioral impacts. This work will be done in collaboration with Harvard University, based on the Nurses’ Health Study II.
Thank you for your support! If you have any questions, please do not hesitate to email me. “
Jill Escher, President of Autism Society San Francisco Bay Area, 10/10/2016.
More DES DiEthylStilbestrol Resources
Out of the past – heritable effects of endocrine disruptors
Video published on 27 May 2016 by FSUMedMedia channel.
Presentation given by Jill Escher on April 8, 2016 at Florida State University’s Symposium on the Developing Brain.
More DES DiEthylStilbestrol Resources
Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population
New light has been shed on the genetic relationship between autistic spectrum disorders (ASD) and ASD-related traits in the wider population, by a team of international researchers including academics from the University of Bristol, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital (MGH).
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms.
Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning.
Autism genes are in all of us, new research reveals, University of Bristol, 21 March 2016.
This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder.
A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
Autism: early death risk a ‘hidden crisis’
A registry study conducted at Karolinska Institutet shows that the risk of premature death is about 2.5 times higher for people with autism spectrum disorder than for the rest of the population.
Mortality has been suggested to be increased in autism spectrum disorder (ASD).
To examine both all-cause and cause-specific mortality in ASD, as well as investigate moderating role of gender and intellectual ability.
Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27 122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2 672 185).
People with autism run a higher risk of premature death, Karolinska Institutet, 21 March 2016.
During the observed period, 24 358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38–2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability.
Premature mortality was markedly increased in ASD owing to a multitude of medical conditions.