Environmental Risk Factors and Biomarkers for Autism Spectrum Disorder: An Umbrella Review of the Evidence

Kim, Jong Yeob; Son, Min Ji; Son, Chei Yun; Raduà, Joaquim; Eisenhut, Michael; Gressier, Florence; Koyanagi, Ai; Carvalho, André F.; Stubbs, Brendon; Solmi, Marco; Rais, Theodor; Lee, Keum Hwa; Kronbichler, Andreas; Dragioti, Elena; Shin, Jae Il; Fusar‐Poli, Paolo

doi:10.2139/ssrn.3327365

Cited by 14 publications

(31 citation statements)

References 2 publications

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“…Yet, the majority of autistic disorders still remains of undetermined origin 4 . ASD causation and clinical pleiotropy involve a complex combination of interacting genetic, epigenetic and immunological factors, which in isolation are non‐causative 2,4–6 …”

Section: Autism Spectrum Disordermentioning

confidence: 99%

“…Studies of experimental models of MIA now take into account different infection types (e.g. viral versus bacterial, acute versus chronic), different gestational periods in which exposure occurs, additional maternal stressors such as hypernutrition and starvation 35 or known human maternal risk factors for neurodevelopmental disorders such as ageing or gestational metabolic syndromes 5,6 . In mice, offspring response to hostile postnatal events, such as maternal care by a surrogate mother, and gender‐specific factors are being evaluated 36 .…”

Section: On the Immune‐mediated Origin Of Asdmentioning

confidence: 99%

“…4 ASD causation and clinical pleiotropy involve a complex combination of interacting genetic, epigenetic and immunological factors, which in isolation are non-causative. 2,[4][5][6] The core autistic features, its onset and clinical trajectories may vary substantially, allowing clinicians to define distinct ASD subtypes. 2 Many individuals present with cognitive or psychiatric comorbidities and minor neurological or morphological atypia (e.g.…”

Section: Autism Spectrum Disordermentioning

confidence: 99%

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Immune regulation of neurodevelopment at the mother–foetus interface: the case of autism

et al. 2020

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and stereotypical behaviours. ASD’s aetiology remains mostly unclear, because of a complex interaction between genetic and environmental factors. Recently, a strong consensus has developed around ASD’s immune‐mediated pathophysiology, which is the subject of this review. For many years, neuroimmunological studies tried to understand ASD as a prototypical antibody‐ or cell‐mediated disease. Other findings indicated the importance of autoimmune mechanisms such as familial and individual autoimmunity, adaptive immune abnormalities and the influence of infections during gestation. However, recent studies have challenged the idea that autism may be a classical autoimmune disease. Modern neurodevelopmental immunology shows the double‐edged nature of many immune effectors, which can be either beneficial or detrimental depending on tissue homeostasis, stressors, neurodevelopmental stage, inherited and de novo gene mutations and other variables. Nowadays, mother–child interactions in the prenatal environment appear to be crucial for the occurrence of ASD. Studies of animal maternal–foetal immune interaction are being fruitfully carried out using different combinations of type and timing of infection, of maternal immune response and foetal vulnerability and of resilience factors to hostile events. The derailed neuroimmune crosstalk through the placenta initiates and maintains a chronic foetal neuroglial activation, eventually causing the alteration of neurogenesis, migration, synapse formation and pruning. The importance of pregnancy can also allow early immune interventions, which can significantly reduce the increasing risk of ASD and its heavy social burden.

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Section: Autism Spectrum Disordermentioning

confidence: 99%

Section: On the Immune‐mediated Origin Of Asdmentioning

confidence: 99%

Section: Autism Spectrum Disordermentioning

confidence: 99%

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Immune regulation of neurodevelopment at the mother–foetus interface: the case of autism

et al. 2020

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“…Various studies have looked for positive correlations between increased prevalence of ASD and in utero SSRI exposure. In a large meta-analysis of environmental risk factors for ASD, SSRI exposure was one of the associations that retained high level of significance (Kim et al, 2019). However, recent comprehensive reviews (Millard et al, 2017;Rotem-Kohavi and Oberlander, 2017), describe the lack of consensus among these clinical studies and meta-analyses.…”

Section: Introductionmentioning

confidence: 99%

“…However, recent comprehensive reviews (Millard et al, 2017;Rotem-Kohavi and Oberlander, 2017), describe the lack of consensus among these clinical studies and meta-analyses. While some report an increased risk of ASD following prenatal SSRI exposure (Boukhris et al, 2016;Croen et al, 2011;Kim et al, 2019), others have countered such conclusions (Malm et al, 2016;Sorensen et al, 2013;Suri et al, 2011). These inconsistencies in human studies, confounded by various factors such as the presence of psychiatric illness, or length of studies, highlight the need for a mechanistic approach to test whether early developmental exposure to SSRIs alone is sufficient to induce neurodevelopmental effects.…”

Section: Introductionmentioning

confidence: 99%

Early developmental exposure to Fluoxetine and Citalopram results in different neurodevelopmental outcomes

Liu

Garcia

Park

et al. 2019

Preprint

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Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for prenatal depression, there exists controversy over the adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated the outcomes of exposure to widely-used SSRIs fluoxetine and citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of citalopram and fluoxetine during a critical developmental period and found that the different groups of tadpoles displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, the citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for all three behaviors tested.Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function across groups; however, tectal cells from fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the citalopram group had increased K+ currents. Both the behavior and electrophysiological findings indicate that cells and circuits in the fluoxetine treated optic tecta are hyperexcitable, while the citalopram group exhibits decreased excitability. Taken all together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI used.This may explain some of the discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.

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Risk and protective factors for mental disorders beyond genetics: an evidence‐based atlas

et al. 2021

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Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer tain. We conducted a "metaumbrella" systematic synthesis of umbrella reviews, which are systematic reviews of metaanalyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on nonpurely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convinc ing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of metaanalyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 metaanalyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social con tacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For nonorganic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or fourfive (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention deficit/hyperactivity disorder (ADHD), they were maternal prepregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer's disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class IIII risk/protective factors were mostly involved in the early neurodevelopmental period. The evidencebased atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expand ing early intervention and preventive strategies for mental disorders.

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Environmental Risk Factors and Biomarkers for Autism Spectrum Disorder: An Umbrella Review of the Evidence

Abstract: Manuscript word count: 4455 words 4 5 Funding 1 None. 2 3

Cited by 14 publications

References 2 publications

Immune regulation of neurodevelopment at the mother–foetus interface: the case of autism

Immune regulation of neurodevelopment at the mother–foetus interface: the case of autism

Early developmental exposure to Fluoxetine and Citalopram results in different neurodevelopmental outcomes

Risk and protective factors for mental disorders beyond genetics: an evidence‐based atlas

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