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      Oxidative Stress, Maternal Diabetes, and Autism Spectrum Disorders

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      Oxidative Medicine and Cellular Longevity
      Hindawi

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          Abstract

          Autism spectrum disorders (ASD) are a group of early-onset neurodevelopmental conditions characterized by alterations in brain connectivity with cascading effects on neuropsychological functions. To date, in the framework of an increasing interest about environmental conditions which could interact with genetic factors in ASD pathogenesis, many authors have stressed that changes in the intrauterine environment at different stages of pregnancy, such as those linked to maternal metabolic pathologies, may lead to long-term conditions in the newborn. In particular, a growing number of epidemiological studies have highlighted the role of obesity and maternal diabetes as a risk factor for developing both somatic and psychiatric disorders in humans, including ASD. While literature still fails in identifying specific etiopathological mechanisms, a growing body of evidence is available about the presence of a relationship between maternal immune dysregulation, inflammation, oxidative stress, and the development of ASD in the offspring. In this framework, results from high-fat diet animal models about the role played by oxidative stress in shaping offspring neurodevelopment may help in clarifying the pathways through which maternal metabolic conditions are linked with ASD. The aim of this review is to provide an overview of literature about the effects of early life insults linked to oxidative stress which may be involved in ASD etiopathogenesis and how this relationship can be explained in biological terms.

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          Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.

          Exposure to prenatal infection has been suggested to cause deficiencies in fetal neurodevelopment. In this study we included all children born in Denmark from 1980, through 2005. Diagnoses of autism spectrum disorders (ASDs) and maternal infection were obtained through nationwide registers. Data was analyzed using Cox proportional hazards regression. No association was found between any maternal infection and diagnosis of ASDs in the child when looking at the total period of pregnancy: adjusted hazard ratio = 1.14 (CI: 0.96-1.34). However, admission to hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester were found to be associated with diagnosis of ASDs in the offspring, adjusted hazard ratio = 2.98 (CI: 1.29-7.15) and adjusted hazard ratio = 1.42 (CI: 1.08-1.87), respectively. Our results support prior hypotheses concerning early prenatal viral infection increasing the risk of ASDs.
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            The epidemiology of autism spectrum disorders.

            Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. They are much more common than previously believed, second in frequency only to mental retardation among the serious developmental disorders. Although a heritable component has been demonstrated in ASD etiology, putative risk genes have yet to be identified. Environmental risk factors may also play a role, perhaps via complex gene-environment interactions, but no specific exposures with significant population effects are known. A number of endogenous biomarkers associated with autism risk have been investigated, and these may help identify significant biologic pathways that, in turn, will aid in the discovery of specific genes and exposures. Future epidemiologic research should focus on expanding population-based descriptive data on ASDs, exploring candidate risk factors in large well-designed studies incorporating both genetic and environmental exposure data and addressing possible etiologic heterogeneity in studies that can stratify case groups and consider alternate endophenotypes.
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              A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

              Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2018
                5 November 2018
                : 2018
                : 3717215
                Affiliations
                Department of Clinical and Experimental Medicine, University of Pisa, Pisa 55100, Italy
                Author notes

                Guest Editor: Maria Luca

                Author information
                http://orcid.org/0000-0002-8296-7201
                Article
                10.1155/2018/3717215
                6247386
                528635fe-d911-4119-a5d4-98438e582685
                Copyright © 2018 Barbara Carpita et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 September 2018
                : 17 October 2018
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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