Article

Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism

Molecular Autism (Impact Factor: 5.49). 01/2013; 4(1):2. DOI: 10.1186/2040-2392-4-2
Source: PubMed

ABSTRACT Background
The mitochondrial genome (mtDNA) is particularly susceptible to damage mediated by reactive oxygen species (ROS). Although elevated ROS production and elevated biomarkers of oxidative stress have been found in tissues from children with autism spectrum disorders, evidence for damage to mtDNA is lacking.

Findings
mtDNA deletions were evaluated in peripheral blood monocytic cells (PBMC) isolated from 2–5 year old children with full autism (AU; n = 67), and typically developing children (TD; n = 46) and their parents enrolled in the CHildhood Autism Risk from Genes and Environment study (CHARGE) at University of California Davis. Sequence variants were evaluated in mtDNA segments from AU and TD children (n = 10; each) and their mothers representing 31.2% coverage of the entire human mitochondrial genome. Increased mtDNA damage in AU children was evidenced by (i) higher frequency of mtDNA deletions (2-fold), (ii) higher number of GC→AT transitions (2.4-fold), being GC preferred sites for oxidative damage, and (iii) higher frequency of G,C,T→A transitions (1.6-fold) suggesting a higher incidence of polymerase gamma incorporating mainly A at bypassed apurinic/apyrimidinic sites, probably originated from oxidative stress. The last two outcomes were identical to their mothers suggesting the inheritance of a template consistent with increased oxidative damage, whereas the frequency of mtDNA deletions in AU children was similar to that of their fathers.

Conclusions
These results suggest that a combination of genetic and epigenetic factors, taking place during perinatal periods, results in a mtDNA template in children with autism similar to that expected for older individuals.

Download full-text

Full-text

Available from: Eleonora Napoli, Apr 28, 2014
1 Follower
 · 
93 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disorder that is characterized by isolated glucocorticoid deficiency. Recently, mutations in the gene encoding for the mitochondrial nicotinamide nucleotide transhydrogenase (NNT) have been identified as a causative gene for FGD; however, no NNT activities have been reported in FGD patients carrying NNT mutations.Methods Clinical, biochemical and molecular analyses of lymphocytes from FDG homozygous and heterozygous carriers for the F215S NNT mutationResultsIn this study, we described an FGD-affected Japanese patient carrying a novel NNT homozygous mutation (c.644 T > C; F215S) with a significant loss-of-function (NNT activity = 31% of healthy controls) in peripheral blood cells' mitochondria. The NNT activities of the parents, heterozygous for the mutation, were 61% of controls.Conclusions Our results indicated that (i) mitochondrial biogenesis (citrate synthase activity) and/or mtDNA replication (mtDNA copy number) were affected at ≤ 60% NNT activity because these parameters were affected in individuals carrying either one or both mutated alleles; and (ii) other outcomes (mtDNA deletions, protein tyrosine nitration, OXPHOS capacity) were affected at ≤ 30% NNT activity as also observed in murine cerebellar mitochondria from C57BL/6 J (NNT-/-) vs. C57BL/6JN (NNT+/+) substrains.General significanceBy studying a family affected with a novel point mutation in the NNT gene, a gene-dose response was found for various mitochondrial outcomes providing for novel insights into the role of NNT in the maintenance of mtDNA integrity beyond that described for preventing oxidative stress.KeywordsFamilial glucocorticoid deficiencymitochondrial biogenesismitochondrial replicationnicotinamide nucleotide transhydrogenaseoxidative phosphorylationoxidative stress
    06/2015; 3. DOI:10.1016/j.bbacli.2014.12.003
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorder (ASD) is a developmental disorder with increasing prevalence worldwide, yet with unclear etiology. To explore the association between maternal exposure to particulate matter (PM) air pollution and odds of ASD in her child. We conducted a nested case-control study of participants in the Nurses' Health Study II (NHS II), a prospective cohort of 116,430 US female nurses recruited in 1989, followed by biennial mailed questionnaires. Subjects were NHS II participants' children born 1990-2002 with ASD (n=245), and children without ASD (n=1522) randomly selected using frequency matching for birth years. ASD was based on maternal report, which was validated against the Autism Diagnostic Interview-Revised in a subset. Monthly averages of PM with diameters ≤2.5 µm (PM2.5) and 2.5-10 µm (PM10-2.5) were predicted from a spatiotemporal model for the continental US and linked to residential addresses. PM2.5 exposure during pregnancy was associated with increased odds of ASD, with an adjusted odds ratio (OR) for ASD per interquartile range higher PM2.5 (4.42 µg/m(3)) of 1.57 (95% CI: 1.22, 2.03) among women with the same address before and after pregnancy (160 cases, 986 controls). Associations with PM2.5 exposure 9 months before or after the pregnancy were weaker in independent models and null when all three time periods were included, while the association with the 9 months of pregnancy remained (OR=1.63; 95% CI: 1.08-2.47). The association between ASD and PM2.5 was stronger for exposure during the third trimester (OR=1.42 per inter-quartile range increase in PM2.5, 95% CI: 1.09, 1.86) than other trimesters (ORs 1.06 and 1.00) when mutually adjusted. There was little association between PM10-2.5 and ASD. Higher maternal exposure to PM2.5 during pregnancy, in particular the third trimester, was associated with greater odds of her child having ASD.
    Environmental Health Perspectives 12/2014; DOI:10.1289/ehp.1408133 · 7.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is a mixture comprised of several components, of which ultrafine particulate matter (UFPM; <100 nm) is of much concern, as these particles can enter the circulation and distribute to most organs, including the brain. A major constituent of ambient UFPM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution may lead to neurotoxicity. In addition to a variety of behavioral abnormalities, two prominent effects caused by air pollution are oxidative stress and neuroinflammation, which are seen in both humans and animals and are confirmed by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered the most relevant. Human and animal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiology of neurodevelopmental disorders, including autistic spectrum disorders. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies.
    01/2014; 2014:736385. DOI:10.1155/2014/736385