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Glutathione & maternal infections during pregnancy: risk factors for autism

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Rosemary, Jul 8, 2010.

  1. Rosemary

    Rosemary Senior Member

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    Glutathione & maternal infections during pregnancy: risk factors for autism

    http://www.generationrescue.org/binstock/090526-Glutathione-maternal-infections.htm

    Teresa Binstock
    Researcher in Developmental & Behavioral Neuroanatomy

    Introduction: As cited below, glutathione (GSH) and related genes are implicated in many cases of autism. Some of the findings describe weak alleles of genes whose products participate in detoxification of various pollutants including mercury, thimerosal, and aluminum. For many years, researchers have known that adverse events during pregnancy (ie, suboptimality factors) are associated with autism. A finding by Zhu et al connects postnatal glutathione status with prenatal infections. Their study is titled, "Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide" (LPS; 16). The following mini-essay provides comments and citations regarding glutathione pathways in autism, with some attention given to infections and glutathione.

    ---------------

    Children with DSM-IV autism or other autism-spectrum disorders (ASDs) manifest a wide range of inter-individual differences, which may arise from etiologic and susceptibility factors specific to each individual. Aside from neurotropic viruses (eg, 1-2), pesticides (eg, 3-4), and pollutants including injectables (eg, 5-6, 7-8), adverse events during pre- and peri-natal periods are associated with autism and other ASDs (eg, 9-10).

    Consistent with obstetric suboptimality findings in autism (9-10), a growing body of evidence suggests mechanisms by which maternal infections may have been etiologically significant in altering brain development. For instance, maternal lipopolysaccharide (LPS) induces cytokines in amniotic fluid and also induces a stress hormone in the fetal brain (11). Furthermore, "Maternal immune activation alters fetal brain development through interleukin-6" (12); and "Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain" (13). Indeed, the cerebellar atypicality Bauman and Kemper erroneously presumed to have occurred always in utero (14) may in some cases have been caused by maternal infection during pregnancy (eg, 15).

    Dave A. Gayle and colleagues provide a succinct summary of prenatal infections in humans:
    "Maternal infections during pregnancy, including urinary tract and dental infections, have long been associated with the risk of preterm labor... and most recently with an increased risk of fetal neurological injury... Although likely acting via ascending rather than systemic routes, symptomatic vaginitis also is associated with an increase risk of preterm labor... In addition, intra-amniotic infection or chorioamnionitis may represent the etiology of spontaneous preterm labor in up to 37.5% of patients with intact membranes and 30% of patients with preterm rupture of membranes (15, 30, 33). Furthermore, chorioamnionitis may result from conservative therapy of preterm premature rupture of membranes, exposing infants to risks associated with an infected amniotic environment." (11;page R1024)

    We ought not infer that the findings reviewed by Gayle et al mean that all cases of autism had prenatal maternal infections as a predisposing factor. Instead and in accord with the aforementioned suboptimality findings in autism, infection during pregnancy may have contributed to some cases of autism or other autism-spectrum disorders (ASDs). Importantly, bacterial infection during pregnancy has been found to induce alterations in glutathione metabolism in the newborn (16). The GSH-infections study is free online.

    That prenatal LPS alters glutathione processing in the newborn is relevant to autism findings already published. For instance, glutathione pathways are affected in subgroups of autistic children (eg, 17-22); and reduced GSH-efficiency in these pathways contributes to impaired detoxification of mercury (23-24, see also 25) and aluminum (26-28), both of which are vaccine ingredients.

    Summary: An increasing number of findings implicate glutathione irregularity in many cases of autism. In some children with autism or a related ASD, prenatal infection may have contributed to atypical brain development via several mechanisms, including alteration of postnatal glutathione status. As suggested by the findings of Zhu et al (16), prenatal infection may have exacerbated glutathione difficulties, especially in children having one or more weak alleles in genes related to GSH.

    References:

    1. Acquired reversible autistic syndrome in acute encephalopathic illness in children.
    DeLong GR et al. Arch Neurol. 1981 Mar;38(3):191-4.

    2. Onset at age 14 of a typical autistic syndrome. A case report of a girl with herpes simplex encephalitis.
    Gillberg C. J Autism Dev Disord. 1986 Sep;16(3):369-75.

    3. Autistic syndrome with onset at age 31 years: herpes encephalitis as a possible model for childhood autism.
    Gillberg IC. Dev Med Child Neurol. 1991 Oct;33(10):920-4.

    4. Paraoxonase [PON1] gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions.
    D'Amelio et al. Mol Psychiatry. 2005 Nov;10(11):1006-16.

    5. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley.
    Roberts EM et al. Environ Health Perspect. 2007 Oct;115(10):1482-9.

    6. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley.
    Roberts EM et al. Environ Health Perspect. 2007 Oct;115(10):1482-9.

    7. From MMR to PDD via Acute Disseminated Encephalomyelitis...
    http://www.generationrescue.org/binstock/090305-ADEM-Binstock.htm

    8. Hepatitis B triple series vaccine and developmental disability in US children aged 1-9 years.
    Gallagher C, Goodman M. Toxicol Environ Chem 2008 90(5):997-1008.
    "The odds of receiving EIS [special education-related services] were approximately nine times as great for vaccinated boys... as for unvaccinated boys... after adjustment for confounders.

    9. Infantile autism: a total population study of reduced optimality in the pre-, peri-, and neonatal period.
    Gillberg C, Gillberg IC. J Autism Dev Disord. 1983 Jun;13(2):153-66.
    "Twenty-five autistic children, constituting a total population sample of children with infantile autism, were compared with 25 sex- and maternity-clinic-matched controls for occurrence of reduced optimality in the pre-, peri, and neonatal period, as noted in medical records. Autistic children showed greatly increased scores for reduced optimality, especially with regard to prenatal factors...

    10. Obstetrical suboptimality in autistic children.
    Bryson SE et al. J Am Acad Child Adolesc Psychiatry. 1988 Jul;27(4):418-22.

    11. Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain.
    Gayle DA et al. Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R1024-9.
    "LPS-induced mRNA changes included upregulation of the stress-related peptide corticotropin-releasing factor in the fetal whole brain, TNF-alpha, IL-6, and IL-10 in the chorioamnion, and TNF-alpha, IL-1 beta, and IL-6 in the placenta. These findings suggest that maternal infections may lead to an unbalanced inflammatory reaction in the fetal environment that activates the fetal stress axis."

    12. Maternal immune activation alters fetal brain development through interleukin-6.
    Smith SE et al. J Neurosci. 2007 Oct 3;27(40):10695-702.

    13. Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain.
    Urakubo A et al. Schizophr Res. 2001 Jan 15;47(1):27-36.

    14. The autism myth of in-utero timing.
    http://members.jorsm.com/~binstock/bk.htm

    15. Uteroplacental inflammation results in blood brain barrier breakdown, increased activated caspase 3 and lipid peroxidation in the late gestation ovine fetal cerebellum.
    Hutton LC et al. Dev Neurosci. 2007;29(4-5):341-54.
    "Placental lipopolysaccharide treatment had substantial effects on the fetal cerebellum, including increasing the number of cells undergoing apoptosis, widespread lipid peroxidation, and extravasation of plasma albumin, suggesting compromise of the cerebellar blood-brain barrier. These effects may account for some of the learning and motor deficits that emerge in neonates from pregnancies compromised by infection."

    16. Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide.
    Zhu Y et al. Neurochem Int. 2007 Mar;50(4):671-80. {free online}
    http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1868495&blobtype=pdf

    We previously reported that injection of bacterial lipopolysaccharide (LPS) into gravid female rats at embryonic day 10.5 resulted in a birth of offspring with fewer than normal dopamine (DA) neurons along with innate immunity dysfunction and many characteristics seen in Parkinson's disease (PD) patients. The LPS-exposed animals were also more susceptible to secondary toxin exposure as indicated by an accelerated DA neuron loss. Glutathione (GSH) is an important antioxidant in the brain. A disturbance in glutathione homeostasis has been proposed for the pathogenesis of PD. In this study, animals prenatally exposed to LPS were studied along with an acute intranigral LPS injection model for the status of glutathione homeostasis, lipid peroxidation, and related enzyme activities. Both prenatal LPS exposure and acute LPS injection produced a significant GSH reduction and increase in oxidized GSH (GSSG) and lipid peroxide (LPO) production. Activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, was up-regulated in acute supranigral LPS model but was reduced in the prenatal LPS model. The GCS light subunit protein expression was also down-regulated in prenatal LPS model. GSH redox recycling enzyme activities (glutathione peroxidase, GPx and glutathione reducdase, GR) and glutathione-S-transferase (GST), gamma-glutamyl transpeptidase (gamma-GT) activities were all increased in prenatal LPS model. Prenatal LPS exposure and aging synergized in GSH level and GSH-related enzyme activities except for those (GR, GST, and gamma-GT) with significant regional variations. Additionally, prenatal LPS exposure produced a reduction of DA neuron count in the substantia nigra (SN). These results suggest that prenatal LPS exposure may cause glutathione homeostasis disturbance in offspring brain and render DA neurons susceptible to the secondary neurotoxin insult.

    17. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
    James SJ et al. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.

    18. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype.
    Williams TA et al. Arch Pediatr Adolesc Med. 2007 Apr;161(4):356-61

    19. Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism.
    James SJ et al. J Autism Dev Disord. 2008 Nov;38(10):1966-75.

    20. Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15.
    Vojdani A et al. J Neuroimmunol. 2008 Dec 15;205(1-2):148-54.

    21. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism.
    James SJ et al. Am J Clin Nutr. 2009 Jan;89(1):425-30.

    22. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.
    James SJ et al. FASEB J. 2009 Mar 23. [Epub ahead of print]

    23. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization.
    Westphal GA et al. Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.

    24. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.
    James SJ et al. Neurotoxicology. 2005 Jan;26(1):1-8.

    25. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal.
    Mller M et al. Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.

    26. Aluminum decreases the glutathione regeneration by the inhibition of NADP-isocitrate dehydrogenase in mitochondria.
    Murakami K, Yoshino M. J Cell Biochem. 2004 Dec 15;93(6):1267-71

    27. Glutathione depletion promotes aluminum-mediated cell death of PC12 cells.
    Satoh E et al. Biol Pharm Bull. 2005 Jun;28(6):941-6.

    28. Aluminum-induced maternal and developmental toxicity and oxidative stress in rat brain: response to combined administration of Tiron and glutathione.
    Sharma P, Mishra KP. Reprod Toxicol. 2006 Apr;21(3):313-

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