Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
May 26, 2009
Introduction: As cited
below, glutathione (GSH) status and related genes are implicated in
many cases of autism. Some 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.
{Not posted at this time}
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.
Müller 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):313-21.
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