Glutathione & maternal infections during pregnancy: risk factors for autism


Senior Member
Glutathione & maternal infections during pregnancy: risk factors for autism

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.


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"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...

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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."

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"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}

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.

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