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Methylglyoxal, advanced glycation end products and autism: Is there a connection?
Medical Hypotheses 78 (2012) 548–552
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Methylglyoxal, advanced glycation end products and autism: Is there a connection? P. Maher ⇑ The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA
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Article history: Received 1 August 2011 Accepted 16 January 2012
a b s t r a c t Autism is a complex and heterogeneous neurodevelopmental disorder of unknown etiology but very likely resulting from both genetic and environmental factors. Recent estimates suggest that it affects 1 in 100–150 individuals in the US. Oxidative stress, inflammation and mitochondrial dysfunction have all been suggested to play key roles in autism and may be linked via alterations in cellular redox homeostasis. The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells and as such plays a critical role in regulating redox-dependent cellular functions. A number of studies have shown that variations in genes involved in GSH metabolism are associated with autism. GSH also modulates the activity of glyoxalase 1 (Glo-1), the rate-limiting enzyme for the removal of reactive dicarbonyls such as methylglyoxal (MG). MG is the major precursor for the formation of advanced glycation end products (AGEs). Both MG and AGEs can induce oxidative stress, inflammation and mitochondrial dysfunction and are implicated in diabetic complications and multiple, age-related neurological diseases. Dietary consumption of AGEs and MG correlates with food intake which has increased 20–30% over the past 20 years. Both MG and AGEs are orally absorbed, leading to increased levels in the blood. Furthermore, in humans, increased MG and AGE levels in maternal blood correlate with increased MG and AGE levels in newborn blood, potentially exposing infants to high oxidative stress and inflammation. It is hypothesized that diet derived MG and AGEs in combination with inborn genetic vulnerabilities that affect the cellular redox status are major contributors to the development of autism and provide a causal link between oxidative stress, inflammation and mitochondrial dysfunction. If future research supports this hypothesis, then by reducing the exposure to these diet-derived factors, it might be possible to decrease the prevalence of at least a subset of autism cases. Ó 2012 Elsevier Ltd. All rights reserved.
Background Autism is a heterogeneous neurodevelopmental disorder defined by a broad spectrum of atypical social, cognitive and verbal behaviors along with repetitive and sometimes self-injurious actions. Despite affecting an increasing number of children, there are no effective treatments for the disorder [1]. Although the exact causes of autism are unknown, many investigators believe that it is likely the result of a combination of genetic vulnerabilities and environmental insults interacting at a critical stage of development [1,2]. Since there is a wide variation in the symptoms and severity of autism, the contribution of each of these factors may vary from patient to patient [3]. Oxidative stress, inflammation and mitochondrial dysfunction have all been suggested to play key roles in autism [4–6] and may be linked via alterations in cellular redox homeostasis. The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells (Fig. 1) and as such plays a critical role in regulating redox-dependent cellular functions [7]. Further⇑ Tel.: +1 858 453 4100x1932; fax: +1 858 535 9062. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2012.01.032
more, GSH and GSH-associated metabolism provide the major line of defense for the protection of cells from oxidative and other forms of toxic stress. Indeed, an impairment in GSH status is thought to be the precipitating event in a wide range of neurological disorders [8]. Therefore, even mild disruptions in GSH metabolism could have a major impact on brain development, particularly in the presence of precipitating environmental factors. Indeed, the induction of transitory GSH depletion during brain development in the rat resulted in cognitive impairment in both juvenile and adult rats [9]. Perhaps the best evidence for the necessity of maintaining proper redox homeostasis for normal brain development comes from studies with oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells [10]. These cells give rise to the myelin-forming oligodendrocytes of the CNS. Pure populations of these cells can be prepared and induced to undergo either proliferation or differentiation by growth in defined media. In a series of elegant studies, Noble et al. first showed [10] that the balance between proliferation and differentiation in O-2A cells could be modulated by manipulation of the intracellular redox state such that a more reducing environment maintained proliferation while a more oxidizing environment promoted differentiation. Furthermore, growth of
P. Maher / Medical Hypotheses 78 (2012) 548–552
Fig. 1. Outline of GSH metabolism. GSH is synthesized from glutamate (glu), cysteine (cys) and glycine (gly) by the sequential actions of glutamate cysteine ligase (GCL) and glutathione synthase (GS). GSH is used to eliminate reactive oxygen species such as hydrogen peroxide (H2O2) and lipid hydroperoxides (LOOH) in a reaction catalyzed by glutathione peroxidases (GPX). The glutathione disulfide (GSSG) produced in this reaction can be converted back to GSH through the action of glutathione reductase (GR). GR requires NADPH for its activity which is mainly supplied from the activity of glucose-6-phosphate dehydrogenase (G6PD), the first enzyme of the pentose phosphate shunt. GSH can also be used to detoxify endogenous and exogenous electrophiles (X) through conjugation via the glutathione-S-transferases (GST).
the cells in the presence of endogenous factors that stimulated proliferation was associated with a more reduced redox state while growth in the presence of endogenous factors that promote differentiation correlated with an increase in intracellular oxidation. Thus, these studies suggested that extracellular factors can promote a more oxidizing or reducing environment in cells and thereby play an important role in regulating the intracellular redox environment and, in consequence, cell fate. In further studies, the same group showed that compounds that make the O-2A progenitor cells more oxidized promote differentiation by reducing the level of receptors for growth factors such as platelet derived growth factor that stimulate proliferation [11]. Similar results were obtained with neural progenitor cells (NPCs) where an oxidizing environment was shown to both inhibit proliferation and stimulate differentiation into astrocytes [12]. This result is consistent with experiments in PC12 cells where nerve growth factor-induced differentiation was enhanced by treatments which decreased the GSH/GSSG ratio thereby inducing a more oxidizing environment and inhibited by treatments which increased the GSH/GSSG ratio, inducing a more reducing environment [13]. Thus, during brain development, GSH loss and/or oxidation could cause premature differentiation of neural cells resulting in inappropriate changes in neuronal and/or glial cell populations. An additional cell fate that is regulated by the cellular redox state is death. Recent studies in nerve cells have demonstrated that GSH can directly regulate apoptosis through two distinct mechanisms: Its interaction with the pro-survival protein Bcl-2 [14] and its inhibition of cytosolic cytochrome C [15]. Studies by Zimmerman et al. [14] showed that Bcl-2 interacts directly with GSH and thereby regulates an essential pool of mitochondrial GSH. Disruption of this interaction leads to mitochondrial oxidative stress and death in primary cultures of nerve cells. Vaughn and Deshmukh [15] showed that the redox environment and specifically GSH levels directly regulate the apoptosis-initiating function of cytosolic cytochrome C in nerve cells by maintaining it in a reduced and therefore less pro-apoptotic form. GSH depletion promotes both a more oxidized redox environment and increased nerve cell death. Among the susceptibility genes implicated in autism are a number involved in the maintenance of GSH metabolism [16–19]. These include glutathione peroxidase [17], several glutathione transferases [16,19], glutaredoxin [18], cystathione gamma lyase [18] and glutamate cysteine ligase [18]. The enzymes encoded by these genes are either involved in GSH synthesis (glutamate cysteine ligase, cystathione gamma lyase), regeneration (glutathione peroxidase) or GSH-mediated detoxification (glutathione transfer-
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ases, glutaredoxin) (Fig. 1). Defects in GSH metabolism in autism are consistent with observations from several laboratories showing that total and reduced GSH levels are significantly lower in the blood of autistic children as compared to normal, age-matched controls, while oxidized GSH is significantly increased [e.g. [16]]. Another gene recently identified as an autism susceptibility factor is glyoxalase 1 (Glo-1) [20]. Glo-1 catalyzes the first and rate-limiting step in the removal of methylglyoxal (MG), a highly reactive dicarbonyl linked to mitochondrial dysfunction, oxidative stress and immune system activation [21]. Importantly, Glo-1 is absolutely dependent on GSH for activity, so disruptions in GSH metabolism will also impact Glo-1 function. MG, along with other reducing sugars such as fructose, is an advanced glycation end product (AGE) precursor. MG is the major contributor to the generation of both intracellular and extracellular AGEs [22]. AGEs are a heterogeneous group of macromolecules that are formed by the non-enzymatic glycation of proteins, lipids and nucleic acids. Humans are exposed to two sources of AGEs: exogenous AGEs that are ingested in foods and endogenous AGEs that are formed in the body [23]. Similarly, the AGE precursor MG can either be ingested in foods [24,25] or formed endogenously as a by-product of glycolysis [21] AGEs interact with the receptor for AGEs (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface receptors resulting in sustained upregulation of inflammatory mediators including tumor necrosis factor a (TNFa), interleukin 6 (IL-6) and C-reactive protein (CRP) [26] as well as activation of NADPH oxidase to produce superoxide [27]. MG and AGEs can also directly increase inflammatory responses in endothelial cells in vitro [28] and the colon in vivo [29]. There is evidence for immune system activation in both the mothers of autistic children as well as the children themselves [30]. Immune system activation during pregnancy has been shown to lead to abnormal gene regulation and brain atrophy in offspring as well as behavioral changes that replicate some of those seen in autism [5]. Importantly, high levels of maternal IL-6 have been implicated in alterations in fetal brain development and impaired social behavior in offspring [5]. Increased levels of IL-6 and TNFa have also been found in brain specimens and cerebral spinal fluid (CSF) from both young and old individuals with autism [30]. AGEs are increasingly prevalent in the diet [23,31]; their presence is dependent upon the type of food and its temperature and method of cooking. In general, foods with higher fat and protein contents have the highest AGE levels [32]. Within these groups, high heat treated foods such as deep-fried potatoes, cookies and fried meat have much higher levels of AGEs [33]. A major impetus for this high temperature processing is that AGEs significantly enhance the flavor, smell and appearance of food products thereby serving as ‘‘appetite enhancing’’ agents [34]. Food intake, as defined by total daily energy consumption, and especially processed food intake, has increased on average by 20–30% over the past few decades in the US [35]. Thus, it is likely that exposure to dietary AGEs and AGE precursors has increased by a similar or greater amount. Dietary AGEs are readily absorbed by humans with 10% of a single AGE-rich protein preparation making it to the bloodstream [34]. In a kinetic study in rats, AGEs were found to be absorbed mostly as single, di- and tri-peptides and 66% remained in contact with tissues for >72 h [34]. Ingestion of an AGE-enriched diet by mice resulted in enhanced levels of both serum and tissue AGEs and increases in markers of oxidative stress [36]. Similarly, short term feeding studies in humans with an AGE-enriched diet led to increases in serum AGEs and markers of inflammation [37] as well as an increase in markers of oxidative stress [38]. Very recently, it was shown that there is a significant correlation between the levels of MG and AGEs in maternal and newborn blood [39]. Furthermore, AGE levels in infant blood significantly increased following the introduction of processed infant food [39]. Indeed, both infant for-
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P. Maher / Medical Hypotheses 78 (2012) 548–552
Fig. 2. Changes in autism prevalence, maternal obesity, gestational diabetes and diabetes in women of child bearing age over the past 20 years. (A) Changes in average autism prevalence (per 1000) in US, UK and Canada [1,50,58], % of women with diabetes in Canada [57], % of women with gestational diabetes in the US [60] and % of maternal obesity in the UK [54] are plotted versus time. (B) Autism prevalence is plotted versus percent women of child bearing age with diabetes and the correlation coefficient calculated by linear regression analysis. (C) Autism prevalence is plotted versus percent women gestational diabetes and the correlation coefficient calculated by linear regression analysis. (D) Autism prevalence is plotted versus percent maternal obesity and the correlation coefficient calculated by linear regression analysis.
mula [23] and sterilized milk [40] have very high levels of AGEs compared with breast milk. MG is also very prevalent in the human diet particularly in sugar-containing soft drinks [24,25] and coffee [41]. Importantly, administration of low levels of MG via the drinking water to mice in utero and continuing after birth significantly decreased blood GSH levels in the adult mice [42]. Similar decreases in blood GSH levels are seen in children with autism [16]. Along with inflammation and oxidative stress, mitochondrial dysfunction is also associated with autism [6,43]. Mitochondrial dysfunction can result from genetic mutations, but this does not seem to be the case for the vast majority of autism patients [43]. Since GSH is the major antioxidant in mitochondria [44], decreases in GSH can directly impact mitochondrial function [45]. Consistent with this idea, lymphoblastoid cells from autistic subjects were shown to have lower levels of mitochondrial GSH as compared with the same cells from age-matched controls [46]. Serum lactate is often used as a surrogate marker of mitochondrial dysfunction and increases in serum lactate levels are frequently found in autistic subjects [6,43]. Lactate is the major end product of anaerobic respiration, and is elevated in response to mitochondrial dysfunction. Importantly, increases in anaerobic metabolism also lead to increases in MG since it is a by-product of glycolysis [21]. In addition, MG itself has been shown to impair mitochondrial function [47], and the overexpression of the MG-degrading enzyme Glo-1 in worms decreases MG-dependent modification of mitochondrial proteins and mitochondrial dys-
function [48]. Thus, a vicious cycle could be established whereby mild mitochondrial dysfunction brought about by a combination of genetic vulnerabilities and an AGE-rich diet could lead to increased glycolysis thereby enhancing the production of MG and leading to more severe mitochondrial dysfunction. Hypothesis Based on these observations, I propose that a combination of inborn genetic vulnerabilities affecting GSH metabolism, Glo-1 and/or mitochondrial function coupled with increased dietary exposure to AGEs and/or the AGE precursor MG could lead to neuropathological changes in the brain and the subsequent behavioral deficits that are characteristic of autism. This hypothesis ties together a number of the observations that have been made regarding the pathophysiological factors underlying autism and suggests an interconnectedness between three factors that have been postulated to play key roles in autism: Oxidative stress, inflammation and mitochondrial dysfunction. Although the idea that a combination of susceptibility genes and environmental factors gives rise to autism is not novel, the hypothesis that diet-derived AGEs and AGE precursors are a key environmental factor in the development of autism is novel. In addition, although both endogenous and dietary AGEs have been associated with diabetes [34] and age-related neurological disorders [22,49], they have not been considered in the context of autism despite evi-
P. Maher / Medical Hypotheses 78 (2012) 548–552
dence that these dietary glycotoxins can cause oxidative stress and inflammation in infants [39]. This hypothesis not only addresses several of the unanswered questions regarding autism but it is readily testable in both animal models and humans. First, and perhaps most importantly, the prevalence of autism in the US has increased significantly over the past 30 years [1,50]. While part of that increase in prevalence can be explained by other factors such as changes in diagnostic criteria, at least 60% appears to represent a real increase [1]. The dietary intake of AGEs has also increased over this period and is postulated to play a key role in the diabetes epidemic [34]. Second, as indicated, autism is extremely heterogeneous [3]. This could readily be explained by distinct arrays of genetic vulnerabilities coupled with different levels of exposure to MG and AGEs both in utero and postnatally which could give rise to a range of symptoms. Third, a very recent study in mono- and di-zygotic twins provided evidence that environmental factors common to both types of twins can explain about 55% of the liability to autism [2]. This observation is consistent with the similar levels of both pre- and post-natal exposure to AGEs and AGE precursors that would be expected to be experienced by both types of twins. Fourth, there are reports that autism symptoms can improve in some children [e.g. [51]]. This could be explained by changes in the diet that would reduce exposure to AGEs and/or MG thereby alleviating their impact on the brain. Predictions Since both obesity and diabetes [34] are associated with higher exposure to AGEs, this hypothesis predicts that there would be an association between these disorders in mothers and higher rates of autism in their offspring. The limited epidemiological studies on this question suggest that this may be the case. First, on a general level, the prevalence of overweight and obesity [52–54] as well as diabetes [55–57] in women of child bearing age in the US, Canada and the UK has increased over the same time frame as the increase in autism [1,50,58] (Fig. 2). One study showed that for mothers with a body mass index (BMI) of 30 or greater at age 18 there was a twofold increase in the risk of having an autistic child [59]. The prevalence of gestational diabetes also increased dramatically between 1989 and 2004 in the US [60] (Fig. 2). A meta-analysis of studies which looked at prenatal risk factors for autism found that gestational diabetes was associated with a twofold increase in the risk of autism [61]. The main therapeutic prediction of this hypothesis is that reducing the exposure of embryos/infants to MG and AGEs can decrease the prevalence of autism. However, exposure to MG and/or AGEs could occur via the mother during pregnancy and/or after birth via the mother’s milk and/or infant and baby food. At this time it is not clear when the critical exposure period would be. Thus, it may be prudent to reduce the exposure to MG and AGEs both in utero and postnatally until further studies are carried out. In addition, it might be possible to do some of these studies in mouse models of autism such as the BTBR mouse. This is a genetically homogeneous inbred strain of mice that displays behavioral traits that reflect all three diagnostic symptoms of autism, including abnormal social interactions, impaired communication and repetitive behaviors [62]. Offspring and/or their mothers could be fed either a normal diet or a low-AGE diet [e.g. [36]] and their behavior tested for characteristics of autism at adulthood. While it is acknowledged that mice are not humans, these types of studies could provide an indication of the window of vulnerability for the exposure to AGEs and AGE precursors that promotes the development of autistic behavior. In summary, I propose that a previously unexplored environmental factor, dietary glycotoxins, plays a key role in the develop-
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ment of at least a subset of autism cases. This hypothesis is readily testable and, if correct, could provide a cost effective and broadly applicable approach to reduce the prevalence of this disorder. Conflict of interest statement The author declares that there are no conflicts of interest. Acknowledgments This work was supported by a grant from the not-for-profit Fritz B. Burns Foundation. The author would like to thank Drs. David Schubert and Michael Nunn for critical reading of the manuscript. References [1] Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 2010;23:103–10. [2] Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011. doi:10.1001/archgenpsychiatry.2011.7. [3] Frith U, Happe F. Autism spectrum disorder. Curr Biol 2005;15:R786–90. [4] Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiol 2006;13:171–81. [5] Parker-Athill EC, Tan J. Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway. Neurosignals 2010;18:113–28. [6] Palmieri L, Persico AM. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta 2010;1797:1130–7. [7] Lewerenz J, Maher P. Control of redox state and redox signaling by neural antioxidant systems. Antioxid Redox Signal 2011;14:1449–65. [8] Bains JS, Shaw CA. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev 1997;25:335–58. [9] Cabungcal J-H, Preissmann D, Delseth C, Cuenod M, Do KQ, et al. Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis 2007;26:634–45. [10] Noble M, Smith J, Power J, Mayer-Proschel M. Redox state as a central modulator of precursor cell function. Ann NY Acad Sci 2003;991:251–71. [11] Li Z, Dong T, Proschel C, Noble M. Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 2007;5:212–31. [12] Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schroter F, et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 2008;10:385–94. [13] Kamata H, Oka S-i, Shibukawa Y, Kakuta J, Hirata H. Redox regulation of nerve growth factor-induced neuronal differentiation of PC12 cells through modulation of the nerve growth factor receptor, TrkA. Arch Biochem Biophys 2005;434:16–25. [14] Zimmerman AK, Loucks FA, Schroeder EK, Bouchard RJ, Tyler KL, et al. Glutathione binding to the Bcl-2 homology-3 domain groove. J Biol Chem 2007;282:29296–304. [15] Vaughn AE, Deshmukh M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome C. Nat Cell Biol 2008;10:1477–83. [16] James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B 2006;141B:947–56. [17] Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH, et al. Genetic variant of glutathione peroxidase 1 in autism. Brain Dev 2010;32:105–9. [18] Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, et al. Glutathione pathway gene variation and risk of autism spectrum disorders. J Neurodevelop Disord 2011. doi:10.1007/s11689-011-9077-. [19] Williams TA, Mars AE, Byske SG, Stenroos ES, Wang R, et al. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med 2007;161:356–61. [20] Barua M, Jenkins EC, Chen W, Kuizon S, Pullarkat RK, et al. Glyoxalase 1 polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity-implications for autism. Autism Res 2011;4:1–9. [21] Thornalley PJ. Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems-role in ageing and disease. Drug Metabol Drug Interact 2008;23:125–50. [22] Desai KM, Chang T, Wang H, Banigesh A, Dhar A, et al. Oxidative stress and aging: is methylglyoxal the hidden enemy? Can J Physiol Pharmacol 2010;88:273–84. [23] Semba RD, Nicklett EJ, Ferrucci L. Does accumulation of advance glycation end products contribute to the aging phenotype. J Gernotol 2010;65A:963–75. [24] Tan D, Wang Y, Lo C-Y, Sang S, Ho C-T. Methylglyoxal: its presence in beverages and potential scavengers. Ann N Y Acad Sci 2008;1126:72–5.
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Methylglyoxal, advanced glycation end products and autism: Is there a connection? P. Maher ⇑ The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA
a r t i c l e
i n f o
Article history: Received 1 August 2011 Accepted 16 January 2012
a b s t r a c t Autism is a complex and heterogeneous neurodevelopmental disorder of unknown etiology but very likely resulting from both genetic and environmental factors. Recent estimates suggest that it affects 1 in 100–150 individuals in the US. Oxidative stress, inflammation and mitochondrial dysfunction have all been suggested to play key roles in autism and may be linked via alterations in cellular redox homeostasis. The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells and as such plays a critical role in regulating redox-dependent cellular functions. A number of studies have shown that variations in genes involved in GSH metabolism are associated with autism. GSH also modulates the activity of glyoxalase 1 (Glo-1), the rate-limiting enzyme for the removal of reactive dicarbonyls such as methylglyoxal (MG). MG is the major precursor for the formation of advanced glycation end products (AGEs). Both MG and AGEs can induce oxidative stress, inflammation and mitochondrial dysfunction and are implicated in diabetic complications and multiple, age-related neurological diseases. Dietary consumption of AGEs and MG correlates with food intake which has increased 20–30% over the past 20 years. Both MG and AGEs are orally absorbed, leading to increased levels in the blood. Furthermore, in humans, increased MG and AGE levels in maternal blood correlate with increased MG and AGE levels in newborn blood, potentially exposing infants to high oxidative stress and inflammation. It is hypothesized that diet derived MG and AGEs in combination with inborn genetic vulnerabilities that affect the cellular redox status are major contributors to the development of autism and provide a causal link between oxidative stress, inflammation and mitochondrial dysfunction. If future research supports this hypothesis, then by reducing the exposure to these diet-derived factors, it might be possible to decrease the prevalence of at least a subset of autism cases. Ó 2012 Elsevier Ltd. All rights reserved.
Background Autism is a heterogeneous neurodevelopmental disorder defined by a broad spectrum of atypical social, cognitive and verbal behaviors along with repetitive and sometimes self-injurious actions. Despite affecting an increasing number of children, there are no effective treatments for the disorder [1]. Although the exact causes of autism are unknown, many investigators believe that it is likely the result of a combination of genetic vulnerabilities and environmental insults interacting at a critical stage of development [1,2]. Since there is a wide variation in the symptoms and severity of autism, the contribution of each of these factors may vary from patient to patient [3]. Oxidative stress, inflammation and mitochondrial dysfunction have all been suggested to play key roles in autism [4–6] and may be linked via alterations in cellular redox homeostasis. The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells (Fig. 1) and as such plays a critical role in regulating redox-dependent cellular functions [7]. Further⇑ Tel.: +1 858 453 4100x1932; fax: +1 858 535 9062. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2012.01.032
more, GSH and GSH-associated metabolism provide the major line of defense for the protection of cells from oxidative and other forms of toxic stress. Indeed, an impairment in GSH status is thought to be the precipitating event in a wide range of neurological disorders [8]. Therefore, even mild disruptions in GSH metabolism could have a major impact on brain development, particularly in the presence of precipitating environmental factors. Indeed, the induction of transitory GSH depletion during brain development in the rat resulted in cognitive impairment in both juvenile and adult rats [9]. Perhaps the best evidence for the necessity of maintaining proper redox homeostasis for normal brain development comes from studies with oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells [10]. These cells give rise to the myelin-forming oligodendrocytes of the CNS. Pure populations of these cells can be prepared and induced to undergo either proliferation or differentiation by growth in defined media. In a series of elegant studies, Noble et al. first showed [10] that the balance between proliferation and differentiation in O-2A cells could be modulated by manipulation of the intracellular redox state such that a more reducing environment maintained proliferation while a more oxidizing environment promoted differentiation. Furthermore, growth of
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Fig. 1. Outline of GSH metabolism. GSH is synthesized from glutamate (glu), cysteine (cys) and glycine (gly) by the sequential actions of glutamate cysteine ligase (GCL) and glutathione synthase (GS). GSH is used to eliminate reactive oxygen species such as hydrogen peroxide (H2O2) and lipid hydroperoxides (LOOH) in a reaction catalyzed by glutathione peroxidases (GPX). The glutathione disulfide (GSSG) produced in this reaction can be converted back to GSH through the action of glutathione reductase (GR). GR requires NADPH for its activity which is mainly supplied from the activity of glucose-6-phosphate dehydrogenase (G6PD), the first enzyme of the pentose phosphate shunt. GSH can also be used to detoxify endogenous and exogenous electrophiles (X) through conjugation via the glutathione-S-transferases (GST).
the cells in the presence of endogenous factors that stimulated proliferation was associated with a more reduced redox state while growth in the presence of endogenous factors that promote differentiation correlated with an increase in intracellular oxidation. Thus, these studies suggested that extracellular factors can promote a more oxidizing or reducing environment in cells and thereby play an important role in regulating the intracellular redox environment and, in consequence, cell fate. In further studies, the same group showed that compounds that make the O-2A progenitor cells more oxidized promote differentiation by reducing the level of receptors for growth factors such as platelet derived growth factor that stimulate proliferation [11]. Similar results were obtained with neural progenitor cells (NPCs) where an oxidizing environment was shown to both inhibit proliferation and stimulate differentiation into astrocytes [12]. This result is consistent with experiments in PC12 cells where nerve growth factor-induced differentiation was enhanced by treatments which decreased the GSH/GSSG ratio thereby inducing a more oxidizing environment and inhibited by treatments which increased the GSH/GSSG ratio, inducing a more reducing environment [13]. Thus, during brain development, GSH loss and/or oxidation could cause premature differentiation of neural cells resulting in inappropriate changes in neuronal and/or glial cell populations. An additional cell fate that is regulated by the cellular redox state is death. Recent studies in nerve cells have demonstrated that GSH can directly regulate apoptosis through two distinct mechanisms: Its interaction with the pro-survival protein Bcl-2 [14] and its inhibition of cytosolic cytochrome C [15]. Studies by Zimmerman et al. [14] showed that Bcl-2 interacts directly with GSH and thereby regulates an essential pool of mitochondrial GSH. Disruption of this interaction leads to mitochondrial oxidative stress and death in primary cultures of nerve cells. Vaughn and Deshmukh [15] showed that the redox environment and specifically GSH levels directly regulate the apoptosis-initiating function of cytosolic cytochrome C in nerve cells by maintaining it in a reduced and therefore less pro-apoptotic form. GSH depletion promotes both a more oxidized redox environment and increased nerve cell death. Among the susceptibility genes implicated in autism are a number involved in the maintenance of GSH metabolism [16–19]. These include glutathione peroxidase [17], several glutathione transferases [16,19], glutaredoxin [18], cystathione gamma lyase [18] and glutamate cysteine ligase [18]. The enzymes encoded by these genes are either involved in GSH synthesis (glutamate cysteine ligase, cystathione gamma lyase), regeneration (glutathione peroxidase) or GSH-mediated detoxification (glutathione transfer-
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ases, glutaredoxin) (Fig. 1). Defects in GSH metabolism in autism are consistent with observations from several laboratories showing that total and reduced GSH levels are significantly lower in the blood of autistic children as compared to normal, age-matched controls, while oxidized GSH is significantly increased [e.g. [16]]. Another gene recently identified as an autism susceptibility factor is glyoxalase 1 (Glo-1) [20]. Glo-1 catalyzes the first and rate-limiting step in the removal of methylglyoxal (MG), a highly reactive dicarbonyl linked to mitochondrial dysfunction, oxidative stress and immune system activation [21]. Importantly, Glo-1 is absolutely dependent on GSH for activity, so disruptions in GSH metabolism will also impact Glo-1 function. MG, along with other reducing sugars such as fructose, is an advanced glycation end product (AGE) precursor. MG is the major contributor to the generation of both intracellular and extracellular AGEs [22]. AGEs are a heterogeneous group of macromolecules that are formed by the non-enzymatic glycation of proteins, lipids and nucleic acids. Humans are exposed to two sources of AGEs: exogenous AGEs that are ingested in foods and endogenous AGEs that are formed in the body [23]. Similarly, the AGE precursor MG can either be ingested in foods [24,25] or formed endogenously as a by-product of glycolysis [21] AGEs interact with the receptor for AGEs (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface receptors resulting in sustained upregulation of inflammatory mediators including tumor necrosis factor a (TNFa), interleukin 6 (IL-6) and C-reactive protein (CRP) [26] as well as activation of NADPH oxidase to produce superoxide [27]. MG and AGEs can also directly increase inflammatory responses in endothelial cells in vitro [28] and the colon in vivo [29]. There is evidence for immune system activation in both the mothers of autistic children as well as the children themselves [30]. Immune system activation during pregnancy has been shown to lead to abnormal gene regulation and brain atrophy in offspring as well as behavioral changes that replicate some of those seen in autism [5]. Importantly, high levels of maternal IL-6 have been implicated in alterations in fetal brain development and impaired social behavior in offspring [5]. Increased levels of IL-6 and TNFa have also been found in brain specimens and cerebral spinal fluid (CSF) from both young and old individuals with autism [30]. AGEs are increasingly prevalent in the diet [23,31]; their presence is dependent upon the type of food and its temperature and method of cooking. In general, foods with higher fat and protein contents have the highest AGE levels [32]. Within these groups, high heat treated foods such as deep-fried potatoes, cookies and fried meat have much higher levels of AGEs [33]. A major impetus for this high temperature processing is that AGEs significantly enhance the flavor, smell and appearance of food products thereby serving as ‘‘appetite enhancing’’ agents [34]. Food intake, as defined by total daily energy consumption, and especially processed food intake, has increased on average by 20–30% over the past few decades in the US [35]. Thus, it is likely that exposure to dietary AGEs and AGE precursors has increased by a similar or greater amount. Dietary AGEs are readily absorbed by humans with 10% of a single AGE-rich protein preparation making it to the bloodstream [34]. In a kinetic study in rats, AGEs were found to be absorbed mostly as single, di- and tri-peptides and 66% remained in contact with tissues for >72 h [34]. Ingestion of an AGE-enriched diet by mice resulted in enhanced levels of both serum and tissue AGEs and increases in markers of oxidative stress [36]. Similarly, short term feeding studies in humans with an AGE-enriched diet led to increases in serum AGEs and markers of inflammation [37] as well as an increase in markers of oxidative stress [38]. Very recently, it was shown that there is a significant correlation between the levels of MG and AGEs in maternal and newborn blood [39]. Furthermore, AGE levels in infant blood significantly increased following the introduction of processed infant food [39]. Indeed, both infant for-
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Fig. 2. Changes in autism prevalence, maternal obesity, gestational diabetes and diabetes in women of child bearing age over the past 20 years. (A) Changes in average autism prevalence (per 1000) in US, UK and Canada [1,50,58], % of women with diabetes in Canada [57], % of women with gestational diabetes in the US [60] and % of maternal obesity in the UK [54] are plotted versus time. (B) Autism prevalence is plotted versus percent women of child bearing age with diabetes and the correlation coefficient calculated by linear regression analysis. (C) Autism prevalence is plotted versus percent women gestational diabetes and the correlation coefficient calculated by linear regression analysis. (D) Autism prevalence is plotted versus percent maternal obesity and the correlation coefficient calculated by linear regression analysis.
mula [23] and sterilized milk [40] have very high levels of AGEs compared with breast milk. MG is also very prevalent in the human diet particularly in sugar-containing soft drinks [24,25] and coffee [41]. Importantly, administration of low levels of MG via the drinking water to mice in utero and continuing after birth significantly decreased blood GSH levels in the adult mice [42]. Similar decreases in blood GSH levels are seen in children with autism [16]. Along with inflammation and oxidative stress, mitochondrial dysfunction is also associated with autism [6,43]. Mitochondrial dysfunction can result from genetic mutations, but this does not seem to be the case for the vast majority of autism patients [43]. Since GSH is the major antioxidant in mitochondria [44], decreases in GSH can directly impact mitochondrial function [45]. Consistent with this idea, lymphoblastoid cells from autistic subjects were shown to have lower levels of mitochondrial GSH as compared with the same cells from age-matched controls [46]. Serum lactate is often used as a surrogate marker of mitochondrial dysfunction and increases in serum lactate levels are frequently found in autistic subjects [6,43]. Lactate is the major end product of anaerobic respiration, and is elevated in response to mitochondrial dysfunction. Importantly, increases in anaerobic metabolism also lead to increases in MG since it is a by-product of glycolysis [21]. In addition, MG itself has been shown to impair mitochondrial function [47], and the overexpression of the MG-degrading enzyme Glo-1 in worms decreases MG-dependent modification of mitochondrial proteins and mitochondrial dys-
function [48]. Thus, a vicious cycle could be established whereby mild mitochondrial dysfunction brought about by a combination of genetic vulnerabilities and an AGE-rich diet could lead to increased glycolysis thereby enhancing the production of MG and leading to more severe mitochondrial dysfunction. Hypothesis Based on these observations, I propose that a combination of inborn genetic vulnerabilities affecting GSH metabolism, Glo-1 and/or mitochondrial function coupled with increased dietary exposure to AGEs and/or the AGE precursor MG could lead to neuropathological changes in the brain and the subsequent behavioral deficits that are characteristic of autism. This hypothesis ties together a number of the observations that have been made regarding the pathophysiological factors underlying autism and suggests an interconnectedness between three factors that have been postulated to play key roles in autism: Oxidative stress, inflammation and mitochondrial dysfunction. Although the idea that a combination of susceptibility genes and environmental factors gives rise to autism is not novel, the hypothesis that diet-derived AGEs and AGE precursors are a key environmental factor in the development of autism is novel. In addition, although both endogenous and dietary AGEs have been associated with diabetes [34] and age-related neurological disorders [22,49], they have not been considered in the context of autism despite evi-
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dence that these dietary glycotoxins can cause oxidative stress and inflammation in infants [39]. This hypothesis not only addresses several of the unanswered questions regarding autism but it is readily testable in both animal models and humans. First, and perhaps most importantly, the prevalence of autism in the US has increased significantly over the past 30 years [1,50]. While part of that increase in prevalence can be explained by other factors such as changes in diagnostic criteria, at least 60% appears to represent a real increase [1]. The dietary intake of AGEs has also increased over this period and is postulated to play a key role in the diabetes epidemic [34]. Second, as indicated, autism is extremely heterogeneous [3]. This could readily be explained by distinct arrays of genetic vulnerabilities coupled with different levels of exposure to MG and AGEs both in utero and postnatally which could give rise to a range of symptoms. Third, a very recent study in mono- and di-zygotic twins provided evidence that environmental factors common to both types of twins can explain about 55% of the liability to autism [2]. This observation is consistent with the similar levels of both pre- and post-natal exposure to AGEs and AGE precursors that would be expected to be experienced by both types of twins. Fourth, there are reports that autism symptoms can improve in some children [e.g. [51]]. This could be explained by changes in the diet that would reduce exposure to AGEs and/or MG thereby alleviating their impact on the brain. Predictions Since both obesity and diabetes [34] are associated with higher exposure to AGEs, this hypothesis predicts that there would be an association between these disorders in mothers and higher rates of autism in their offspring. The limited epidemiological studies on this question suggest that this may be the case. First, on a general level, the prevalence of overweight and obesity [52–54] as well as diabetes [55–57] in women of child bearing age in the US, Canada and the UK has increased over the same time frame as the increase in autism [1,50,58] (Fig. 2). One study showed that for mothers with a body mass index (BMI) of 30 or greater at age 18 there was a twofold increase in the risk of having an autistic child [59]. The prevalence of gestational diabetes also increased dramatically between 1989 and 2004 in the US [60] (Fig. 2). A meta-analysis of studies which looked at prenatal risk factors for autism found that gestational diabetes was associated with a twofold increase in the risk of autism [61]. The main therapeutic prediction of this hypothesis is that reducing the exposure of embryos/infants to MG and AGEs can decrease the prevalence of autism. However, exposure to MG and/or AGEs could occur via the mother during pregnancy and/or after birth via the mother’s milk and/or infant and baby food. At this time it is not clear when the critical exposure period would be. Thus, it may be prudent to reduce the exposure to MG and AGEs both in utero and postnatally until further studies are carried out. In addition, it might be possible to do some of these studies in mouse models of autism such as the BTBR mouse. This is a genetically homogeneous inbred strain of mice that displays behavioral traits that reflect all three diagnostic symptoms of autism, including abnormal social interactions, impaired communication and repetitive behaviors [62]. Offspring and/or their mothers could be fed either a normal diet or a low-AGE diet [e.g. [36]] and their behavior tested for characteristics of autism at adulthood. While it is acknowledged that mice are not humans, these types of studies could provide an indication of the window of vulnerability for the exposure to AGEs and AGE precursors that promotes the development of autistic behavior. In summary, I propose that a previously unexplored environmental factor, dietary glycotoxins, plays a key role in the develop-
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ment of at least a subset of autism cases. This hypothesis is readily testable and, if correct, could provide a cost effective and broadly applicable approach to reduce the prevalence of this disorder. Conflict of interest statement The author declares that there are no conflicts of interest. Acknowledgments This work was supported by a grant from the not-for-profit Fritz B. Burns Foundation. The author would like to thank Drs. David Schubert and Michael Nunn for critical reading of the manuscript. References [1] Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 2010;23:103–10. [2] Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 2011. doi:10.1001/archgenpsychiatry.2011.7. [3] Frith U, Happe F. Autism spectrum disorder. Curr Biol 2005;15:R786–90. [4] Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiol 2006;13:171–81. [5] Parker-Athill EC, Tan J. Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway. Neurosignals 2010;18:113–28. [6] Palmieri L, Persico AM. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta 2010;1797:1130–7. [7] Lewerenz J, Maher P. Control of redox state and redox signaling by neural antioxidant systems. Antioxid Redox Signal 2011;14:1449–65. [8] Bains JS, Shaw CA. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev 1997;25:335–58. [9] Cabungcal J-H, Preissmann D, Delseth C, Cuenod M, Do KQ, et al. Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis 2007;26:634–45. [10] Noble M, Smith J, Power J, Mayer-Proschel M. Redox state as a central modulator of precursor cell function. Ann NY Acad Sci 2003;991:251–71. [11] Li Z, Dong T, Proschel C, Noble M. Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 2007;5:212–31. [12] Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schroter F, et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 2008;10:385–94. [13] Kamata H, Oka S-i, Shibukawa Y, Kakuta J, Hirata H. Redox regulation of nerve growth factor-induced neuronal differentiation of PC12 cells through modulation of the nerve growth factor receptor, TrkA. Arch Biochem Biophys 2005;434:16–25. [14] Zimmerman AK, Loucks FA, Schroeder EK, Bouchard RJ, Tyler KL, et al. Glutathione binding to the Bcl-2 homology-3 domain groove. J Biol Chem 2007;282:29296–304. [15] Vaughn AE, Deshmukh M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome C. Nat Cell Biol 2008;10:1477–83. [16] James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B 2006;141B:947–56. [17] Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH, et al. Genetic variant of glutathione peroxidase 1 in autism. Brain Dev 2010;32:105–9. [18] Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, et al. Glutathione pathway gene variation and risk of autism spectrum disorders. J Neurodevelop Disord 2011. doi:10.1007/s11689-011-9077-. [19] Williams TA, Mars AE, Byske SG, Stenroos ES, Wang R, et al. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med 2007;161:356–61. [20] Barua M, Jenkins EC, Chen W, Kuizon S, Pullarkat RK, et al. Glyoxalase 1 polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity-implications for autism. Autism Res 2011;4:1–9. [21] Thornalley PJ. Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems-role in ageing and disease. Drug Metabol Drug Interact 2008;23:125–50. [22] Desai KM, Chang T, Wang H, Banigesh A, Dhar A, et al. Oxidative stress and aging: is methylglyoxal the hidden enemy? Can J Physiol Pharmacol 2010;88:273–84. [23] Semba RD, Nicklett EJ, Ferrucci L. Does accumulation of advance glycation end products contribute to the aging phenotype. J Gernotol 2010;65A:963–75. [24] Tan D, Wang Y, Lo C-Y, Sang S, Ho C-T. Methylglyoxal: its presence in beverages and potential scavengers. Ann N Y Acad Sci 2008;1126:72–5.
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