Elsevier

Life Sciences

Volume 75, Issue 21, 8 October 2004, Pages 2539-2549
Life Sciences

Oxidative stress in autism: Increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin - the antioxidant proteins

https://doi.org/10.1016/j.lfs.2004.04.038Get rights and content

Abstract

Autism is a neurological disorder of childhood with poorly understood etiology and pathology. We compared lipid peroxidation status in the plasma of children with autism, and their developmentally normal non-autistic siblings by quantifying the levels of malonyldialdehyde, an end product of fatty acid oxidation. Lipid peroxidation was found to be elevated in autism indicating that oxidative stress is increased in this disease. Levels of major antioxidant proteins namely, transferrin (iron–binding protein) and ceruloplasmin (copper–binding protein) in the serum, were significantly reduced in autistic children as compared to their developmentally normal non-autistic siblings. A striking correlation was observed between reduced levels of these proteins and loss of previously acquired language skills in children with autism. These results indicate altered regulation of transferrin and ceruloplasmin in autistic children who lose acquired language skills. It is suggested that such changes may lead to abnormal iron and copper metabolism in autism, and that increased oxidative stress may have pathological role in autism.

Introduction

Autism is a severe neurological disorder with onset before the age of 3 years. It is associated with severe impairment in language, cognition and socialization (Lord et al., 2000). Autism is classified under the pervasive developmental disorders (PDD), a group of disorders that involve a combination of impairments in communication, reciprocal social interactions and stereotyped patterns of interest / behavior. PDD includes autism, Asperger's disorder (an autistic condition not associated with language delay or general intellectual impairments), childhood disintegrative disorder, and a range of atypical and milder forms (PDD - not otherwise specified).

Extensive studies have demonstrated that oxidative stress plays a vital role in the pathology of several neurological diseases such as Alzheimer disease (Christen, 2000), Down syndrome (Kannan and Jain, 2000), Parkinson disease (Bostantjopoulou et al., 1997, Torsdottir et al., 1999) and Schizophrenia (Herken et al., 2001, Akyol et al., 2002). Under normal conditions, a dynamic equilibrium exists between the production of reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, singlet oxygen, and hydrogen peroxide, and the antioxidant capacity of the cell. Stress and injury to cells occur when redox homeostasis is altered, and ROS generation overpowers the biochemical defenses of the cell. Lipid peroxidation reflects a chain reaction between polyunsaturated fatty acids and ROS producing lipid peroxides and hydrocarbon polymers that are both highly toxic to the cell (Tappel, 1973, Jain, 1984, Horton and Fairhurst, 1987). Currently, the studies on oxidative stress in autism are limited (Yorbik et al., 2002, Sogut et al., 2003). Sogut et al. (2003) reported low activity of plasma antioxidant enzymes, namely glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in autism. Yorbik et al. (2002) on the contrary, observed similar activities of these enzymes in autism as compared to controls. We report here that peroxidation of lipids is increased in the plasma of autistic children as compared to their developmentally normal non-autistic siblings suggesting an increased oxidative stress in autism.

Ceruloplasmin and transferrin are major antioxidant proteins that are synthesized in several tissues including brain. Ceruloplasmin is an α2-serum glycoprotein that transports 95% of copper in blood. It has a major role in the metabolism of copper to which it binds reversibly. It also acts as ferroxidase and SOD, and it protects polyunsaturated fatty acids in red blood cell membranes from active oxygen radicals (Sass-Kortsak, 1965, Arnaud et al., 1988). Transferrin is present principally in serum, but is also found at lower concentrations in other body fluids. Its main function is the transport of iron to proliferating cells, and it is also an important growth factor (Loeffler et al., 1995). Ferrous ion contributes to oxidative stress by catalyzing the conversion of hydrogen peroxide to highly toxic hydroxyl radicals by Fenton reaction. Transferrin acts as an antioxidant by reducing the concentration of free ferrous ion. We compared serum ceruloplasmin and transferrin levels in the autistic children and their non-autistic developmentally normal siblings, and report that levels of both these antioxidant proteins are reduced in autism.

Section snippets

Subjects

Members of 19 families (Group A), i.e., children with autism, and their developmentally normal (non-autistic) siblings were studied to compare ceruloplasmin and transferrin levels, and another 11 families (Group B) were studied for lipid peroxidation studies. Siblings were taken as controls because variations such as race, diet, socio-economic status and genetic background are similar between autistic children and their normal siblings. Therefore, the alterations noted were because of autism

Increased lipid peroxidation in the plasma of autistic children

We compared the MDA contents in the plasma of children with autism and their non-autistic siblings (Fig. 1). The MDA contents in plasma were significantly (p < 0.005, paired t-test; p < 0.005, unpaired t-test, n = 15) higher in autism (Mean ± S.E. = 0.4969 ± 0.025 nmole / ml) as compared to non-autistic siblings (Mean ± S.E. = 0.396 ± 0.019 nmole / ml); indicating that lipid peroxidation is increased in autism. The data was also significant when (a) autistic children (Mean ± S.E. = 0.4966 ±

Discussion

Autism is a severe neurodevelopmental disorder (Lord et al., 2000) that affects approximately 6 per 1000 live births (Fombonne, 2003). Although this disease is behaviorally defined, its biochemical defects, diagnostic markers and biochemical targets for its treatment are unknown.

Lipid peroxidation caused by oxidative stress is a well-established mechanism of cellular injury (Tappel, 1973, Horton and Fairhurst, 1987, Kannan and Jain, 2000). This process results in the production of lipid

Acknowledgment

This work was in part supported by funds from New York State Office of Mental Retardation and Developmental Disabilities, and by Cure Autism Now Foundation's pilot grant.

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