Increased ω-3 polyunsaturated fatty acid/arachidonic acid ratios and upregulation of signaling mediator in individuals with autism spectrum disorders

Abstract

Aims

The investigation of links between the ratio of omega-3/omega-6 PUFAs and neuronal signaling is a research priority in autism spectrum disorders (ASD).

Main methods

We examine the relationships between the plasma ratios of docosahexaenoid acid (DHA)/arachidonic acid (AA) and eicopentaenoic acid (EPA)/AA and biomarkers of AA-related signaling mediators such as ceruloplasmin, transferrin and superoxide dismutase, in the behavioral symptoms of 28 individuals with ASD (mean age 13.5 ± 4.6 years) and 21 age- and gender-matched normal healthy controls (mean age 13.9 ± 5.7 years). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). We conducted controlling for dietary intake and assessed the dietary intake of nutrients.

Key findings

There were no significant differences in intake of nutrients such as omega-3 and omega-6 PUFAs, saturated and unsaturated fatty acid, DHA, AA, iron and copper. Plasma EPA, DHA, and arachidic acid levels, and plasma DHA/AA and EPA/AA ratios were significantly higher, while plasma AA and adrenic acid were significantly lower in the 28 individuals with ASD than in the 21 normal controls. The ABC scores were significantly higher in the ASD group compared to the control group. The plasma ceruloplasmin levels in the ASD group were significantly reduced compared to those in the control group.

Significance

Increased plasma DHA/AA and EPA/AA ratios may be related to low plasma levels of ceruloplasmin which has neuroprotective properties. Reduced plasma ceruloplasmin levels may diminish the protective capacity against brain damage, and may contribute to the pathophysiology of behavioral symptoms in individuals with ASD.

Introduction

Studying alterations in the composition of PUFAs and related signal mediators may be a major strategy in understanding the pathophysiology of autism spectrum disorders (ASD) [1]. The omega-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and the omega-6 PUFA arachidonic acid (AA) are important in nervous system function [2], signal transduction [3], proper synapse formation [4] and neurotransmission [4]. Previous studies reported a marked reduction in plasma DHA levels [5], [6] with changes in the plasma omega-3/omega-6 ratio [7]. The balance between omega-3 and omega-6 PUFAs is well known to be critical for normal brain function and development [8], [9], [10]. A recent clinical study reported that the relationship between omega-3 PUFAs and AA is antagonistic to maintaining homeostasis at high EPA and DHA concentrations. The incorporation of omega-3 PUFAs lowers the AA concentration [11], [12], thereby down-regulating the synthesis of eicosanoids, the mediators of AA signaling in the cell membrane [12]. Dietary omega-3 PUFAs may attenuate tissue AA levels and eicosanoid formation [13]. The antagonism of AA signaling may have important effects upon cell signaling in the central nervous system [15], [16], modifying biomedical and behavioral effects [15]. This competitive interaction between omega-3 PUFAs and AA reflects an increase in the plasma omega-3/AA ratios [8], [9], [11].

In respect to signaling mediators in ASD, alterations in ceruloplasmin (Cp) [17], superoxide dismutase (SOD) [18] and transferrin (Tf) [19] have been reported as pathophysiological factors. Cp is an important copper signaling biomarker of neuronal function [20] and a natural neuroprotective protein [21], [22]. Cp reduces the synthesis of AA-derived eicosanoid mediators, such as leukotrienes [23] and cyclooxygenase-2 [24]. SOD is a biomarker of copper signaling [25]. AA [26] and essential PUFAs [27] increased the activity of SOD. Moreover, protecting SOD activity has been related to the excess production of the AA-derived eicosanoid family prostaglandin F2 [28]. Tf is an iron-signaling mediator [29]. The Tf receptor protein is elevated by DHA-enrichment [30]. Collectively, Cp, SOD and Tf are related to the functions of AA, DHA and PUFAs. Changes in the blood levels of SOD, TF and CP have been shown to indicate altered antioxidant status [31], [32], [33], vulnerability to oxidative stress [34], [35], and copper dyshomeostasis [36], [37] in ASD patients. However, the importance of the interaction between the altered composition of PUFAs and the AA-related signaling mediators (Cp, Tf and SOD) remains unclear.

We hypothesized that increased plasma DHA/AA and EPA/AA ratios are related to the down-regulation of AA-dependent signaling mediators in the behavioral symptoms of individuals with ASD. Thus, the levels of 23 fatty acid fractions and three AA-related signaling mediators in the plasma were determined. Plasma fatty acid levels were expressed as the percentage of total fatty acids and in μg/ml to examine the correlation among the fatty acids. Because there are multiple subfamilies of AA-derived eicosanoid signaling mediators [38] and these mediators are affected by multiple factors [39], we examined plasma Cp, SOD and Tf levels as known AA-related signaling mediators. We conducted controls for dietary intake and to assess the intake of nutrients.