Increased ω-3 polyunsaturated fatty acid/arachidonic acid ratios and upregulation of signaling mediator in individuals with autism spectrum disorders
Graphical abstract
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.
Section snippets
Participants
A total of 49 young, physically healthy individuals who were from the Kansai area (Hyogo and Osaka Prefectures) of Japan participated in this study. They were recruited from medical care facilities of the Research Institute of Pervasive Developmental Disorders of Ashiya University by the order of their submission to medical consultation between January 2012 and July 2014. Diagnoses were performed based on the DSM-IV-TR criteria and were additionally confirmed by the Autism Diagnostic
Study population
The behavioral symptoms of the 28 young individuals with ASD included restricted, repetitive and stereotyped patterns of behavior, interests and activities (n = 9), irritability and crying (n = 3) and stereotyped behavior (n = 16). The mean total ABC score was 65.96 ± 28.96. An earlier study reported a total ABC score of 85.6 ± 27.3 for children and adolescents with ASD who were treated with neuroleptics [59] (Table 1). Thus, our patients suffered from moderate ASD symptoms, including restricted
Discussion
Plasma PUFA levels have been shown to reflect changes in brain PUFA levels [60]. In this study, the plasma EPA, DHA, DPA and arachidic acid levels and the plasma DHA/AA and EPA/AA ratios were significantly higher, while the plasma AA, adrenic acid and Cp levels were significantly lower in the 28 individuals with ASD than in the 21 normal controls (Table 1). In the case of the fatty acid levels in the plasma expressed as the mean ± SD in μg/ml, the significant difference in the plasma levels of
Conflict of interest statement
All authors must disclose any financial and personal relationships with other people or organizations that could inappropriately influence our work.
Acknowledgments
We appreciated the assistance of Dr. Yuji Kobayashi (Information and Planning Department, SRL, Inc., Tokyo, Japan) with the assessment of the plasma levels of PUFAs, Cp, SOD and Tf. Dr. Kunio Yui received a Grant-in-Aid for Scientific Research on Innovative Areas (Grant No 21200017) (2010–2012) and a Grant-in-Aid for Scientific Research (C) (2014–2016) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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