The University of Fukui identifies lipid metabolites related to the prediction of autism spectrum disorder

The percentage of children diagnosed with autism spectrum disorder (ASD) is increasing year by year, with 3.2% of children being diagnosed at 5-year-old health checkups in Japan and 1 in 36 8-year-old children diagnosed in the United States. ASD develops early in the first 20 years of life due to interactions between genetic and environmental factors, and prediction of its onset will facilitate early support for children with ASD and early guidance for pregnant women and parents.

Professor Hideo Matsuzaki of the Research Center for Child Mental Development, Assistant Professor Takaharu Hirai of the College of Nursing, Faculty of Medical Sciences at the University of Fukui, and their colleagues analyzed the associations of epoxy and dihydroxy fatty acid concentrations in cord blood with ASD characteristics in children after birth using the Hamamatsu Birth Cohort for Mothers and Children. They found that arachidonic acid-derived dihydroxy fatty acids affected both the severity of ASD characteristics and adaptive functions in 6-year-old children. The findings are likely to contribute to ultra-early detection of signs ASD and were published in Psychiatry and Clinical Neurosciences.

Although the exact cause of ASD is unclear, clinical research reports suggest that abnormalities in the immune system of the mother during pregnancy may contribute its development after birth. Polyunsaturated fatty acids are metabolized via three major enzymatic pathways. Notably, metabolism in the CYP pathway produces anti-inflammatory epoxy fatty acids, followed by inflammatory dihydroxy fatty acids via the action of soluble epoxide hydrolase (sEH). It has been shown that mRNA expression of the sEH gene is high in the postmortem brains of patients with ASD.

In addition, exposure to a herbicide during pregnancy has been shown to decrease epoxy fatty acid levels and increase sEH levels in the blood, resulting in ASD-like behavioral abnormalities in the offspring of pregnant mice. Administering sEH inhibitors to pregnant mice improves ASD-like behavior in their offspring. The research group believed that decreased epoxy fatty acid levels and increased dihydroxy fatty acid levels (a state of maternal immune activation) during fetal life contributed to ASD in children after birth.

Of the 1,258 neonates born to 1,138 mothers enrolled in the Hamamatsu Birth Cohort Study for Mothers and Children, 200 mothers (mean age: 32 years) who visited the obstetrics department between 2007 and 2011 and 200 children were included in this study. At 6 years of age, the children underwent assessments of the severity of ASD characteristics (e.g., gestures associated with intention-to-communicate, eye contact, sharing feelings with others, and amount of reciprocal communication) and adaptive functioning (e.g., changing the volume of voice depending on location and situation, being able to apologize for inadvertent mistakes, changing behavior based on familiarity level, and recognizing teasing from family members and friends as humor or affection). The research team also quantified metabolites derived from linoleic, arachidonic, eicosapentaenoic, and docosahexaenoic acids in cord blood.

Multivariate linear regression analysis was performed to examine the association of CYP pathway metabolites with the severity of ASD characteristics and adaptive functioning. The results showed that a dihydroxy fatty acid derived from arachidonic acid (11,12-diHETrE) influenced the severity of ASD characteristics and adaptive functioning, whereas other fatty acid metabolites did not exert their effects. An increase of one unit in this dihydroxy fatty acid is associated with a 1.25-fold increase in the predicted value of impairment in social interaction among ASD characteristics. Moreover, the severity of adaptive functioning impairment related to socialization (coping) in 6-year-old children was found to increase with the dihydroxy fatty acid level.

In girls, a 1-unit increase in this dihydroxy fatty acid is associated with a 1.31-fold increase in the predicted impairment in social interaction. In boys, only repetitive/restrictive behaviors were affected. Regarding why only dihydroxy fatty acids derived from arachidonic acid exert effects, Hirai said, "I think that MCP1 may be involved. This hydroxy fatty acid is an endogenous substance involved in inflammatory signaling and contributes to monocyte chemotaxis in the presence of MCP1, an inflammatory cytokine. It has been reported that increased MCP1 in the fetal mouse brain causes ASD-like behavior after birth, but ASD-like behavior improves in the absence of MCP1."

In the present study, among polyunsaturated fatty acids, dihydroxy fatty acids derived from arachidonic acid were found to affect both the severity of ASD characteristics and social adaptive functioning. Dihydroxy fatty acid dynamics during the fetal period may be central to maternal immune activation involved in ASD pathogenesis, making noninvasive predictive assessments of ASD using cord blood collected immediately after birth potentially possible.

Matsuzaki said, "The lack of association between epoxy fatty acids and ASD was contrary to our hypothesis. This is the first finding that has been demonstrated in humans. The roles of sEH and cytochrome P450 acting upstream of this metabolic pathway need to be elucidated to verify the relationship between dihydroxy fatty acids and ASD. Moving forward, we are going to collaborate with companies and other organizations to advance research toward the practical application of the diagnostic method."

Journal Information
Publication: Psychiatry and Clinical Neurosciences
Title: Arachidonic acid-derived dihydroxy fatty acids in neonatal cord blood relate symptoms of autism spectrum disorders and social adaptive functioning: Hamamatsu Birth Cohort for Mothers and Children (HBC Study)
DOI: 10.1111/pcn.13710