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)

Abstract

Aim: Autism spectrum disorder (ASD) is associated with abnormal lipid metabolism, such as a high total ratio of omega-6 to omega-3 in polyunsaturated fatty acids (PUFAs). PUFAs are metabolized to epoxy fatty acids by cytochrome P450 (CYP); then, dihydroxy fatty acid is produced by soluble epoxide hydrolase. This study examined the association between PUFA metabolites in the cord blood and ASD symptoms and adaptive functioning in children.

Methods: This prospective cohort study utilized cord blood to quantify PUFA metabolites of the CYP pathway. The Autism Diagnostic Observation Schedule (ADOS-2) and Vineland Adaptive Behaviors Scales, Second Edition (VABS-II) were used to assess subsequent ASD symptoms and adaptive functioning in children at 6 years. The analysis included 200 children and their mothers.

Results: Arachidonic acid-derived diols, 11,12-diHETrE was found to impact ASD symptom severity on the ADOS-2-calibrated severity scores and impairment in the socialization domain as assessed by the VABS-II (P = 0.0003; P = 0.004, respectively). High levels of 11,12-diHETrE impact social affect in ASD symptoms (P = 0.002), while low levels of 8,9-diHETrE impact repetitive/restrictive behavior (P = 0.003). Notably, there was specificity in the association between diHETrE and ASD symptoms, especially in girls.

Conclusion: These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth. Given that the role of diol metabolites in neurodevelopment in vivo is completely uncharacterized, the results of this study provide important insight into the role of diHETrE and ASD pathophysiology.

Keywords: adaptive functioning; arachidonic acid; autism; cord blood; dihydroxy eicosatetraenoic acid.

Fig. 1

Flow diagram for selecting study population.

Fig. 2

Schematic figure of arachidonic acid (AA) metabolism in neonatal cord blood and its relation to ASD. AA released from phospholipid membranes is metabolized to 5,6‐, 8,9‐, 11,12‐, and 14,15‐EET by CYP epoxygenases, represented by CYP2J2, CYP2C8 and CYP2C9. SEH hydrolyzes four EETs to 5,6‐, 8,9‐, 11,12‐, and 14,15‐diHETrE with very low biological activity. Of these, high levels of 11,12‐diHETrE in cord blood impact subsequent ASD symptoms, particularly SA, in children and are also associated with adaptive functions in sociability. In contrast, 8,9‐diHETrE at low levels impact RRB. (ASD, autism spectrum disorders; CYP, cytochrome P450; diHETrE, dihydroxy eicosatrienoic acid; EET, epoxy eicosatrienoic acid; RRB, repetitive/restrictive behavior; sEH, soluble epoxide hydrolase; SA, social affect).