Researchers have identified a link between elevated levels of certain metabolites in the blood of newborns and an increase in symptoms of autism spectrum disorder (ASD) in children by age six. Analysis of specific fatty acid metabolites in newborn blood samples has shown promise as a predictor of risk for developing ASD.
Autism spectrum disorder (ASD) is a developmental condition that affects about 1 in 44 children and is most evident in early childhood through childhood.
ASD involves changes in behavior and social interaction and is often studied to understand its causes. One hypothesis is that ASD may be related to “immune dysfunction,” an altered response of the immune system that plays an important role in brain development.
Studies of brains from people with ASD after death show signs of “neuroinflammation” — that is, specific inflammation of brain tissue.
In these studies, scientists have observed that certain immune cells in the brain, called microglia, appear to be “activated” or on high alert. Microglia help protect the brain and are responsible for “cleaning up” tissues, but when they are constantly on high alert, they can affect brain development.
Studies have also found that the number and type of genes present in these cells correlate with the severity of ASD symptoms, suggesting a link between brain inflammation and autistic symptoms.
Because ASD begins to develop early in life, many studies have focused on pregnancy and factors that may impact fetal development.
In experiments with mice, scientists exposed pregnant mice to substances that trigger inflammation and observed that the offspring developed behaviors that resembled those of ASD.
In humans, severe and persistent fever in pregnant women has also been associated with an increased risk of ASD in their offspring, supporting the hypothesis that inflammation during pregnancy may be a risk factor.
A large study conducted in Norway, the Norwegian Autism Birth Cohort, analyzed 200 samples of umbilical cord blood and maternal blood during pregnancy.
They found that high levels of certain immune-stimulating substances (such as interleukin-1RA, and tumor necrosis factor-α, among others) were associated with an increased risk of ASD.
These immunological factors are responsible for promoting or regulating inflammation and suggest that “maternal immune activation” (MIA) may be a key risk factor for the development of ASD.
Polyunsaturated fatty acids (PUFAs) play an important role in modulating immune processes. In the context of ASD, a specific type of PUFA, known as arachidonic acid (AA), has been identified in altered amounts in children with ASD, with an elevated ratio of omega-6 to omega-3 fatty acids. This imbalance impacts the production of molecules involved in inflammation.
PUFAs are processed in the body by three main pathways, producing both anti-inflammatory and pro-inflammatory compounds.
One of these anti-inflammatory compounds, epoxyeicosatrienoic acid (EET), is crucial for healthy brain development, helping, for example, with the growth of neurons.
Inflammatory compounds, such as diols (byproducts of PUFAs), can intensify inflammatory processes, which impacts the central nervous system.
Another study investigated the effects of glyphosate (a herbicide) on pregnant mice. When exposed to high concentrations of glyphosate, the offspring developed behaviors similar to ASD, in addition to having altered levels of EET and an increase in inflammatory diols.
However, when the mice were given inhibitors that block the formation of these diols, there was an improvement in the social behaviors of the offspring, suggesting that these inflammatory compounds may play an important role in the development of ASD.
In human studies, researchers analyzed PUFA metabolites in cord blood samples from infants and then monitored the children’s development until age 6, observing whether ASD symptoms were present.
The assessment was done using specific scales and tests, such as the Autism Diagnostic Observation Schedule (ADOS-2) and the Vineland Adaptive Behavior Scales (VABS-II).
In the study, it was found that high levels of one type of diol (11,12-diHETrE) impacted the severity of ASD symptoms, especially in social interaction, while low levels of another diol (8,9-diHETrE) were related to repetitive behaviors.
Interestingly, the presence of these compounds in cord blood was shown to be particularly relevant to ASD symptoms in girls.
These studies indicate that the presence of certain inflammatory metabolites and the immune response during pregnancy may play a crucial role in the development of ASD.
More specifically, high levels of inflammatory compounds derived from PUFAs during pregnancy appear to create a biological environment that may predispose to the development of ASD symptoms, especially when there are lower levels of anti-inflammatory compounds.
Future studies may focus on understanding how regulating these metabolites may help minimize risk and even contribute to new methods of prevention and intervention.
Schematic figure of arachidonic acid (AA) metabolism in neonatal umbilical cord blood and its relationship with ASD. AA released from phospholipid membranes is metabolized into 5,6-, 8,9-, 11,12-, and 14,15-EET by CYP epoxygenases, represented by CYP2J2, CYP2C8, and CYP2C9. SEH hydrolyzes four EETs into 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 symptoms of ASD, particularly SA, in children and are also associated with adaptive functions in sociability. In contrast, 8,9-diHETrE at low levels impacts RRB. (ASD, autism spectrum disorders; CYP, cytochrome P450; diHETrE, dihydroxyicosatrienoic acid; EET, epoxyicosatrienoic acid; RRB, repetitive/restrictive behavior; sEH, soluble epoxide hydrolase; SA, social affect). https://doi.org/10.1111/pcn.13710
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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)
Hirai T, et al.
Psychiatry and Clinical Neurosciences. 23 July 2024
Abstract:
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.
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.
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.
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.
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