Untargeted Metabolomics Screen of Mid‐pregnancy Maternal Serum and Autism in Offspring

Abstract

Discovering pathophysiologic networks in a blood‐based approach may help to generate valuable tools for early treatment or preventive measures in autism. To date targeted or untargeted metabolomics approaches to identify metabolic features and pathways affecting fetal neurodevelopment have rarely been applied to pregnancy samples, that is, an early period potentially relevant for the development of autism spectrum disorders (ASD). We conducted a population‐based study relying on autism diagnoses retrieved from California Department of Developmental Services record. After linking cases to and sampling controls from birth certificates, we retrieved stored maternal mid‐pregnancy serum samples collected as part of the California Prenatal Screening Program from the California Biobank for children born 2004 to 2010 in the central valley of California. We retrieved serum for 52 mothers whose children developed autism and 62 population controls originally selected from all eligible children matched by birth year and child's sex. Also, we required that these mothers were relatively low or unexposed to air pollution and select pesticides during early pregnancy. We identified differences in metabolite levels in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N‐glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21‐steroid hormone biosynthesis and metabolism. Disturbances in these pathways have been shown to be relevant for neurodevelopment in rare genetic syndromes or implicated in previous studies of autism. This study provides new insight into maternal mid‐pregnancy metabolic features possibly related to the development of autism and an incentive to explore whether these pathways and metabolites are useful for early diagnosis, treatment, or prevention. Lay Summary This study found that in mid‐pregnancy the blood of mothers who give birth to a child that develops autism has some characteristic features that are different from those of blood samples taken from control mothers. These features are related to biologic mechanisms that can affect fetal brain development. In the future, these insights may help identify biomarkers for early autism diagnosis and treatment or preventive measures. Autism Res 2020, 13: 1258–1269. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Maternal Plasma Metabolic Profile Demarcates a Role for Neuroinflammation in Non-Typical Development of Children

“…For example, one could imagine two metabolites that have the same concentrations in TD and ASD, but whose correlation changes with age or other conditions (e.g, diet; example [ 48 ]). Much of the literature on biomarkers of ASD and/or IDD has focused on the search for individual molecules, or statistical combinations of molecules, which are predictive of ASD-related morbidity or diagnosis [ 16 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ]. However, few metabolomic studies have moved beyond individual, isolated biomarkers, focusing instead on metabolic pathway analysis, in which whole metabolic pathways are analyzed for significant changes.…”

“…However, few metabolomic studies have moved beyond individual, isolated biomarkers, focusing instead on metabolic pathway analysis, in which whole metabolic pathways are analyzed for significant changes. To cite a few examples, at the prenatal level, Ritz et al [ 16 ] showed differences in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N -glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21-steroid hormone biosynthesis and metabolism in maternal mid-pregnancy serum samples from women residing in California and whose children later developed ASD. Nolin et al [ 88 ] reported deficits in the serine biosynthetic pathway as a main source of anaplerosis for the Krebs’ cycle in amniotic fluids from women carrying a fetus with a FMR1 premutation vs. noncarriers.…”

“…To fulfill this immediate need, metabolic profiling performed on readily-accessible body fluids, such as serum, plasma, blood, urine or saliva, is one of the most important techniques that provides a complete view of the metabolic status and uncovering metabolic perturbations in pathways [ 4 , 5 , 6 ] for diagnosis of many diseases [ 7 ], including metabolic disorders [ 8 ], motor neuron disease [ 9 ], Parkinson’s disease [ 10 ] and Alzheimer’s disease [ 11 ], as well as chemical toxicity and aging [ 12 , 13 , 14 , 15 ]. There are few studies to date that have examined pre- and peri-natal metabolic pathways in relation to later development of ASD [ 16 , 17 , 18 ], with limited insights isnto the link between key metabolites, their role in intermediary metabolism and recurrent risk in families affected by autism. To this end, in this study, we assessed the metabolome from 3rd-trimester maternal plasma and from umbilical cord plasma samples in association with clinical classification of ASD or non-typical development (Non-TD) compared to typical development (TD) in high-familial-risk younger siblings of children with ASD.…”

Altered Metabolism of Mothers of Young Children with Autism Spectrum Disorder: A Case Control Study

“…Similar to that study, further research has found that combining low maternal high-density lipoprotein cholesterol along with high maternal plasma branched-chain amino acid levels and the child being male led to an increased risk of the child being diagnosed with ASD (36). Another study involving maternal metabolite levels prepregnancy from blood samples stored from that time, found that mothers who had children with ASD showed differences in several metabolic pathways including bile acid pathways, glycosphingolipid synthesis, N-glycan and pyrimidine metabolism, and C21-steroid hormone biosynthesis and metabolism (37).…”

Altered Metabolism of Mothers of Young Children with Autism Spectrum Disorder: A Case Control Study

“…Similar to that study, further research has found that combining low maternal high-density lipoprotein cholesterol along with high maternal plasma branched-chain amino acid levels and the child being male led to an increased risk of the child being diagnosed with ASD (40). Another study involving maternal metabolite levels prepregnancy from blood samples stored from that time, found that mothers who had children with ASD showed differences in several metabolic pathways including bile acid pathways, glycosphingolipid synthesis, N-glycan and pyrimidine metabolism, and C21-steroid hormone biosynthesis and metabolism (41).…”