Abstract
Neurodevelopmental regression (NDR) is a subtype of autism spectrum disorder (ASD) that manifests as loss of previously acquired developmental milestones. Early life dysregulation of nutritional metals and/or exposure to toxic metals have been associated with ASD, but the underlying biological mechanisms by which metals influence neurodevelopment remain unclear. We hypothesize that metals influences neurodevelopment through dysregulation of bioenergetics. Prenatal and early postnatal metal exposures were measured using validated tooth-matrix biomarkers in 27 ASD cases (13 with NDR) and 7 typically-developing (TD) controls. Mitochondrial respiration and glycolysis were measured in peripheral blood mononuclear cells using the Seahorse XF96. Children with ASD demonstrated lower prenatal and postnatal Copper (Cu) and prenatal Nickel concentrations and Copper-to-Zinc (Cu/Zn) ratio as compared with TD children. Children with ASD and NDR showed greater metal-related disruption of cellular bioenergetics than children with ASD without NDR. For children with ASD and NDR mitochondrial respiration decreased as prenatal Manganese concentration increased and increased as prenatal Zinc concentration increased; glycolysis decreased with increased exposure to prenatal Manganese and Lead and postnatal Manganese. For children with ASD without a history of NDR, glycolysis increased with increased postnatal exposure to Tin. Language and communication scores in children with ASD were positively related to prenatal Cu exposure and Cu/Zn ratio. This study suggests that prenatal nutritional metals may be important for neurodevelopment in children with ASD, and that exposure to toxic metals and differences in nutritional metal exposures is associated with dysregulation of cellular bioenergetics, particularly in the NDR subtype of ASD.
Highlights
Autism spectrum disorder (ASD) is a behaviorally defined disorder, which is associated with significant pathophysiology[1]
We demonstrate that metal exposure during gestation is related to physiological changes in bioenergetics that persist into childhood for children with ASD, primarily in those with a history of Neurodevelopmental regression (NDR)
As both nutritional and toxic metal exposure are known to disrupt bioenergetics and bioenergetics is disrupted in ASD, it was hypothesized that prenatal and postnatal exposure to metals was associated with long-term physiological changes in mitochondrial and glycolytic metabolism
Summary
Autism spectrum disorder (ASD) is a behaviorally defined disorder, which is associated with significant pathophysiology[1]. Some studies estimate ASD to affect 1 in 45 individuals in the United States[2]. ASD research has focused on genetics[1], recent estimates suggest that inherited single gene and chromosomal defects only account for a minority of ASD cases[3] and that ASD most likely arises from a complicated interaction between genetic predisposition and Commonly studied environmental toxicants include gestation and early-life exposure to fine air particulate matter (e.g., PM2.5), which is linked to an increase in ASD risk[7,8,9]. Recent research has demonstrated that exposure to metals, which can be nutritional and/or toxic during gestation and early life, can increase the risk of developing ASD11,12.
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