Prenatal air pollution influences neurodevelopment and behavior in autism spectrum disorder by modulating mitochondrial physiology

Richard E Frye,Sirish C Bennuri,Raymond F Palmer,Janet Cakir,Paul Curtin,Christine Austin,Marie Tippett,S Jill James,Stepan Melnyk,Shannon Rose,Leanna Delhey,Manish Arora

doi:10.1038/s41380-020-00885-2

Abstract

We investigate the role of the mitochondrion, an organelle highly sensitive to environmental agents, in the influence of prenatal air pollution exposure on neurodevelopment and behavior in 96 children with autism spectrum disorder (ASD) [45 with neurodevelopmental regression (NDR); 76% Male; mean (SD) age 10 y 9 m (3 y 9 m)]. Mitochondrial function was assessed using the Seahorse XFe96 in fresh peripheral blood mononuclear cells. Second and third trimester average and maximal daily exposure to fine air particulate matter of diameter ≤2.5 µm (PM2.5) was obtained from the Environmental Protection Agency’s Air Quality System. Neurodevelopment was measured using the Vineland Adaptive Behavior Scale 2nd edition and behavior was assessed using the Aberrant Behavior Checklist and Social Responsiveness Scale. Prenatal PM2.5 exposure influenced mitochondrial respiration during childhood, but this relationship was different for those with (r = 0.25–0.40) and without (r = −0.07 to −0.19) NDR. Mediation analysis found that mitochondrial respiration linked to energy production accounted for 25% (SD = 2%) and 10% (SD = 2%) of the effect of average prenatal PM2.5 exposure on neurodevelopment and behavioral symptoms, respectively. Structural equation models estimated that PM2.5 and mitochondrial respiration accounted for 34% (SD = 4%) and 36% (SD = 3%) of the effect on neurodevelopment, respectively, and that behavior was indirectly influenced by mitochondrial respiration through neurodevelopment but directly influenced by prenatal PM2.5. Our results suggest that prenatal exposure to PM2.5 disrupts neurodevelopment and behavior through complex mechanisms, including long-term changes in mitochondrial respiration and that patterns of early development need to be considered when studying the influence of environmental agents on neurodevelopmental outcomes.

Highlights

Autism spectrum disorder (ASD) is a behaviorally defined disorder [1] which may affect as many as 1 in 45 children in the United States [2]
To provide a perspective of the values of the outcome measures in ASD, overall comparisons between those with ASD with and without neurodevelopmental regression (NDR) and typically developing (TD) controls with respect to mitochondrial function and PM2.5 is given in Supplementary Table S2
Those with a history of NDR demonstrated a positive relationship between prenatal air pollution exposure and mitochondrial respiration involved in Adenosine triphosphate (ATP) production (ALR, Maximal Respiratory Capacity (MRC), Reserve Capacity (RC)) and control of oxidative stress (PLR), such that mitochondrial respiration increased with higher prenatal exposures to air pollution with small-to-medium sized effects

Summary

Introduction

Autism spectrum disorder (ASD) is a behaviorally defined disorder [1] which may affect as many as 1 in 45 children in the United States [2]. Recent estimates suggest that inherited single gene and chromosomal defects account for a minority of ASD cases [3] and that ASD most likely arises from a complicated interaction between genetic predisposition and environmental exposures [4, 5]. Short-term and long-term PM2.5 exposure is linked to many chronic diseases, including pulmonary and cardiovascular disease [6]. Air pollution, including PM2.5 exposure, during gestation and early life increases the risk of developing ASD [7]. Environmental agents such as PM2.5 are epidemiologically associated with ASD, the biological mechanisms which mitigate their effects are poorly understood [8]

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