Mast Cells as a Key Link Between Developmental Exposure to toxicants and Neurodevelopmental Risk

Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), have dramatically increased in prevalence, suggesting that environmental factors contribute to their etiology. While exposure to environmental contaminants is increasingly linked to neurodevelopmental abnormalities, the underlying mechanisms remain poorly understood. Mast cells—immune cells present in nearly all tissues, including the brain—are uniquely positioned to bridge environmental exposures with neuroimmune regulation. Their ability to rapidly release bioactive mediators in response to immune challenges makes them critical players in chronic peripheral and central inflammatory responses. However, their role in neurodevelopmental disorders remains largely unexplored. Our previous findings show that developmental exposure to Firemaster® 550 (FM550), a widely used flame retardant associated with neurodevelopmental impairments, induces persistent mast cell hyperactivity. This hyperactivity amplifies sickness and neuroinflammatory responses to immune challenges, leading to behavioral deficits in a sex-specific manner. We hypothesize that FM550 exposure reprograms mast cell progenitors into a hyperactive state, resulting in tissue- specific immune dysregulation that increases susceptibility to systemic inflammation and neurodevelopmental disorders. This project will address this hypothesis through three independent yet interconnected aims: (1) determine the distinct contributions of peripheral and brain mast cells to systemic and behavioral outcomes resulting from developmental FM550 exposure, (2) assess whether FM550 exposure induces tissue-specific mast cell hyperactivity, with peripheral mast cells upregulating mediators that drive acute sickness and systemic inflammation while brain mast cells promote microglial activation and blood-brain barrier disruption, and (3) determine whether FM550 exposure induces epigenetic modifications that enhance signaling in key mast cell activation pathways, revealing how environmental toxicants shape long-term neuroimmune susceptibility.This interdisciplinary project integrates behavioral neuroscience, immunology, and toxicology with advanced molecular and epigenetic techniques. By elucidating the mast cell-mediated mechanisms linking environmental toxicants to neurodevelopmental disorders, this research will provide critical insights into environmentally driven neuropsychiatric conditions and generate a comprehensive dataset that could be used to identify new targets for intervention. Project Number: 1R01ES038233-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: David Aylor (+2 co-PIs) | Institution: NORTH CAROLINA STATE UNIVERSITY RALEIGH, RALEIGH, NC | Award Amount: $361,849 | Activity Code: R01 | Study Section: Neurotoxicology and Alcohol Study Section[NAL] View on NIH RePORTER: https://reporter.nih.gov/project-details/11277745