Developmental PBDE exposure persistently impairs mast cell function in vivo and drives sex-specific morphological and transcriptional changes in bone marrow-derived mast cells.

Polybrominated diphenyl ethers (PBDEs) are synthetic flame retardants once widely used in furniture, electronics, and other consumer products. Although phased out in the early 2000s, their persistence and recycling into new materials have led to continued contamination and widespread human exposure, raising concern for infants, who are highly vulnerable to long-term neurodevelopmental, endocrine, and metabolic disruption. Whether developmental PBDE exposure affects mast cell functions, however, remains unexplored. Mast cells are conserved immune cells distributed throughout the body that act as first responders to environmental threats-including allergens, pathogens, and toxicants-by orchestrating neural, endocrine, and immune signaling. Dysregulated mast cell activity has been implicated in multisystem pathologies such as neuroinflammation, obesity, and chemical intolerance, suggesting they may contribute to vulnerabilities resulting from developmental PBDE exposure. We found that maternal exposure to ∼87 μg/kg/day PBDE during pregnancy and lactation-a dose previously linked to metabolic and neurobehavioral effects-induces persistent mast cell dysfunction in male and female mice. Adult offspring exhibited blunted anaphylaxis-associated hypothermia and plasma histamine release in vivo, as well as reduced capacity to sustain histamine and serotonin release following Mrgprb2 stimulation ex vivo. These deficits occurred without detectable changes in tissue-resident mast cell numbers or activation. Bone marrow-derived mast cells (BMMCs) revealed sex-specific alterations in storage capacity: males accumulated increased numbers of "empty" granules, whereas females displayed hypertrophy with reduced granule density. RNA sequencing further demonstrated widespread, sex-specific transcriptional changes, with minimal overlap between males and females. Nonetheless, downregulation of granule biogenesis and cytokine signaling pathways suggested shared disruption of effector functions, while divergent regulation of serotonin receptor signaling may underlie distinct morphological phenotypes. Together, these findings identify mast cells as novel immune targets of developmental PBDE exposure, reveal sex-specific mechanisms of dysfunction, and highlight mast cells as potential mediators linking toxicant exposure to long-term multisystem vulnerabilities.