Franges, J.; Malinowski, L.; De Alwis, C.; Doolittle, T.; Dixon, H.; Tang, Y.; Watson, H.; Peace, J.; Jima, D.; Sombers, L.; McCarthy, G.; Patisaul, H.; Stapleton, H.; Duque-Wilckens, N.

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 chemical persistence, recycling into new materials, and leaching from waste sites have led to ongoing environmental contamination and widespread human exposure, especially through diet and indoor dust. This is particularly concerning for developing individuals, who not only accumulate the highest levels via placental transfer, breastfeeding, and behavioral factors, but are also especially vulnerable to long-term effects. Despite well-documented impacts of developmental PBDE exposure on neurobehavioral, endocrine, and metabolic systems, the effects on the immune system remain comparatively underexplored. To begin addressing this gap, we focused on mast cells, innate immune cells well-positioned to contribute to the multisystemic effects of developmental exposures. Mast cells are long-lived, tissue-resident cells enriched at barrier surfaces and perivascular sites throughout the body, including the brain. Their widespread distribution, extensive receptor repertoire, and unique ability to store and rapidly release bioactive mediators from cytoplasmic granules position them as key modulators of immune, endocrine, and nervous system function. Using oral exposure to two doses of a PBDE mixture throughout pregnancy and lactation in mice, we show that maternal exposure to ~87 ug/kg/day, aligned with the lower end of doses known to affect metabolic and neurobehavioral outcomes in preclinical models and within 10-fold of levels measured in human serum and placenta, leads to persistent dysfunction in mast cell mediator release in adult male and female offspring. This was evidenced by blunted anaphylaxis-associated hypothermia and plasma histamine release in vivo. These deficits were not due to changes in tissue-resident mast cell numbers, but rather to an impaired capacity to sustain histamine release over time. Studies in bone marrow-derived mast cells (BMMCs) revealed that histamine synthesis was intact, but granule maturation and stimulus-induced calcium mobilization were disrupted, in association with downregulation of genes such as IGF2R, ITGA4, ITGB6, and NGFR. Given that the bone marrow is the primary postnatal source of mast cells, these findings suggest that PBDEs induce lasting reprogramming at the level of hematopoietic progenitors. This may have broad implications not only for mast cell function across tissues, but also for other immune cell lineages that arise from the same progenitor pool. In sum, this study provides the first evidence that developmental exposure to PBDEs induces long-lasting impairments in mast cell functions, suggesting a previously unrecognized mechanism by which early-life exposure to environmental toxicants could contribute to persistent physiological and behavioral dysfunctions.