Publications — duquewilckenslab.com

Jared Franges, Lauren Malinowski, Chathuri De Alwis, Taylor Doolittle, Hannahlee Dixon, Yang Tang, Helen Watson, Jasmine Peace, Dereje Jima, Leslie Sombers, Gregory McCarthy, Heather Patisaul, Heather M. Stapleton, Natalia Duque-Wilckens

doi:https://doi.org/10.1101/2025.06.28.661534

Abstract

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, here we show that maternal exposure to ∼87 μg/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—with broad implications not only for mast cell function across tissues, but potentially for other immune cell lineages as well. 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

Natalia Duque-Wilckens, Dimitri Joseph, Meesum Syed, Brianna Sm ith, Nidia Maradi aga, Szu-Ying Yeh, Vidhula Sri nivasan, Fabiola Sotomayor, Kait Durga, Eric Nest ler, Adam J Moes ers, AJ Robison

bioRxiv [Preprint]. 2025 Mar 27:2024.05.06.592755.

doi: 10.1101/2024.05.06.592755.

Link

Duque-Wilckens, N., Teis, R., Sarno, E., Stoeltig, F., Khalid, S., Dairi, Z., Douma, A., Maradiaga, N., Hench, S., Dharshika, C., Thelen, K., Gulbransen, B., Robison, A.J., Moeser, A.J.

Brain, Behav, Immun. 2022. Mar 23:S0889-1591(22)00077-0.

Link

Minie, V*., Petric, R., Ramos-Maciel, S. , Wright, E.C., Trainor, B.C., Duque-Wilckens, N*

*Corresponding author

Appl. Anim. Behav. Sci. 2021, June 29, 2021.105381.

Link

Gao, Y., Duque-Wilckens, N., Aljazi, M., Wu, Yan., Moeser, A.J., Mias, G.I., Robison, A.J., He, J.

iScience, 2022, Jan 7;25(2):103742.

Link

Gao, Y.†, Duque-Wilckens, N.†, Aljazi, M., Wu, Yan., Moeser, A.J., Mias, G.I., Robison, A.J., He, J.

†Equally contributing authors

Commun Biol, 2021 June 18, 18;4(1):756

Link

Duque-Wilckens, N., Torres, L., Yokoyama*, S., Minie*, V. , Tran*, A., Petkova, S., Hao, R., Ramos-Maciel, S., Rios, R., Jackson, K., Flores-Ramirez, F., Garcia-Carachure, I., Pesavento, P., Iniguez, S., Grinevich, V., Trainor, B.C.

PNAS, 2020 October 20, 117 (42) 26406-26413

Link

Steinman MQ†, Duque-Wilckens, N.†, Trainor, B.C.

†Equally contributing authors.

Biol Psychiatry, 2019 May 15;85(10):792-801

Link

Duque-Wilckens, N., Steinman, M.Q., Busnelli, M., Chini, B., Yokoyama*, S., Pham*, M., Laredo, S.A., Hao, R., Perkeybile, A.M., Minie*, V., Tan*, P.B., Bales, K. & Trainor, B.C.

Biol Psychiatry, 2018 Feb 1;83(3):203-213.

Link

Duque-Wilckens, N., Steinman, M.Q., Laredo, S.A., Hao, R., Perkeybile, A.M., Bales, K.L. & Trainor, B.C.

Neuropharmacology, 2016 Nov; 110: 59-68

Link

Peen, N.F., Duque-Wilckens, N., Trainor, B.C.

Horm Behav, 2021, Mar;129:104933

Pubmed link

Mcclain, J.N, Mazzotta, E.A., Maradiaga, N., Duque-Wilckens, N., Grants, I., Robison, A.J., Christofi, F.L., Moeser, A.J., Gulbransen, B.D. .

Am J Physiol Gastrointest Liver Physiol 2020 Dec 1;319(6):G655-G668.

Pubmed link

Williams, A. Duque-Wilckens, N., Ramos-Maciel, S. Campi, K.L., Bhela, S.K., Xu, C.K., Jackson, K., Chini, B., Pesavento, P.A., Trainor, B.C.

Neuropsychopharmacol. 2020 Mar 20. doi: 10.1038/s41386-020-0657-4.

Pubmed link

Mayer HS, Crepeau M, Duque-Wilckens N, Torres LY, Trainor BC, Stolzenberg DS.

J Neuroendocrinol. 2019 Sep;31(9):e12734

Pubmed link

Leonzino M, Ponzoni L, Braida D, Gigliucci V, Busnelli M, Ceresini I, Duque-Wilckens N, Nishimori K, Trainor BC, Sala M, Chini B.

Horm Behav. 2019 Aug;114:104543.

Pubmed link

Williams ES, Manning CE, Eagle AL, Swift-Gallant A, Duque-Wilckens N, Chinnusamy S, Moeser A, Jordan C, Leinninger G, Robison AJ.

Biol Psychiatry. 2020 Mar 15;87(6):492-501

Pubmed link

Rodriguez-Jorquera, I., Vitale, N., Garner, L. , Perez-Venegas, D., Galbán-Malagón, C. , Duque-Wilckens, N. & Toor, G.

Current Pollution Reports, 2017; Sept 3:206-219

Link

Steinman, M.Q., Duque-Wilckens, N., Greenberg, G.D., Hao, R., Campi, K.L., Laredo, S., Laman-Maharg, A., Manning, C.A., Doig, I.E., Lopez, E.M., Walch, K., Bales, K. & Trainor, B.C.

Biological Psychiatry, 2016 80: 406-414.

Pubmed link

Duque-Wilckens, N. & Trainor, B.C.

Psychoneuroendocrinology. 2022 Jun;140:105709. doi: 10.1016/j.psyneuen.2022.105709.

Pubmed link

Scientific publications

"Mysteries, however small, are fascinating because there's always the possibility that their solution may lead to a fundamental shift in our understanding of the world".

McFadden and Al-Khalili, Life on the Edge.

Scientific publications

Developmental PBDE exposure impairs histamine release from mast cells by altering granule maturation and calcium signaling in adult male and female mice

FosB/ΔFosB activation in mast cells regulates gene expression to modulate allergic inflammation in male mice

Early life adversity drives sex-specific anhedonia and meningeal immune gene expression through mast cell activation.

Enriched laboratory housing increases sensitivity to social stress in female California mice (Peromyscus Californicus).

Impaired KDM2B-mediated PRC1 recruitment to chromatin causes defective neural stem cell self-renewal and ASD/ID-like behaviors.

Loss of methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

Complementary Neural Circuits for Divergent Effects of Oxytocin: Social Approach Versus Social Anxiety

Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in females

Inhibition of vasopressin V1a receptors in the medioventral bed nucleus of the stria terminalis has sex- and context-specific anxiogenic effects.

Convergent neuroendocrine mechanisms of social buffering and stress contagion

Histamine-dependent interactions between mast cells, glia, and neurons are altered following early-life adversity in mice and humans

Social Approach and Social Vigilance Are Differentially Regulated by Oxytocin Receptors in the Nucleus Accumbens.

Histone deacetylase inhibitor treatment promotes spontaneous caregiving behaviour in non-aggressive virgin male mice.

Impaired approach to novelty and striatal alterations in the oxytocin receptor deficient mouse model of autism

ndrogen-Dependent Excitability of Mouse Ventral Hippocampal Afferents to Nucleus Accumbens Underlies Sex-Specific Susceptibility to Stress.

Contamination of the Upper Class: Occurrence and Effects of Chemical Pollutants in Terrestrial Top Predators

Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin.

Oxytocin release in stressful times

"Mysteries, however small, are fascinating because there's always the possibility that their solution may lead to a fundamental shift in our understanding of the world".

McFadden and Al-Khalili, Life on the Edge.