Perinatal androgen exposure impacts mast cell development and sex differences in mast cell-mediated pathophysiology

Abstract

Abstract Mast cell (MC)-associated diseases exhibit a sex bias with females often exhibiting more severe symptoms. Further, these sex biases exist in both prepubertal children and adults indicating that mechanisms other than adult sex hormones are involved. In previous studies, we showed that, compared with female MCs, male MCs store and release less histamine which coincided with reduced severity of MC-mediated anaphylaxis, and that these sex differences emerge prior to puberty. The early life mechanisms responsible for the emergence of sex differences in MC-associated disease remain poorly understood. Here we tested the hypothesis that perinatal androgen exposure, a major sexual organization event in males, drives sex differences in MC-mediated pathophysiology. Adult female mice that were previously exposed to high levels of androgens in the perinatal period (E16-PN7) via perinatal testosterone propionate administration had reduced IgE-mediated serum histamine levels and hypothermic responses compared with control females. In contrast, perinatal exposure of males to the endocrine disruptor DEHP, with known anti-androgenic effects, exacerbated IgE-mediated histamine levels and hypothermia. MC-deficient sash mice engrafted with BMMCs from adult perinatally androgenized females, exhibited reduced serum histamine and hypothermia responses compared with WT BMMC engrafted sash controls. Together, these data demonstrate that androgen exposure during the perinatal period shapes MC phenotype and MC-mediated anaphylaxis and thus could be an important determinant of differences in later life MC disease risk between the sexes.