Perinatal androgens drive sex differences in mast cell phenotype and severity of mast cell disease

Abstract

Abstract Highly prevalent and debilitating mast cell (MC)-associated immune disorders, such as allergy and irritable bowel syndrome exhibit a female sex bias in childhood and adulthood. The mechanisms underlying sex differences in MC disorders are unknown. Previously, we found adult female mice exhibited greater serum histamine and more severe MC-associated pathophysiology that coincided with an increased capacity to synthesize and store immune mediators, compared with males. Further, recent data showed sex differences in the MC exist prior to puberty, suggesting a mechanism independent of adult sex hormones. Here, we investigated the role of perinatal androgens, a key early life component of sexual differentiation, in sex differences in MC phenotype and MC disease. Testosterone proprionate (100 μg sc qd) or vehicle was given to pregnant female mice E16-P0 and directly to pups PN1-7. IgE-mediated anaphylaxis was performed in gonadectomized control male (CM), control female (CF) and perinatally androgenized female (AF) offspring at 8 wk of age. Serum histamine levels (CM 768 ± 106, CF 1406 ± 200, AF 676 ± 110 ng/mL) and hypothermia responses (Δ temp: CM −4.87 ± 0.45, CF − 7.28 ± 0.48, AF − 4.8 ± 0.39 °C) were ~2x lower in AF than CF mice, while AF and CM mice had similar responses. Further, bone marrow MC from AF mice had lower histamine content (AF 1305 ± 82: CF 2082 ± 94 ng/106cells) and 47% lower histamine release to IgE-FcɛRI stimulus compared to CF mice. Together, we demonstrate that sex differences in MC phenotype and disease susceptibility are established early in life by perinatal androgens. These findings provide insight into the mechanisms of sex differences in MC-associated immune disorders that could lead to new therapeutic targets for MC diseases.