Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
Comparative Biomedical Sciences Program, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27603.
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23751-23761. doi: 10.1073/pnas.1915075117. Epub 2020 Sep 11.
Mast cell (MC)-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a sex bias, with females at increase risk. While much attention has been directed toward adult sex hormones as drivers of sex differences, that female sex bias in MC-associated diseases is evident in prepubertal children, suggesting early-life origins of sex differences which have yet to be explored. Utilizing rodent models of MC-mediated anaphylaxis, our data here reveal that, 1) compared with females, males exhibit significantly reduced severity of MC-mediated anaphylactic responses that emerge prior to puberty and persist into adulthood, 2) reduced severity of MC-mediated anaphylaxis in males is linked with the naturally high level of perinatal androgens and can be recapitulated in females by perinatal exposure to testosterone proprionate, 3) perinatal androgen exposure guides bone marrow MC progenitors toward a masculinized tissue MC phenotype characterized by decreased concentration of prestored MC granule mediators (e.g., histamine, serotonin, and proteases) and reduced mediator release upon degranulation, and 4) engraftment of MC-deficient Kit mice with adult male, female, or perinatally androgenized female MCs results in MC-mediated anaphylaxis response that reflects the MC sex and not host sex. Together, these data present evidence that sex differences in MC phenotype and resulting disease severity are established in early life by perinatal androgens. Thus, factors affecting levels of perinatal androgens could have a significant impact on MC development and MC-associated disease risk across the life span.
肥大细胞（MC）相关疾病，包括过敏/过敏反应和神经炎症性疼痛障碍，表现出性别偏向，女性风险增加。虽然人们已经关注成年性激素作为性别差异的驱动因素，但 MC 相关疾病中的女性性别偏向在青春期前儿童中就已经很明显，这表明性别差异的起源早于生命早期，尚未得到探索。利用 MC 介导的过敏反应的啮齿动物模型，我们的数据显示：1）与女性相比，男性表现出 MC 介导的过敏反应严重程度显著降低，这种情况出现在青春期前，并持续到成年期；2）男性 MC 介导的过敏反应严重程度降低与围产期雄激素的自然高水平有关，并且可以通过围产期暴露于丙酸睾酮在女性中重现；3）围产期雄激素暴露指导骨髓 MC 祖细胞向男性化的组织 MC 表型分化，其特征是预先储存的 MC 颗粒介质（例如，组胺、血清素和蛋白酶）浓度降低，脱颗粒时介质释放减少；4）将缺乏 MC 的 Kit⁻/- 小鼠与成年雄性、雌性或围产期雄激素化雌性 MC 移植，导致 MC 介导的过敏反应反应反映了 MC 的性别，而不是宿主的性别。总之，这些数据表明，MC 表型和由此产生的疾病严重程度的性别差异是由围产期雄激素在生命早期建立的。因此，影响围产期雄激素水平的因素可能会对整个生命周期的 MC 发育和 MC 相关疾病风险产生重大影响。
