Hartwig Isabel R V, Bruenahl Christian A, Ramisch Katherina, Keil Thomas, Inman Mark, Arck Petra C, Pincus Maike
Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,
J Mol Med (Berl). 2014 Oct;92(10):1093-104. doi: 10.1007/s00109-014-1167-9. Epub 2014 Jun 3.
Observational as well as experimental studies support that prenatal challenges seemed to be associated with an increased risk for allergic airway diseases in the offspring. However, insights into biomarkers involved in mediating this risk are largely elusive. We here aimed to test the association between endogenous and exogenous factors documented in pregnant women, including psychosocial, endocrine, and life style parameters, and the risk for allergic airway diseases in the children later in life. We further pursued to functionally test identified factors in a mouse model of an allergic airway response. In a prospectively designed pregnancy cohort (n = 409 families), women were recruited between the 4th and 12th week of pregnancy. To investigate an association between exposures during pregnancy and the incidence of allergic airway disease in children between 3 and 5 years of age, multiple logistic regression analyses were applied. Further, in prenatally stressed adult offspring of BALB/c-mated BALB/c female mice, asthma was experimentally induced by ovalbumin (OVA) sensitization. In addition to the prenatal stress challenge, some pregnant females were treated with the progesterone derivative dihydrodydrogesterone (DHD). In humans, we observed that high levels of maternal progesterone in early human pregnancies were associated with a decreased risk for an allergic airway disease (asthma or allergic rhinitis) in daughters (adjusted OR 0.92; 95% confidence interval [CI] 0.84 to 1.00) but not sons (aOR 1.02, 95% CI 0.94-1.10). In mice, prenatal DHD supplementation of stress-challenged dams attenuated prenatal stress-induced airway hyperresponsiveness exclusively in female offspring. Reduced levels of maternal progesterone during pregnancy-which can result from high stress perception-increase the risk for allergic airway diseases in females but not in males. Key messages: Lower maternal progesterone during pregnancy increases the risk for allergic airway disease only in female offspring. Prenatal progesterone supplementation ameliorates airway hyperreactivity in prenatally stressed murine offspring.
观察性研究和实验性研究均支持，产前面临的挑战似乎与后代患过敏性气道疾病的风险增加有关。然而，对于介导这种风险的生物标志物，我们仍知之甚少。我们的目的是检测孕妇体内记录的内源性和外源性因素（包括心理社会、内分泌和生活方式参数）与儿童日后患过敏性气道疾病风险之间的关联。我们还进一步试图在过敏性气道反应的小鼠模型中对已确定的因素进行功能测试。在一个前瞻性设计的妊娠队列（n = 409个家庭）中，孕妇在怀孕第4周至第12周期间入组。为了研究孕期暴露因素与3至5岁儿童过敏性气道疾病发病率之间的关联，我们进行了多项逻辑回归分析。此外，在BALB/c交配的BALB/c雌性小鼠的产前应激成年后代中，通过卵清蛋白（OVA）致敏实验性诱导哮喘。除了产前应激挑战外，一些怀孕雌性小鼠接受了孕酮衍生物二氢孕酮（DHD）治疗。在人类中，我们观察到，孕早期母体孕酮水平较高与女儿患过敏性气道疾病（哮喘或过敏性鼻炎）的风险降低有关（校正比值比0.92；95%置信区间[CI] 0.84至1.00），但与儿子无关（校正比值比1.02，95% CI 0.94 - 1.10）。在小鼠中，对受应激挑战的母鼠产前补充DHD仅在雌性后代中减轻了产前应激诱导的气道高反应性。孕期母体孕酮水平降低（这可能是由于高应激感知所致）会增加雌性而非雄性患过敏性气道疾病的风险。关键信息：孕期母体孕酮水平较低仅会增加雌性后代患过敏性气道疾病的风险。产前补充孕酮可改善产前应激小鼠后代的气道高反应性。
