Prenatal acetaminophen medication affects offspring’s immunity.

对乙酰氨基酚（APAP，例如Paracetamol®，Tylenol®）是妊娠期间推荐服用的唯一镇痛和解热药物。最近的流行病学研究表明，产前APAP药物与儿童日后患哮喘的风险增加有关。APAP主要在肝脏中代谢，产生有毒和无毒代谢物。在胎儿中，肝脏暂时作为主要的造血器官发挥作用，为其他胎儿器官中的免疫发育提供祖细胞，如胸腺T细胞发育。我们推测APAP可能影响母体对妊娠的免疫适应，并损害胎儿的免疫发育。我们建立了一个小鼠模型，以确定产前APAP对母亲，胎儿和成年后代的健康的影响。事实上，APAP加重了妊娠小鼠的肝毒性，减少了胎肝造血干细胞（HSC）数量，并增加了后代过敏性气道炎症的严重程度。现在的初步结果表明，这些APAP的影响是可逆的补充肝细胞谷胱甘肽，拮抗APAP代谢物的毒性作用。在前瞻性纵向妊娠队列PRINCE（儿童健康的产前检查）中，我们观察到40%的孕妇在怀孕期间至少服用一次APAP。此外，当母亲使用APAP时，新生儿脐带血中的HSC数量减少，当在妊娠晚期使用APAP时，这种影响尤其深刻。下一个资助期的目标集中在破译产前APAP药物对小鼠后代免疫力的影响，例如哮喘和新生儿病毒感染的风险和严重程度。此外，我们试图挽救产前APAP药物使用APAP-解毒剂的不良反应。我们的翻译方法包括评估新生儿HSC的成熟状态，并确定在妊娠期间服用APAP的母亲所生幼儿的脐带血和外周血中T细胞亚群的变化。这些发现将与儿童免疫力低下有关，例如早期感染的频率高，疫苗接种反应差或哮喘发作。通过使用PRINCE研究中可用的数据，这种转化方法将成为可能。该提案是独特的，因为有可能在明确定义的小鼠模型中结合强平移臂研究产前APAP药物的机制提示和功能后果，其中可以深入记录妊娠期间APAP药物的时间，剂量和持续时间，并可以评估其对儿童健康的免疫学和临床后果。

Acetaminophen (APAP, e.g. Paracetamol®, Tylenol®) is the only analgesic and antipyretic medication recommended to be taken during pregnancy. Recent epidemiological studies suggest an association between antenatal APAP medication and an increased risk for asthma in children later in life. APAP is mainly metabolized in the liver, yielding to toxic and non-toxic metabolites. In the foetus, the liver transiently functions as the main hematopoietic organ, providing progenitor cells for immune development in other foetal organs, such as thymic T cell development. We hypothesized that APAP might affect maternal immune adaptation to pregnancy and impairs foetal immune development. We established a mouse model to determine the effect of antenatal APAP on maternal, foetal, and adult offspring’s health. Indeed, APAP aggravated hepatotoxicity in pregnant mice, reduced foetal liver hematopoietic stem cell (HSC) numbers, and increased the severity of allergic airway inflammation in the offspring. Preliminary results now indicated that these APAP effects are reversible by replenishing hepatocytes with glutathione, which antagonizes the toxic effects of APAP metabolites. In the prospective longitudinal pregnancy cohort PRINCE (PRENATAL DETERMINANTS OF CHILDREN`S HEALTH), we observed that 40% of pregnant women took APAP at least once during pregnancy. Moreover, HSC numbers were reduced in cord blood of newborns upon maternal use of APAP, this effect was particularly profound when APAP was used during the third trimester. The objectives of the next funding period focus on deciphering the consequences of antenatal APAP medication on offspring’s immunity in mice, such as the risk and severity of asthma and neonatal viral infections. Moreover, we seek to rescue the adverse effects of antenatal APAP medication using APAP-trageted antidotes. Our translational approach includes to assess the maturation status of neonatal HSC and to determine alterations in T cell subpopulations in cord blood and peripheral blood of young children born to mothers who took APAP during pregnancy. These findings will be linked to a poor immunity in childhood, such as a high frequency of early life infections, a poor vaccination response or the onset of asthma. This translational approach will be possible by using the data available in the PRINCE study. The proposal is unique due to the possibility to study mechanistic cued and functional consequences of antenatal APAP medication in a well-defined mouse model in combination with a strong translational arm, where an in-depth documentation of time, dosage and duration of APAP medication during pregnancy is available and can be evaluated with regard to its immunological and clinical consequences for children’s health.