Prenatal acetaminophen medication affects offspring’s immunity.

产前对乙酰氨基酚药物会影响后代的免疫力。

• 批准号: 269322529
• 负责人: Professorin Dr. Gisa Tiegs
• 金额: --
• 依托单位: Institut für Experimentelle Immunologie und Hepatologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269322529?language=en
• 关键词: Prenatal; acetaminophen; medication; affects; offspring

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.

对乙酰氨基酚（APAP，例如扑热息痛®、泰诺®）是唯一建议在怀孕期间服用的镇痛和解热药物。最近的流行病学研究表明，产前 APAP 药物与儿童以后患哮喘的风险增加之间存在关联。 APAP主要在肝脏代谢，产生有毒和无毒代谢物。在胎儿中，肝脏暂时充当主要造血器官，为其他胎儿器官的免疫发育（例如胸腺 T 细胞发育）提供祖细胞。我们假设 APAP 可能会影响母体对妊娠的免疫适应并损害胎儿的免疫发育。我们建立了小鼠模型来确定产前 APAP 对母亲、胎儿和成年后代健康的影响。事实上，APAP 会加重怀孕小鼠的肝毒性，减少胎儿肝脏造血干细胞 (HSC) 的数量，并增加后代过敏性气道炎症的严重程度。现在的初步结果表明，通过用谷胱甘肽补充肝细胞，这些 APAP 效应是可逆的，谷胱甘肽可以拮抗 APAP 代谢物的毒性作用。在前瞻性纵向妊娠队列 PRINCE（儿童健康的产前决定因素）中，我们观察到 40% 的孕妇在怀孕期间至少服用一次 APAP。此外，母亲使用 APAP 后，新生儿脐带血中的 HSC 数量减少，这种影响在妊娠晚期使用 APAP 时尤为明显。下一个资助期的目标重点是破译产前 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，我们寻求使用针对 APAP 的解毒剂来挽救产前 APAP 药物的不良反应。我们的转化方法包括评估新生儿 HSC 的成熟状态，并确定妊娠期间服用 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。这些发现可能与儿童期免疫力差有关，例如早期感染频率高、疫苗接种反应差或哮喘发作。通过使用 PRINCE 研究中的可用数据，这种转化方法将成为可能。该提案的独特之处在于可以在明确的小鼠模型中结合强大的平移臂来研究产前 APAP 药物的机械提示和功能后果，其中可以提供妊娠期间 APAP 药物的时间、剂量和持续时间的深入记录，并且可以评估其对儿童健康的免疫学和临床后果。