Project Details
Projekt
Prenatal acetaminophen medication affects offspring’s immunity.
Applicant
Professorin Dr. Gisa Tiegs
Subject Area
Gynaecology and Obstetrics
Pharmacology
Rheumatology
Pharmacology
Rheumatology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 255154572
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.
DFG Programme
Clinical Research Units
