Maternal Liver Damage Programs Offspring Allergic Inflammation in Mice

Introduction: Liver disease can occur in the pregnant patient and pregnancy may occur in a patient with chronic liver disease, which in both cases severe consequences in the mother and fetus are expected. Prenatal risk factors may affect the development of allergies and human studies provided considerable indications for a correlation between the use of Acetaminophen (APAP) and an increased risk of the children to develop allergies. APAP is mainly metabolized in the liver, and freely crosses the placenta, resulting in pharmacologically active levels in the developing fetus. In the fetus, the liver transiently functions as the main hematopoietic organ providing progenitor cells, which seed in the thymus to undergo T cell development.

Objectives: More than 20% of pregnant women uptake APAP and APAP hepatotoxicity is the most common cause of death due to acute liver failure in the developed world. The epidemiological findings suggest that use of APAP in pregnancy is associated with increased asthma symptoms in children. Employing a mouse model of allergic airway inflammation, we have therefore sought to study the potential effects of prenatal APAP administration and the possible liver damage on the risk of allergic disorders among the offspring.

Methods: The hepatotoxicity of APAP administration in pregnant mice was analyzed using different biochemical, histological, and immunological assays. An ovalbumin (OVA)-sensitized mouse model of allergic airway inflammation was employed and the offspring of APAP treated mice were monitored for the severity of airway inflammation using histologic and flow cytometric analysis.

Results: We observed an increase of liver damage after APAP injection to pregnant mice in comparison to the virgins. Administration of a single dose APAP (250 mg/kg) to pregnant mice was associated with a sharp elevation of plasma transaminases and granulocyte infiltration into livers of dams. Furthermore, an increase in the severity of allergic inflammation was detected since higher leukocyte infiltration to the airways and eosinophil infiltration in bronchoalveolar lavage (BAL) among offspring of APAP treated mothers than controls were demonstrated. The percentage of Siglec-F+ cells in BAL of control animals was 37%, which increased to 71% in offspring of mice administered with APAP during pregnancy. Additionally, the increase in eosinophil infiltration in BAL was confirmed by cytospin preparations. Eosinophil counts in BAL among offspring of APAP-administered dams increased from 34% to 58%.

Conclusions: We demonstrated that use of APAP during pregnancy is associated with an increased susceptibility to APAP-induced hepatotoxicity in dams and the severity of allergic inflammation in the offspring. Full characterization of liver-mediated immune adaptation to pregnancy in APAP-treated dams and their fetus may clarify the mechanisms responsible for the increase in severity of allergic inflammation among the offspring.