title: Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring.
abstract: OBJECTIVE
  During pregnancy, acetaminophen is one of the very few medications recommended by physicians to treat fever or pain. Recent insights from epidemiological studies suggest an association between prenatal acetaminophen medication and an increased risk for development of asthma in children later in life. The underlying pathogenesis of such association is still unknown.
  
  
  METHODS
  We aimed to develop a mouse model to provide insights into the effect of prenatal acetaminophen on maternal, fetal and adult offspring's health. The toxic effect of acetaminophen was studied in mice on 1) maternal liver; mirrored by biomarkers of liver injury, centrilobular necrosis, and infiltration of granulocytes; 2) fetal liver; reflected by the frequency of hematopoietic stem cells, and 3) postnatal health; evaluated by the severity of allergic airway inflammation among offspring.
  
  
  RESULTS
  We observed an increased susceptibility towards acetaminophen-induced liver damage in pregnant mice compared to virgins. Moreover, hematopoietic stem cell frequency in fetal liver declined in response to acetaminophen. Furthermore, a greater severity of airway inflammation was observed in offspring of dams upon prenatal acetaminophen treatment, identified lung infiltration by leukocytes and eosinophil infiltration into the airways.
  
  
  CONCLUSIONS
  Our newly developed mouse model on prenatal use of acetaminophen reflects findings from epidemiological studies in humans. The availability of this model will allow improvement in our understanding of how acetaminophen-related hepatotoxicity is operational in pregnant individuals and how an increased risk for allergic diseases in response to prenatal acetaminophen is mediated. Such insights, once available, may change the recommendations for prenatal acetaminophen use.
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: k.karimi@uke.de.
authors.forename: Khalil
authors.initials: K
authors.lastname: Karimi
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Keßler
authors.affiliation: Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Thiele
authors.affiliation: Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katherina
authors.initials: K
authors.lastname: Ramisch
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Erhardt
authors.affiliation: I. Medical Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Huebener
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Roja
authors.initials: R
authors.lastname: Barikbin
authors.affiliation: Laboratory for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Arck
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: g.tiegs@uke.de.
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects; D000328:Adult; D032721:Adult Children; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000503:physiopathology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D053686:Fetal Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D012720:Severity of Illness Index
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
keywords: Allergic inflammation; Eosinophil infiltration; Hematopoietic stem cells; Hepatotoxicity; Pregnancy immune adaptation