Prenatal Acetaminophen Affects Maternal Immune and Endocrine Adaptation to Pregnancy, Induces Placental Damage, and Impairs Fetal Development in Mice

TY - JOUR

T1 - Prenatal Acetaminophen Affects Maternal Immune and Endocrine Adaptation to Pregnancy, Induces Placental Damage, and Impairs Fetal Development in Mice

AU - Thiele, Kristin

AU - Solano, Maria E

AU - Huber, Samuel

AU - Flavell, Richard A

AU - Kessler, Timo

AU - Barikbin, Roja

AU - Jung, Roman

AU - Karimi, Khalil

AU - Tiegs, Gisa

AU - Arck, Petra C

N1 - Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PY - 2015/10

Y1 - 2015/10

N2 - Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.

AB - Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.

U2 - 10.1016/j.ajpath.2015.06.019

DO - 10.1016/j.ajpath.2015.06.019

M3 - SCORING: Journal article

C2 - 26254283

VL - 185

SP - 2805

EP - 2818

JO - AM J PATHOL

JF - AM J PATHOL

SN - 0002-9440

IS - 10

ER -