RT Journal Article
SR Electronic
T1 Health-relevant phenotypes in the offspring of mice given CAR activators prior to pregnancy
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.082925
DO 10.1124/dmd.118.082925
A1 Karin Dietrich
A1 Jan Baumgart
A1 Leonid Eshkind
A1 Lea Reuter
A1 Ute Godtel-Armbrust
A1 Elke Butt
A1 Michael Musheev
A1 Federico Marini
A1 Piyush More
A1 Tanja Grosser
A1 Christof Niehrs
A1 Leszek Wojnowski
A1 Marianne Mathas
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/08/28/dmd.118.082925.abstract
AB The hepatic induction in response to drugs and environmental chemicals affects drug therapies and energy metabolism. We investigated whether the induction is transmitted to the offspring. We injected 3-day and 6-week-old F0 female mice with the activator of the nuclear receptor CAR (constitutive androstane receptor, NR1I3) TCPOBOP and mated them 1-6 weeks afterwards. We detected in the offspring long-lasting alterations of CAR-mediated drug disposition, energy metabolism, and lipid profile. The transmission to F1 was mediated by TCPOBOP transfer from the F0 adipose tissue via milk, as revealed by embryo transfer, cross-fostering experiments, and liquid chromatography-mass spectrometry analyses. The important environmental pollutant PCB153 activated CAR in the F1 generation similarly to TCPOBOP. Our findings indicate that chemicals accumulating and persisting in adipose tissue may exert liver-mediated, health-relevant effects on F1 offspring simply via physical transmission with milk. Such effects may occur even if treatment has been terminated far ahead of conception. This should be considered in assessing developmental toxicity and in the long-term follow-up of offspring of mothers exposed to both approved and investigational drugs, and to chemicals known or suspected of accumulation in adipose tissue.