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 1827
OP 1835
DO 10.1124/dmd.118.082925
VO 46
IS 11
A1 Karin Dietrich
A1 Jan Baumgart
A1 Leonid Eshkind
A1 Lea Reuter
A1 Ute Gödtel-Armbrust
A1 Elke Butt
A1 Michael Musheev
A1 Federico Marini
A1 Piyush More
A1 Tanja Grosser
A1 Christof Niehrs
A1 Leszek Wojnowski
A1 Marianne Mathäs
YR 2018
UL http://dmd.aspetjournals.org/content/46/11/1827.abstract
AB 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 TCPOBOP, an activator of the nuclear receptor constitutive androstane receptor (CAR, NR1I3), and mated them 1–6 weeks afterward. We detected in the offspring long-lasting alterations of CAR-mediated drug disposition, energy metabolism, and lipid profile. The transmission to the first filial generation (F1) was mediated by TCPOBOP transfer from the F0 adipose tissue via milk, as revealed by embryo transfer, crossfostering experiments, and liquid chromatography–mass spectrometry analyses. The important environmental pollutant PCB153 activated CAR in the F1 generation in a manner similar 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 in 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 with known or suspected accumulation in adipose tissue.