PT  - JOURNAL ARTICLE
AU  - Karin Dietrich
AU  - Jan Baumgart
AU  - Leonid Eshkind
AU  - Lea Reuter
AU  - Ute Gödtel-Armbrust
AU  - Elke Butt
AU  - Michael Musheev
AU  - Federico Marini
AU  - Piyush More
AU  - Tanja Grosser
AU  - Christof Niehrs
AU  - Leszek Wojnowski
AU  - Marianne Mathäs
TI  - Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy
AID  - 10.1124/dmd.118.082925
DP  - 2018 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1827--1835
VI  - 46
IP  - 11
4099  - http://dmd.aspetjournals.org/content/46/11/1827.short
4100  - http://dmd.aspetjournals.org/content/46/11/1827.full
SO  - Drug Metab Dispos2018 Nov 01; 46
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.