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  • Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy.

Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy.

Drug metabolism and disposition: the biological fate of chemicals (2018-08-30)
Karin Dietrich, Jan Baumgart, Leonid Eshkind, Lea Reuter, Ute Gödtel-Armbrust, Elke Butt, Michael Musheev, Federico Marini, Piyush More, Tanja Grosser, Christof Niehrs, Leszek Wojnowski, Marianne Mathäs
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

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Anti-CYP2b10 Antibody, serum, Chemicon®
Sigma-Aldrich
Anti-Rabbit IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody
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Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in sheep, affinity isolated antibody, buffered aqueous solution