Health-relevant phenotypes in the offspring of mice given CAR activators prior to pregnancy

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. Female F0 mice used to obtain F1 offspring were induced with TCPOBOP (3 mg/kg) three days after birth. We considered 6-day-old and 3-month-old mice of the F0 and of the F1 generation for mRNA-sequencing. For each group the RNA of 2 to 6 mice was pooled into one sample. We then sequenced TCPOBOP treated mice as well as their F1 offspring together with the respective corn oil controls.