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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE109630 | GEO | 2018/08/23

REPOSITORIES: GEO

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Genome-wide analysis of gene expression in adipose tissue of female mice after continuous high fat diet feeding

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2008-08-23 | E-GEOD-12509 | biostudies-arrayexpress

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Project description:PURPOSE: To examine if a parental high fat diet (HFD) influences metabolic health in two generations of offspring, and alters the germ cell (GC) transcriptome. PROCEDURE: GC-eGFP Sprague Dawley rats were weaned onto HFD (45% fat) or Control Diet (CD; 10% fat). After metabolic testing, founders (F0) were bred with controls, establishing the F1 generation. Germ cells from F0 males were isolated and their RNA sequenced. F1 rats were bred with control rats at 17 weeks to generate F2 offspring. FINDINGS: HFD resulted in 9.7% and 14.7% increased weight in male and female F0 respectively. F1 offspring of HFD mothers were heavier than controls. F1 daughters of HFD-fed males were also heavier. F2 male offspring derived from HFD-fed maternal grandfathers were 7.2% heavier, and exhibited increases of 31% in adiposity, 97% in plasma leptin and 300% in luteinising hormone to testosterone ratio. HFD exposure did not alter the F0 GC transcriptome. CONTROLS: Matched CD was consumed by all animals not consuming the HFD. Animals were compared to a parallel cohort of CD rats. CONCLUSIONS: HFD consumption by maternal grandfathers results in a disrupted metabolic phenotype in grandsons. This effect is not mediated by alterations to the GC transcriptome.

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