Xenobiotic agonists of
constitutive androstane receptor (CAR) induce many hepatic
drug metabolizing
enzymes, but following prolonged exposure, promote
hepatocellular carcinoma, most notably in male mouse liver. Here, we used
nuclear RNA-seq to characterize global changes in the mouse liver transcriptome following exposure to the CAR-specific agonist
ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]
benzene (
TCPOBOP), including changes in novel long noncoding RNAs that may contribute to
xenobiotic-induced pathophysiology.
Protein-coding genes dysregulated by 3 h
TCPOBOP exposure were strongly enriched in KEGG pathways of
xenobiotic and
drug metabolism, with stronger and more extensive gene responses observed in female than male liver. After 27 h
TCPOBOP exposure, the number of responsive genes increased >8-fold in males, where the top enriched pathways and their upstream regulators expanded to include factors implicated in cell cycle dysregulation and
hepatocellular carcinoma progression (
cyclin-D1, oncogenes E2f, Yap, Rb, Myc, and proto-oncogenes β-
catenin, FoxM1, FoxO1, all predicted to be activated by
TCPOBOP in male but not female liver; and
tumor suppressors p21 and p53, both predicted to be inhibited). Upstream regulators uniquely associated with 3 h
TCPOBOP-exposed females include TNF/NFkB pathway members, which negatively regulate CAR-dependent proliferative responses and may contribute to the relative resistance of female liver to
TCPOBOP-induced
tumor promotion. These responses may be modified by the many long noncoding liver RNAs we show are dysregulated by
TCPOBOP or
pregnane-X-receptor agonist exposure, including lncRNAs proximal to CAR target genes Cyp2b10, Por, and Alas1. These data provide a comprehensive view of the CAR-regulated transcriptome and give insight into the mechanism of sex-biased susceptibility to CAR-dependent mouse liver
tumorigenesis.