Impact of neonatal activation of nuclear receptor CAR (Nr1i3) on Cyp2 gene expression in adult mouse liver

Abstract

Perinatal exposure to environmental chemicals is proposed to reprogram development and alter disease susceptibility later in life. Supporting this, neonatal activation of the nuclear receptor CAR (Nr1i3) by TCPOBOP induces persistent expression of mouse hepatic Cyp2 genes into adulthood, attributed to long-term epigenetic memory of the early life exposure [Hepatology (2012) 56:1499-1509]. Here, we confirm that the same high-dose (15x ED50) neonatal TCPOBOP exposure used in that work induces prolonged (12 weeks) increases in hepatic Cyp2 expression; however, we show that the persistence of expression can be fully explained by the persistence of residual TCPOBOP in liver tissue. When the long-term presence of TCPOBOP in tissue was eliminated by decreasing the neonatal TCPOBOP dose 22-fold (0.67x ED50), strong neonatal increases in hepatic Cyp2 expression were still obtained but did not persist into adulthood. Furthermore, the neonatal ED50-range TCPOBOP exposure did not sensitize mice to a subsequent, low-dose TCPOBOP treatment. In contrast, neonatal treatment with phenobarbital, a short half-life (t1/2=8 h) agonist of CAR and of PXR (Nr1i2), induced high-level neonatal activation of Cyp2 genes and also altered their responsiveness to low-dose phenobarbital exposure at adulthood by either increasing (Cyp2b10) or decreasing (Cyp2c55) expression. Thus, neonatal xenobiotic exposure can reprogram hepatic Cyp2 genes and alter their responsiveness to exposures later in life. These findings highlight the need to carefully consider xenobiotic dose, half-life and persistence in tissue when evaluating the long-term effects of early life environmental chemical exposures.