| Popis: |
Environmental exposures during a critical window of developmental plasticity can alter disease susceptibility later in life. The nuclear receptor CAR (constitutive androstane receptor) is a known xenobiotic sensor that is activated by environmental chemicals to regulate the transcription of genes involved in hepatic drug metabolism, energy homeostasis, and hepatic carcinogenesis. This study investigated long-term gene expression changes in adult mouse liver followed by neonatal activation of CAR by its agonists at environmentally and physiologically relevant doses. The results demonstrated that previously reported long-term expression changes of Cyp2 genes, which encode monooxygenases, caused by neonatal exposure to the CAR-specific agonist, TCPOBOP (1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene), were likely due to the persistence of residual TCPOBOP in the liver. Additionally, I showed that the neonatal exposure to another CAR agonist, phenobarbital, could induce altered Cyp2 gene regulation at adulthood, which may be due to epigenetic reprogramming. These findings provide new insights into the role of CAR in liver physiology and the impact of early life environmental exposures on disease susceptibility. They also highlight the importance of careful experimental design in studying the long-term effects of environmental chemicals and could have implications for the development of therapeutics targeting CAR in liver- related disorders. |
