Zhu Hanhan, Liu Guangming, Chang Qi, Yan Mengyao, Yang Kun, Li Yanxin, Nie Yali, Li Xiaotian, Han Shengna, Wang Pei, Zhang Lirong
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Department of Pharmacology, School of Pharmacy, Zhengzhou University, Zhengzhou 450001, China.
Toxics. 2023 Jan 15;11(1):82. doi: 10.3390/toxics11010082.
Inflammation is a major regulator of drug-metabolizing enzymes (DMEs), therefore contributing to the interindividual variability of drug effects. However, whether prenatal inflammation affects DMEs expression in offspring remains obscure. This study investigated the effects of prenatal lipopolysaccharide (LPS) exposure on hepatic expression of inflammatory-related genes, nuclear receptors, and DMEs in offspring mice. Prenatal LPS exposure on gestational day (GD) 10 led to higher expression of NF-κB, Pxr, and Cyp2b10, while lower expression of Car, Ahr, Cyp3a11, and Ugt1a1 in postnatal day (PD) 30 offspring. However, multiple doses of LPS exposure on GD10-14 resulted in higher levels of inflammatory-related genes, Cyp1a2, and Cyp2b10, and lower levels of Pxr and Cyp3a11 in PD30 offspring liver. For PD60 offspring, decreased hepatic expression of NF-κB and IL-6, and increased expression of Pxr and Cyp3a11 were seen in single-dose LPS groups, whereas opposite results were observed in the multiple-dose LPS groups. Notably, enhanced H3K4me3 levels in the PXR response elements of the promoter were observed in the liver of PD60 offspring mice from dams treated with multiple doses of LPS during pregnancy. Overall, this study suggests that parental LPS exposure could persistently alter the hepatic expression of DMEs, and histone modifications may contribute to the long-term effects.
炎症是药物代谢酶（DMEs）的主要调节因子，因此导致了药物效应的个体间差异。然而，产前炎症是否会影响后代DMEs的表达仍不清楚。本研究调查了产前暴露于脂多糖（LPS）对后代小鼠肝脏中炎症相关基因、核受体和DMEs表达的影响。在妊娠第10天（GD10）产前暴露于LPS，导致出生后第30天（PD30）后代中NF-κB、Pxr和Cyp2b10的表达升高，而Car、Ahr、Cyp3a11和Ugt1a1的表达降低。然而，在GD10 - 14多次暴露于LPS导致PD30后代肝脏中炎症相关基因、Cyp1a2和Cyp2b10水平升高，而Pxr和Cyp3a11水平降低。对于PD60后代，单剂量LPS组肝脏中NF-κB和IL-6的表达降低，Pxr和Cyp3a11的表达增加，而在多剂量LPS组中观察到相反的结果。值得注意的是，在孕期接受多剂量LPS处理的母鼠所生的PD60后代小鼠肝脏中，观察到启动子的PXR反应元件中H3K4me3水平增强。总体而言，本研究表明亲本暴露于LPS可持久改变DMEs的肝脏表达，并且组蛋白修饰可能导致长期影响。
