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ToxSci Advance Access originally published online on June 23, 2005
Toxicological Sciences 2005 87(1):38-45; doi:10.1093/toxsci/kfi239
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Perinatal Lipopolysaccharide Exposure Downregulates Pregnane X Receptor and Cyp3a11 Expression in Fetal Mouse Liver

De-Xiang Xu*,{dagger},1, Yuan-Hua Chen*, Jian-Ping Wang*, Mei-Fang Sun*, Hua Wang*, Ling-Zhen Wei* and Wei Wei{dagger},{ddagger}

* Department of Toxicology, and {dagger} Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, P.R. China; {ddagger} Key Laboratory of Anti-inflammatory and Immunopharmacology of Anhui Province, Hefei, 230032, P.R. China

Received April 11, 2005; accepted June 2, 2005

The pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates cytochrome P450 3A (CYP3A) gene transcription in a ligand-dependent manner. Lipopolysaccharide (LPS)-induced downregulation on PXR and cyp3a11 in adult mouse liver has been well characterized. In this study, we investigated the effects of maternal LPS exposure on PXR and cyp3a11 expression in fetal mouse liver. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1~0.5 mg/kg) on gestational day (GD) 17. PXR and cyp3a11 mRNA levels were determined using RT-PCR. Erythromycin N-demethylase (ERND) activity was used as an indicator of CYP3A expression in this study. Results showed that LPS significantly downregulated PXR and cyp3a11 mRNA levels and ERND activity in fetal liver in a dose-dependent manner. LPS-induced downregulation of PXR and cyp3a11 mRNA expression and ERND activity was attenuated after pregnant mice were pretreated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiment revealed that LPS significantly increased lipid peroxidation in fetal liver, which was also attenuated by PBN pretreatment. Furthermore, LPS-induced downregulation of PXR and cyp3a11 mRNA expression and ERND activity was prevented by maternal pretreatment with N-acetylcysteine (NAC). Maternal pretreatment with NAC also inhibited LPS-initiated lipid peroxidation and GSH depletion in fetal liver. However, maternal LPS treatment did not affect nitrite plus nitrate concentration in fetal liver. Correspondingly, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase (iNOS), has no effect on LPS-induced downregulation of PXR and cyp3a11 expression and ERND activity in fetal liver. These results indicated that maternal LPS exposure downregulates PXR and cyp3a11 in fetal mouse liver. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR and cyp3a11 in fetal mouse liver.

Key Words: lipopolysaccharide; fetal liver; pregnane X receptor; cytochrome P450 3A; reactive oxygen species.


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