Dataset Information

Down-regulation of ABCG2 and ABCB4 transporters in the placenta of rats exposed to cadmium.

ABSTRACT: As a maternal and developmental toxicant, cadmium (Cd) possesses weak penetrability through the placental barrier. However, the underlying mechanism remains unclear. To gain insight into the protein molecules associated with Cd toxicity in placenta and explore their roles in Cd transportation, a reproductive animal experiment was carried out using Sprague-Dawley rats. We performed proteomic analysis of the placenta by Difference Gel Electrophoresis (DIGE) combined with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Tandem Mass Spectroscopy (MALDI-TOF/TOF MS). The DIGE assay identified 15 protein spots that were differentially expressed with a greater than 1.5-fold change in placenta of Cd-treated rats compared to the control rats. Based on the expression patterns and biological functions of the proteins, we selected the ABCG2 and ABCB4 transporter proteins for further analysis. Western blot analysis showed that Cd exposure could down-regulate the expression of ABCG2 and ABCB4 in the placenta. There was a negative dose-response relationship between Cd exposure and the expression of ABCG2 or ABCB4 protein. These results indicated that down-regulation of ABCG2 and ABCB4 transporters may regulate Cd across through placenta and thus affect the in vivo toxic effect of Cd to fetus.

SUBMITTER: Liu L

PROVIDER: S-EPMC5122379 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Down-regulation of ABCG2 and ABCB4 transporters in the placenta of rats exposed to cadmium.

Liu Lili L Zhou Liang L Hu Shuiwang S Zhou Shanyu S Deng Yingyu Y Dong Ming M Huang Jianxun J Zeng Yuli Y Chen Xiaoyan X Zhao Na N Li Hongling H Ding Zhenhua Z

Oncotarget 20160601 25

As a maternal and developmental toxicant, cadmium (Cd) possesses weak penetrability through the placental barrier. However, the underlying mechanism remains unclear. To gain insight into the protein molecules associated with Cd toxicity in placenta and explore their roles in Cd transportation, a reproductive animal experiment was carried out using Sprague-Dawley rats. We performed proteomic analysis of the placenta by Difference Gel Electrophoresis (DIGE) combined with Matrix-Assisted Laser Deso ...[more]

PMID: 27203216

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Project description:Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.

Dataset Information

Down-regulation of ABCG2 and ABCB4 transporters in the placenta of rats exposed to cadmium.

Publications

Down-regulation of ABCG2 and ABCB4 transporters in the placenta of rats exposed to cadmium.

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