Downregulation of BCRP (ABCG2) in Placenta of Rat Model of Preeclampsia
Bibliographic record
Abstract
BACKGROUND Recent studies in our laboratory demonstrated downregulation of breast cancer resistance protein (BCRP/ABCG2) in placenta obtained from women with preeclampsia (PE). Pregnant women with PE are often prescribed medications to manage disease progression and prevent adverse outcomes. Many of these drugs, as well as other clinically relevant therapeutics are substrates for BCRP. BCRP is highly expressed in placenta and plays an important role in preventing xenobiotics from crossing the placenta and entering the fetal compartment. Thus, the impact of PE and BCRP downregulation on fetal drug exposure needs to be examined. As studies in pregnant women are often not feasible, use of preclinical models is an important approach. Thus, our objective was to characterize transporter changes in an endotoxin rat model of PE to determine its utility and predictive value for future drug disposition studies. This frequently utilized PE model is associated with maternal immune activation and induction of PE‐like symptoms including high blood pressure, proteinuria and pathology which are characteristic of human disease. METHODS Pregnant rats were injected intraperitoneally with 10 μg/kg of bacterial endotoxin (LPS) on GD13, followed by 40 μg/kg LPS daily until GD 16. Controls were injected with sterile saline. Urine was collected daily. Dams were sacrificed on GD17 or GD18 for collection of maternal plasma, placentas, and fetuses (n=7‐8/group/day). Plasma levels of TNF‐α and IL‐6 were quantified by ELISA Kit. Tissues were analyzed for the expression of transporters by using qPCR and western blot. Urine was analyzed using creatinine colorimetric and protein assays. RESULTS Consistent with previous reports, the urinary ratio of protein/creatinine was significantly elevated in PE dams on GDs 16‐18, demonstrating proteinuria. As compared to controls, maternal plasma concentrations and placental mRNA levels of the pro‐inflammatory cytokines, TNF‐α and IL‐6, were significantly higher in the PE group on GD17 and GD18. The mRNA levels of BCRP was significantly decreased by 40‐60 % in placenta of PE dams on GD17 and GD18 along with a corresponding decrease in protein expression on GD18. Significantly lower mRNA levels of Abcb1a, Abcb1b and Slco2b1 were observed in the PE group. PE was also associated with significantly decreased transcript levels of Bcrp, Abcb1a and Abc1b in fetal brains. CONCLUSION Our data demonstrates that the endotoxin PE rat model exhibits proteinuria and immune activation consistent with human disease. Importantly, our observations of decreased placenta expression of BCRP in this PE model is consistent with findings in humans. This indicates that this preclinical model may serve as a useful translational tool to examine the impact of PE on the disposition and fetal exposure of BCRP drug substrates.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".