A comprehensive analysis of metabolomics and transcriptomics to reveal major metabolic pathways and potential biomarkers of human preeclampsia placenta

Background: The etiology of preeclampsia (PE) remains unclear. With the utilization of metabolomics, dysregulated production of several metabolic components in human plasma, such as lipids, amino acids, androgens and estrogens, was found to be important in the pathogenesis of PE. Transcriptomics adds more in-depth information, and the integration of transcriptomics and metabolomics may yield further insight into PE pathogenesis than either one alone. Objectives: We investigated the placental metabolomics and transcriptomics of PE patients to identify affected metabolic pathways and potential biological targets for exploring the disease pathogenesis. Methods: Integrated transcriptomics and metabolomics were used to analyze five paired human placentas from patients with severe PE and normal pregnancies. This was followed by further validation of our findings in a publicly available dataset of 173 PE vs. 157 control placentas. In addition, weighted gene coexpression network construction was performed to assess the correlation between genetic alterations and diseases. Results: We identified 66 and 41 differentially altered metabolites in negative and positive ion modes, respectively, in the PE group compared to the control group, and found 2,560 differentially expressed genes. Several pathways were aberrantly altered in the PE placenta at both the metabolic and transcriptional levels, including steroid hormone biosynthesis, the cAMP signaling pathway, neuroactive ligand-receptor interactions, taste transduction and prion diseases. Additionally, we found 11 differential metabolites and 11 differentially expressed genes involved in the steroid hormone biosynthesis pathway, indicating impaired metabolism of steroid hormones in the PE placenta. Furthermore, we found that CYP11A1, HSD3B2, and HSD17B6 are highly correlated with diseases. Conclusion: Our findings provide a profile of the dysregulated steroid hormone biosynthesis in PE placenta, we observed a dysregulated cortisol-to-cortisone ratio, testosterone accumulation, decreased testosterone downstream metabolites, impaired production of estrone and estriol, and aberrant hydroxylation and methylation of estradiol. Disorders of placental steroid hormone metabolism might be a consequence or a compensatory change in pathological placentation in PE, which underscores the need to investigate the physiology of steroid hormone metabolites in the etiology of PE.