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A multidimensional proteomic strategy for the characterization of the human amnion proteome

ABSTRACT: The loss of fetal membrane (FM) integrity and function in early pregnancy can have devastating consequences for the fetus and the newborn. However, the current fragmentary knowledge of FM biology has largely hampered the development of preventive FM sealing and healing strategies. Here, by an optimized protein sample preparation and offline fractionation before LC-MS/MS analysis we present an exhaustive human term amnion proteome characterization. The more than 5000 identified proteins greatly outnumbered previous reports. A Gene-Set Enrichment Analysis (GSEA) depicted ‘extracellular matrix’ and ‘cell-substrate junction‘ as two significantly enriched categories. Therefore, protein-protein interaction plots using these categories enabled the establishment of novel potential amniotic membrane cell-to-ECM interactions. Together, this thorough human amnion proteome, additionally to providing a basis for the study of compromised and preterm ruptured fetal membranes, could be a stepping-stone for the development of novel healing-inducing biomaterials.

INSTRUMENT(S): Q Exactive HF, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fetal Membrane, Amnion

SUBMITTER: Eva Avilla-Royo

LAB HEAD: PD Dr. sc. nat. Martin Ehrbar

PROVIDER: PXD019410 | Pride | 2021-11-04

REPOSITORIES: Pride

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Project description:The Göttingen Minipig is gaining ground as nonrodent species in safety testing of drugs for pediatric indications. Due to developmental changes in pharmacokinetics (PK) and pharmacodynamics (PD), physiologically-based pharmacokinetic (PBPK) models are built to better predict drug exposure in children and to aid species selection for nonclinical safety studies. These PBPK models require high quality physiological and PK/PD data such as protein abundance of drug metabolizing enzymes. These data are available for man and rat, but scarce for the Göttingen Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) protein abundance in the developing Göttingen Minipig by using mass spectrometry. In addition, sex-related differences in CYP protein abundance and correlation of CYP enzyme activity with CYP protein abundance were assessed. The following age groups were included: gestational day (GD) 84 - 86 (n = 8), GD 108 (n = 6), postnatal day (PND) 1 (n = 8), PND 3 (n = 8), PND 7 (n = 8), PND 28 (n = 8) and adult (n = 8). Liver microsomes were extracted and protein abundance was compared to that in adult animals. Next, the CYP protein abundance was correlated to CYP enzyme activity in the same biological samples. In general, CYP protein abundance gradually increased during development. However, we observed a stable protein expression over time for CYP4A24 and CYP20A1 and for CYP51A1, a high protein expression during the fetal stages was followed by a decrease during the first month of life and an increase towards adulthood. Sex-related differences were observed for CYP4V2_2a and CYP20A1 at PND 1 with highest expression in females for both isoforms. In the adult samples, sex-related differences were detected for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with higher values in female compared to male Göttingen Minipigs. The correlation analysis between CYP protein abundance and CYP enzyme activity showed that CYP3A22 protein abundance correlated clearly with the metabolism of midazolam at PND 7. These data are remarkably comparable to human data and provide a valuable step forward in the construction of a neonatal and juvenile Göttingen Minipig PBPK model.

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A multidimensional proteomic strategy for the characterization of the human amnion proteome

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