93-OR: Low Maternal Insulin Sensitivity Associates with DNA-Related Functions in Human First-Trimester Trophoblast

Abstract

In first trimester (FT) of pregnancy the human placenta is rapidly growing making it sensitive to environmental influence. We hypothesized that the altered intrauterine milieu associated with maternal obesity modifies placental proteome and function. We used maternal BMI and leptin as measures of obesity and adiposity, characterized the glucose-insulin axis (glucose, C-peptide, insulin sensitivity (ISHOMA)) and quantified fatty acids (GC) in maternal fasted serum (n=123-323). Among those, only higher C-peptide levels and lower ISHOMA were associated with obesity. Subsequent untargeted proteomics (LC-MS/MS, qTOF Bruker maXis ETD II) in FT placentas (weeks 5-6 p.m.) from lean (n=11) and obese (n=11) women and Principal Component Analysis clustered the samples in two groups. Only ISHOMA differed between both clusters (ISHOMA cluster 1: median 0.95, IQR 0.69-1.17; ISHOMA cluster 2: median 0.57, IQR 0.20 - 1.00, P<0.05). Comparing proteomic profiles between ISHOMA groups (separated by median ISHOMA 0.61) identified 86 proteins enriched in the low ISHOMA cluster (P<0.05, FDR 0.05). Biological processes (KEGG pathway analysis) enriched in this group were related to DNA replication and cell cycle (FDR<0.001). Members of the MCM family, involved in DNA damage response and cell cycle arrest, associated with low ISHOMA. This suggested trophoblast growth related processes depend on ISHOMA. Semi-quantitative in-situ analysis found decreased trophoblast proliferation (Ki67, n=22, Δ -33.4%, p<0.05) and increased apoptosis (TUNEL assay, n=22, 5.6 fold, p<0.05) in the low ISHOMA group. These differences were related to an increased DNA damage (𝛄;;H2AX, n=12, 6.9 fold, p<0.001). We conclude that low ISHOMA associated with maternal obesity in FT of pregnancy induces placental proteome changes related to DNA metabolism. This might alter trophoblast, i.e., placental, growth early in pregnancy, which is known to associate with fetal growth and birth weight. Disclosure J. Bandres-Meriz: None. D. Hoch: None. S. Honeder: None. A. Majali-Martinez: None. E. Herrera: None. M. Schittmayer: None. R. Birner-Gruenberger: None. G. Desoye: None.