Maternal Obesity Alters Placental Cell Cycle Regulators in the First Trimester of Human Pregnancy: New Insights for BRCA1

Abstract

In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. In this work, we focus on maternal obesity to assess whether an altered intrauterine milieu modulates expression and protein levels of placental cell cycle regulators in early human pregnancy. For this purpose, we use first trimester placental tissue from lean and obese women (gestational week 5+0–11+6, n = 58). Using a PCR panel, a cell cycle protein array, and STRING database analysis, we identify a network of cell cycle regulators increased by maternal obesity in which breast cancer 1 (BRCA1) is a central player. Immunostaining localizes BRCA1 predominantly to the villous and the extravillous cytotrophoblast. Obesity-driven BRCA1 upregulation is not able to be explained by DNA methylation (EPIC array) or by short-term treatment of chorionic villous explants at 2.5% oxygen with tumor necrosis factor α (TNF-α) (50 mg/mL), leptin (100 mg/mL), interleukin 6 (IL-6) (100 mg/mL), or high glucose (25 nM). Oxygen tension rises during the first trimester, but this change in vitro has no effect on BRCA1 (2.5% and 6.5% O2). We conclude that maternal obesity affects placental cell cycle regulation and speculate this may alter placental development.

Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth

“…Furthermore, PP2A can control genome integrity by coupling the metabolic processes with DNA damage responses [ 84 ]. The breast cancer type 1 susceptibility protein (BRCA1), a tumor suppressor, regulates the cell cycle and DNA damage repair in the placenta [ 85 ]. It also functions as a regulator of glucose and lipid metabolism, as well as mitochondrial respiration [ 86 , 87 , 88 ].…”

Matrix metalloproteinase 15 plays a pivotal role in human first trimester cytotrophoblast invasion and is not altered by maternal obesity

“…However, we cannot rule out that obesity affects any other of the complex mechanisms governing CTB invasion, independent on MMP15. We recently demonstrated an influence of maternal obesity on placental cell cycle in early pregnancy 50 . Thus, other biological processes in the first trimester might be affected by maternal obesity and indirectly have an impact on CTB invasion.…”

Type 1 Diabetes Mellitus and the First Trimester Placenta: Hyperglycemia-Induced Effects on Trophoblast Proliferation, Cell Cycle Regulators, and Invasion

“…To determine whether T1DM compromises cell cycle regulation already in early pregnancy, we assessed the level of 60 proteins related to cell cycle control and cell proliferation in first trimester placental tissue from control pregnancies and those complicated with T1DM (gestational week (GW) [5][6][7][8][9][10][11]. Protein array results showed a decrease in the protein levels of the proliferation marker Ki67 (−26%; p < 0.05) and the cell cycle regulators checkpoint kinase 1 (chk1, −25%; p < 0.05), p73 (−26%; p < 0.05), and cell division cycle 34 (CDC34, −20%; p = 0.09) in T1DM (Figure 1A).…”

“…Ki67 immunostaining was performed on 3 µm thick sections of paraffin-embedded first trimester placental tissue as previously described [6]. Briefly, after deparaffinization and antigen retrieval in 10 mM citrate buffer (pH 6) at 110 • C for 10 min, Ki67 immunohistochemistry was performed using the UltraVision LP Detection System (HRP polymer kit, Thermo Fisher Scientific, Rockford, IL, USA) as per manufacturer's guidelines.…”

“…Since early in pregnancy the placenta is predominantly exposed to the maternal circulation, these processes are regulated by the maternal metabolic, endocrine, and inflammatory environment [4,5]. Hence, conditions associated with derangements in the maternal milieu, such as obesity and diabetes, affect placental function already at this early period in pregnancy [6,7].…”