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Selected Publication:
Bandres Meriz, J.
Obesity Effects on the Maternal-placental Dialogue in the First Trimester of Pregnancy
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 122
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- Authors Med Uni Graz:
- Advisor:
- Desoye Gernot
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- Abstract:
- Maternal obesity is a risk factor for pregnancy complications and future health of the offspring. In the first trimester of pregnancy, the placenta grows rapidly, making it sensitive to changes in the intrauterine environment such as maternal obesity. We hypothesized that metabolism differs between pregnant women with normal weight and overweight/obesity in the first trimester of pregnancy. In addition, we hypothesized that these changes in the maternal environment affect placental development already in the first trimester. The present study aimed to identify disarrangements in circulating metabolites in women with overweight/obesity and in the proteome of placentas exposed to an obesity-associated environment. For this purpose, maternal serum and matched placental tissue were obtained during voluntary pregnancy termination between 4 and 11 weeks of pregnancy. Gestational age, maternal age and body mass index (BMI) were recorded. In addition, leptin, glucose, C-peptide and insulin sensitivity (ISHOMA index) were measured in maternal serum. To investigate changes in circulating fatty acids, main fatty acid species (n = 18) were measured (gas chromatography) in 123 women and compared between normal weight and women with overweight/obesity. Additionally, other clinical traits such as leptin, glucose, C-peptide and ISHOMA were considered in the analysis. When possible, fetal sex was determined (RT-qPCR) using placenta tissue and included in the analysis. For a deeper characterization of maternal metabolism, untargeted metabolomics followed by stringent statistical analysis was employed (n = 111). To investigate changes in placentas exposed to the obesity-associated environment, untargeted proteomics was used in 19 first trimester placentas (week 5+0 - 6+6 based on last menstrual period). To confirm and further explore the proteomics findings, the key identified proteins were immunolocalized in situ. In addition, the first trimester trophoblast cell line ACH-3P was used for functional assays in vitro. The key findings were: 1)Maternal BMI and leptin did not associate with circulating fatty acid concentrations. Total n-3 fatty acids were decreased in women with high C-peptide or low ISHOMA. In addition, women with high C-peptide bearing a female fetus had decreased circulating docosahexaenoic acid concentration, which was not found in male fetuses. 2)Proxies of the glucose-insulin axis (glucose, C-peptide and ISHOMA) associated with more circulating metabolites than proxies of obesity-adiposity (BMI and leptin). The most robust associations were those between C-peptide and palmitoleoyl ethanolamide and between C-peptide and N-acetyl-L-alanine. 3)Exposure to an obesity-associated environment in utero altered first trimester placental proteome. Maternal ISHOMA was the clinical trait significantly associated with these changes. Placentas of women with low ISHOMA had increased levels of MCM proteins, which are involved in DNA replication and DNA damage repair. 4)MCM proteins further correlated with C-peptide and mainly located in cytotrophoblast nuclei. In addition, MCM6 was co-localized with γH2AX (DNA damage marker). In vitro, treatment of ACH-3P cells with a patho-physiological insulin concentration or oxygen tension did not increase DNA damage (γH2AX) nor DNA damage repair (MCMs). These findings show metabolic differences between women with normal weight and overweight/obesity in the first trimester of pregnancy and altered placental proteome in placentas exposed to an obesity-associated environment in vivo.