Serotonin (5HT) is a multifunctional signaling molecule, best known as the central nervous system neurotransmitter. In addition, 5HT plays important extra-cerebral roles, both in adulthood and during development. Disturbed 5HT homeostasis has been linked to many mental health conditions and is emerging as important contributor also to obesity and related metabolic disorders.

However, causes of 5HT disturbances are yet poorly understood. Rising evidence suggests that DNA methylation, a dynamic process sensitive to environmental cues, plays a crucial role in the regulation of 5HT signaling through modifying transcriptional activity of genes encoding 5HT-regulating proteins (transporters, receptors and enzymes). In order to search for early developmental origins of altered 5HT functioning in humans, here we aim to establish a comprehensive biobank of human perinatal specimens and investigate the impact of altered maternal metabolic state in pregnancy on placental and the newborn's 5HT system.

We hypothesize that maternal metabolic, proinflammatory and/or endocrine changes associated with obesity and gestational diabetes mellitus (GDM) may affect placental and fetal 5HT system through DNA methylation-mediated mechanisms.

Hence, we aim to: 1) explore the relationship of maternal gestational glycemia and pregestational body mass index (pBMI) with placental DNA methylation and expression of 5HT-related genes known to be functional in human placental cells; 2) explore the relationship of maternal gestational glycemia and pBMI with the newborn's 5HT system by quantifying cord blood DNA methylation of multiple 5HT-regulating genes and measuring cord blood 5HT-related biochemical/functional parameters (5HT level, platelet 5HT uptake and platelet aggregation); 3) investigate in vitro effects of glucose and inflammatory cytokines on DNA methylation and expression of 5HT-related genes as well as on function of the corresponding gene products in human placental cells (trophoblasts and fetoplacental endothelial cells).

The obtained results will increase our knowledge about molecular mechanisms that regulate 5HT system during early human development and may lead to better understanding of conditions associated with disturbed 5HT homeostasis.

Research Team

• Maja Perić, Ruđer Bošković Institute
• Marina Horvatiček, Ruđer Bošković Institute
• Ivona Bečeheli, Ruđer Bošković Institute
• Lipa Čičin-Šain, Ruđer Bošković Institute
• Maja Kesić, Ruđer Bošković Institute
• Marina Ivanišević, Clinical Hospital Centre Zagreb
• Mirta Starčević, Clinical Hospital Centre Zagreb
• Saša Kralik, Clinical Hospital Centre Zagreb
• Maja Žutić, Catolic University of Croatia, Department of Psychology
• Sandra Nakić Radoš, Catolic University of Croatia, Department of Psychology
• Maja Anđelinović, Catolic University of Croatia, Department of Psychology
• Dubravka Hranilović, University of Zagreb, Faculty of Science
• Barbara Nikolić, University of Zagreb, Faculty of Science
• Gernot Desoye, Medical University of Graz

Publications

1. Baković P, Kesić M, Perić M, Bečeheli I, Horvatiček M, George M, Čičin-Šain L, Desoye G, Wadsack C, Panzenboeck U, Štefulj J (2021) Differential serotonin uptake mechanisms at the human maternal–fetal interface. Int J Mol Sci 22, 7807. doi: 10.3390/ijms22157807
2. Horvatiček M, Perić M, Bečeheli I, Klasić M, Žutić M, Kesić M, Desoye G, Nakić Radoš S, Ivanišević M, Hranilovic D, Štefulj J (2022) Maternal Metabolic State and Fetal Sex and Genotype Modulate Methylation of the Serotonin Receptor Type 2A Gene (HTR2A) in the Human Placenta. Biomedicines 10, 467. doi: 10.3390/biomedicines10020467
3. Perić M, Bečeheli I, Čičin-Šain L, Desoye G, Štefulj J (2022) Serotonin System in the Human Placenta - The Knowns and Unknowns. Front Endocrinol 13, 1061317. doi: 10.3389/fendo.2022.1061317
4. Perić M, Horvatiček M, Tandl V, Bečeheli I, Majali-Martinez A, Desoye G, Štefulj J (2023) Glucose, Insulin and Oxygen Modulate Expression of Serotonin-Regulating Genes in Human First-Trimester Trophoblast Cell Line ACH-3P. Biomedicines 11, 1619. doi: 10.3390/biomedicines11061619
5. Žutić M (2023) Biopsychosocial Models of Peripartum Depression: A Narrative Review. Clínica y Salud 34, 91-99. doi: 10.5093/clysa2023a16
6. Baković P, Kesić M, Kolarić D, Štefulj J, Čičin-Šain L. Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone (2023) Int J Mol Sci 24, 2169. doi: 10.3390/ijms24032169
7. Konjevod M, Rešetar M, Matošić A, Čičin-Šain L, Štefulj J (2023) Association of Functional Polymorphism in TPH2 Gene with Alcohol Dependence and Personality Traits: Study in Cloninger's Type I and Type II Alcohol-Dependent Inpatients. Genes 14, 413. doi: 10.3390/genes14020413
8. Hranilovic D, Stefulj J, Zill P (2021) Editorial: Developmental abnormalities of serotonin homeostasis in behavioral and metabolic disorders: from epigenetic mechanisms to protein function. Front Neurosci 15, 659356. doi: 10.3389/fnins.2021.659356

Presentations at scientific and public conferences

1. Štefulj, J., Horvatiček, M., Perić, M., Baković, P., Čičin-Šain, L., Klasić, M., Nikolić, B., Hranilović, D., Anđelinović, M., Matijaš, M., Nakić Radoš, S., Ivanišević, M., Perković, K., Vukušić Mijačika, M., Ilijić Krpan, M., Starčević, M., Kralik, S., Panzenboeck, U. & Desoye, G (2019) Prenatal programming of altered serotonin functioning: maternal gestational diabetes, obesity and emotional stress as potential risk factors. 2nd International Scientific Conference Brain and Mind: Promoting Individual and Community Wellbeing, Book of Abstracts pp 97-98. Zagreb, Hrvatska, 12.12.2019.-14.12.2019.
2. Horvatiček, M., Perić, M., Bečeheli, I., Klasić, M., Nikolić, B., Hranilović, D., Ivanišević, M. & Štefulj, J. (2021) Placental and cord blood DNA methylation of the serotonin receptor type 2A gene: Modulation by fetal sex and genotype and maternal metabolic state. 45th FEBS Congress Molecules of Life: Towards New Horizons, FEBS Open Bio 11 (S1) pp. 136-137. Ljubljana, Slovenija, 03.07.2021.-08.07.2021.
3. Horvatiček, M., Baković, P., Ercegovac, Z., Kesić, M., Čičin-Šain, L., Starčević, M., Ivanišević, M. & Štefulj, J. (2021) Serotonin uptake into human cord blood platelets: modulation by maternal metabolic state. 45th FEBS Congress, Molecules of Life: Towards New Horizons, FEBS Open Bio 11 (S1) pp. 205-206. Ljubljana, Slovenija, 03.07.2021.-08.07.2021.
4. Bečeheli, I., Horvatiček, M., Perić, M., Nikolić, B., Klasić, M., Hranilović, D., Ivanišević, M., Desoye, G. & Štefulj, J. (2021) Sex-specific interrelation between glucose levels and SLC6A4 gene methylation in maternal and fetal blood. EMBO/EMBL Symposium: Metabolism Meets Epigenetics. Heidelberg, Njemačka, 17.11.2021.-20.11.2021.
5. Žutić, M., Horvatiček, M., Brekalo, M., Nakić Radoš, S. & Štefulj Jasminka (2021) Biopsychosocial determinants of peripartum depression symptoms – a longitudinal study design. IV Annual Meeting 2021 of the Portuguese Language Group of the Marcé Society for Perinatal Mental Health: Challenges in Perinatal Mental Health, Abstract Book pp. 5. Matosinhos, Portugal, 02.12.2021.-03.12.2021.
6. Perić, M., Horvatiček, M., Bečeheli, I., Ivanišević, M. & Štefulj, J. (2022) Relationship between placental serotonin transporter gene (SLC6A4) expression, maternal metabolic state, and infant birthweight. IX. SLIMP virtual meeting, Placenta 122, pp. 17, doi:10.1016/j.placenta.2022.03.071. Bogotá, Kolumbija, 04.05.-06.05.2022.
7. Perić, M., Horvatiček, M., Tandl, V., Majali-Martinez, A., Bečeheli, I., Desoye, G. & Štefulj, J. (2022) Effects of glucose, insulin and oxygen on mRNA expression of serotonin-regulating genes in human first trimester trophoblast cell line ACH-3P. 54th Annual DPSG Meeting, Book of Abstract pp. 50-51. Madrid, Španjolska, 08.09.2022.-10.09.2022.
8. Žutić, M., Horvatiček, M., Ivanišević, M., Brekalo, M., Nakić Radoš, S. & Štefulj, J. (2022) Prevalence and correlates of depression symptoms among pregnant women with and without gestational diabetes mellitus. 42nd SRIP Annual Virtual Conference, Abstract Book pp. 35. Virtualno, 15.09.2022.-16.09.2022.
9. Bečeheli, I., Horvatiček, M., Perić, M., Nikolić, B., Hranilović, D., Starčević, M., Ivanišević, M., Desoye, G. & Štefulj, J. (2022) The association between cord blood DNA methylation of serotonin-regulating genes and body fat-related characteristics in newborns. FEBS Advanced Course, 4th Danube Conference on Epigenetics, P-05. Budimpešta, Mađarska, 18.10.2022.-21.10.2022.