The role of melatonin on the heritable variation in the endocrine pancreas of the offspring of rats in hypomelatoninemia during pregnancy: From B cell transdifferentiation to epigenetics.

• Grant number: 21/09923-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): April 01, 2022
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: José Cipolla Neto
• Grantee: Patrícia Rodrigues Lourenço Gomes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/24327-5 - Melatonin physiology and pathophysiology, basic and clinical studies: characterization of the primary and secundary Hypomelatoninemia Syndromes, AP.TEM

Abstract

Energy metabolism is organized to deal with the body's needs and their variations over 24 hours. Melatonin, which is elevated at night, is synthesized by the pineal gland and acts to synchronize physiological functions, including energy metabolism. In the fetus, although the fetal pineal gland produces melatonin, its rhythm is determined by the mother's production of pineal melatonin, this transplacental melatonin is responsible for coordinating organ and tissue development, neural development and plasticity, and metabolic programming. Furthermore, studies describe the role of melatonin as an epigenetic modulator, mainly in neuronal cells, breast cancer and neuropsychiatric disorders. Studies evaluating the role of melatonin on epigenetic alterations on energy metabolism and the tissues responsible for its regulation are scarce or absent. Therefore, the study proposes to investigate the appearance of endocrine pancreas dysfunctions and metabolic disorders throughout the life of the offspring generated in the absence of melatonin, and to evaluate the connection of these findings to possible B cell transdifferentiation and epigenetic alterations. For this, it will be evaluated 1) at what time of life the offspring will present the first pancreatic/metabolic dysfunctions, 2) the significant presence of changes in the factors that propose B-cell dedifferentiation, co-marking of hormones in the pancreatic islet (cell architecture of the islet), as well as analyzing the events of apoptosis, cell proliferation and cell functionality B (GSIS), 3) the influence of sex on the proposed variables, and 4) the presence of epigenetic factors (DNA methylation) linked to the changes found . Thus, we will analyze both male and female offspring, separately, from 1) control mothers, 2) pinealectomized mothers and 3) pinealectomized mothers submitted to melatonin replacement during pregnancy and lactation. Once weaned, the offspring will be separated by origin of the mothers and by sex and, after completing one month of life, the first monthly euthanasia will begin, until we identify damages in the functioning of the endocrine pancreas. As soon as we identify the moment in the animal's life in which there is pancreatic injury, the islets will be submitted to analysis to identify cell transdifferentiation, as well as DNA methylation and genes that promote the alterations possibly found.