Influence of exposure to endocrine disruptors on the development of animals carrying the genetic polymorphism of type D2 deiodinase (Ala92-D2).

• Grant number: 24/01802-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2024
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Miriam Oliveira Ribeiro
• Grantee: Yasmin Macedo Turtera
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Presbiteriana Mackenzie (UPM). Instituto Presbiteriano Mackenzie. São Paulo , SP, Brazil

Abstract

The hormone T4 enters the cells through transporters expressed in the plasma membrane and is converted to T3, the active form of thyroid hormone, by the deiodinases. Approximately 12 to 36% of the global population carries a single nucleotide polymorphism (SNP) in the DIO2 gene (rs225014) that encodes type 2 deiodinase (D2), resulting in the Ala92-D2 polymorphism. Studies published by our group have shown that Ala92-D2 exhibits lower catalytic activity, resulting in local hypothyroidism in the striatum, amygdala, prefrontal cortex, hippocampus, and cerebellum, even though these animals are systemic euthyroid. Considering that the population is exposed to an increasing number of substances called endocrine disruptors (EDs) that are associated with endocrine dysregulation, the aim of this study will be to evaluate whether intrauterine exposure to a mixture of EDs impacts the susceptibility to development in animals with the Ala92-D2 polymorphism. Our hypothesis is based on unpublished results from our laboratory showing alterations in the development of Ala92-D2 offspring in both males and females. Our methodological approach will involve behavioral and molecular parameter analysis in hippocampus, pituitary, hippocampus and amigdala of offspring from female mice exposed to a mixture of EDs (bisphenol A, triclosan, and methylparaben) during the prenatal period. The parameters to be studied include physical and reflex development, play behavior, and social interaction of the offspring. After behavioral tests, some animals will undergo euthanasia for hypothalamus and pituitary gland removal to measure the gene expression of Tshb, Cga, Trh, and Dio2. The thyroid gland will also be removed to measure the gene expression of thyroid transcription factors (Nkx2.1, Pax8, Foxe1), thyroid differentiation markers (Slc5a5, Tshr, Tpo, Tg, Mct8), and deiodinases (Dio1, Dio3). The remaining animals will be anesthetized and undergo perfusion for analysis of Iba-1 and GFAP expression by immunohistochemistry as measures of microglia activation and astrogliosis, respectively.