Impact of exposure to endocrine disruptores during embrionary devolopment in cognition of mice carrying the genetic polymorphism Ala92-Dio2

• Grant number: 24/01081-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Miriam Oliveira Ribeiro
• Grantee: Stefany Kolndorfer Machado
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Presbiteriana Mackenzie (UPM). Instituto Presbiteriano Mackenzie. São Paulo , SP, Brazil

Abstract

The prohormone T4 enters target cells through transporters expressed in the plasma membrane, where it can be converted into its active form T3 by the action of deiodinases. Approximately 12 to 36% of the global population exhibits a single nucleotide polymorphism (SNP) in the DIO2 gene (rs225014) that codes for type 2 deiodinase (D2), resulting in the Ala92-D2 polymorphism. Studies conducted by our group have shown that male Ala92-D2 mice exhibit moderate impairments in memory, which worsen with aging. On the other hand, young female Ala92-D2 mice exhibit severe cognitive impairments. We have also demonstrated that Ala92-D2 exhibits lower catalytic activity, resulting in local hypothyroidism in the striatum, amygdala, prefrontal cortex, hippocampus, and cerebellum, despite these animals displaying systemic euthyroidism. Furthermore, transcriptome analysis of these structures has shown alterations in genes involved in neuroinflammation and apoptosis pathways.Considering that the human population is exposed to an increasing number of substances known as endocrine disruptors (EDs), which are associated with endocrine system dysregulation and neuroinflammation, the aim of this study will be to evaluate whether intrauterine exposure to a mixture of EDs impacts the susceptibility to cognitive impairments in animals with the Ala92-D2 polymorphism. Our hypothesis is based on previous unpublished results from our laboratory demonstrating increased activation of astrocytes and microglia in female Ala92-D2 mice, as assessed by the measurement of translocator protein (TSPO) expression using the radiopharmaceutical [11C] PK11195.Our methodological approach will involve behavioral analysis and molecular parameter assessment in central nervous system structures such as the hippocampus, amygdala, and prefrontal cortex of offspring from female mice exposed to a mixture of EDs (bisphenol A, triclosan, and methylparaben) during pregnancy. The behavioral parameters to be studied include evaluation of declarative memory, visuospatial memory, working memory, and locomotor activity. Immediately after the behavioral tests, some animals will undergo [11C] PK11195 infusion followed by euthanasia for amygdala, hippocampus, frontal cortex, and striatum sample collection, in order to measure inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, IBA-1, L-1alpha, TNF-beta, IL-10, and IL-4). The remaining animals will be anesthetized and subjected to perfusion for immunohistochemical analysis of Iba-1 and GFAP expression as measures of microglial activation and astrogliosis, respectively.