Influence endocrine disruptors on cognitive alterations induced by genetic polymorphism of type 2 deiodinase (Ala92-D2)

• Grant number: 24/04581-2
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2025
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Miriam Oliveira Ribeiro
• Grantee: Miriam Oliveira Ribeiro
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Presbiteriana Mackenzie (UPM). Instituto Presbiteriano Mackenzie. São Paulo , SP, Brazil
• Associated researchers: Antonio Carlos Bianco ; Caroline Serrano Do Nascimento

Abstract

The pro-hormone T4 enters target cells through transporters expressed in the plasma membrane and is converted to its active form, T3, by the action of deiodinases. Approximately 12 to 36% of the world population carries a single nucleotide point mutation (SNP) in the DIO2 gene (rs225014) that expresses type 2 deiodinase (D2), resulting in the Ala92-D2 polymorphism. Studies published by our group show that male mice with Ala92-D2 exhibit moderate memory impairments that worsen with aging. In contrast, females exhibit broader and more severe cognitive impairments even at a young age. These cognitive changes may result from the lower catalytic activity of Ala92-D2 leading to localized hypothyroidism in brain nuclei such as the striatum, amygdala, prefrontal cortex, hippocampus, and cerebellum, despite a systemic euthyroidism. Changes in neuroinflammation and apoptosis pathways determined by transcriptome analysis in these animals may also play a significant role in their phenotype. Previous unpublished results from our laboratory show that female Ala92-D2 carriers exhibit increased activation of astrocytes and microglia when evaluated by the expression of translocator protein (TSPO) expression using the radiopharmaceutical 11C-PK11195 followed by positron emission tomography (PET) suggests the role of the neuroinflammation in the phenotype observed in both male and female Ala92-D2. Considering that the population is exposed to an increasing number of substances called endocrine disruptors (EDs), which are associated with endocrine system dysregulation and neuroinflammation, we hypothesize that individuals carrying the Ala92-D2 polymorphism are at higher risk for behavioral alterations induced by EDs. Therefore, this study aims to evaluate whether intrauterine exposure to a mixture of EDs impacts susceptibility to cognitive impairments in animals with the Ala92-D2 polymorphism. Our methodological approach will involve behavioral analysis and molecular parameter analysis in structures of the Central Nervous System, such as the hippocampus, amygdala, and prefrontal cortex of male and female animals exposed to a mixture of EDs (bisphenol A, triclosan, and methylparaben) during their embryonic development. The behavioral parameters to be studied include locomotor activity and declarative and visuospatial memory. Immediately after the behavioral tests, some of the animals will undergo the procedure of infusion with 11C-PK11195 to determine neuroinflammation. Subsequently, the animals will be euthanized to remove the amygdala, hippocampus, frontal cortex, and striatum for measurement of inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, IBA-1, L-1alpha, TNF-beta, IL-10, and IL-4) by real-time PCR. The remaining animals will be anesthetized and subjected to perfusion for analysis by immuno-histochemistry of NF-Kb expression (p50 and p65) as a measure of inflammation, of Iba-1 as a measure of microglial activation and GFAP as a measure of astrogliosis. (AU)