A deficiência leve de iodo durante o período intrauterino desregula o eixo hipotálamo-hipófise-tireoide dos animais da prole durante a vida adulta
Data
2024
Autores
Oliveira, Mikaeli Vieira Ribeiro 
Orientadores
Nascimento, Caroline Serrano
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
O iodo é crucial para biossíntese dos hormônios tireoidianos e para o desenvolvimento embrionário adequado da tireoide. Embora a deficiência severa de iodo, durante a gestação e a lactação, cause efeitos prejudiciais bem documentados, as consequências da deficiência leve de iodo (MID) ainda não são totalmente compreendidas. A MID durante a gestação é uma realidade em muitos países, mesmo em regiões com suprimento adequado de iodo na dieta. Estudos anteriores destacaram o impacto adverso da MID no desenvolvimento neurológico da prole, mas dados sobre o impacto na função tireoidiana são escassos. Sendo assim, o presente estudo teve como objetivo investigar as repercussões da MID durante a gestação na programação de disfunções tireoidianas nos indivíduos da prole durante a idade adulta. Métodos: Camundongos fêmeas CD1 foram submetidas a uma dieta deficiente em iodo e água suplementada com níveis normais (NI; 0,18 mg/L) ou levemente deficiente em iodo (MID; 0,08 mg/L) durante a prenhez. A expressão gênica e proteica no hipotálamo, hipófise, tireoide e fígado dos machos adultos (PND90) das proles foram avaliadas utilizando-se qPCR e Western blotting. Além disso, este estudo explorou os mecanismos epigenéticos regulados pela MID. Resultados: A exposição materna à dieta levemente deficiente em iodo aumentou a expressão gênica do hormônio liberador de tireotrofina (Trh) e da expressão gênica e proteica da subunidade beta da tireotrofina (TSHB) no hipotálamo e hipófise dos animais das proles, respectivamente. A expressão gênica do co-transportador sódio-iodeto (Slc5a5), receptor de TSH (Tshr), tireoperoxidase (Tpo), tireoglobulina (Tg), paired box 8 (Pax8), proteína forkhead E1 (Foxe1) apresentou-se aumentada na tireoide dos nos animais do grupo MID em relação aos animais do grupo controle. Coerentemente, o conteúdo proteico de NIS e TPO apresentou-se aumentado na tireoide desses animais. Alterações em mecanismos epigenéticos foram observadas em animais do grupo MID, como a diminuição da expressão de Dnmt1, Hdac3 e Kdm5c, bem como, o aumento da expressão de Hat1, Ezh2 e Kdm6a. Adicionalmente, os animais do grupo MID apresentaram níveis mais altos de histonas H3 e H4 acetiladas, aumento do conteúdo de H3 trimetilada na lisina 4 e redução do conteúdo de H3 trimetilada na lisina 27 em relação aos animais do grupo controle. Conclusão: O estudo sugere que a exposição à deficiência levemente deficiente em iodo durante a gestação é tão prejudicial quanto a deficiência severa de iodo na programação do eixo hipotálamo-hipófise-tireoide dos animais da progênie. Consequentemente, nossos dados sugerem que o monitoramento da ingestão de iodo durante a gravidez é crucial para prevenir a ocorrência de distúrbios tireoidianos na progênie durante a vida adulta.
Iodine is crucial in the biosynthesis of thyroid hormones and essential for proper thyroid embryonic development. While severe iodine deficiency during pregnancy and lactation has welldocumented harmful effects, the consequences of mild iodine deficiency (MID) remain not fully understood. MID during pregnancy is a reality in numerous countries, even in regions with seemingly adequate iodine supply in the diet. Previous studies have highlighted the adverse impact of MID on neurological development in offspring, but comprehensive data on thyroid function, particularly in progeny at different developmental stages, are lacking. This study aimed to investigate the repercussions of MID during pregnancy on the programming of thyroid dysfunctions during adulthood. Methods: Female CD1 mice were subjected to iodinedeficient animal chow and iodinesupplemented water, either at normal (NI; 0.18 mg/L) or mild iodine deficiency (MID; 0.08 mg/L) levels during pregnancy. Gene and protein expression in adult (PND90) male offspring animals' hypothalamus, pituitary, thyroid, and liver were evaluated using qPCR and Western blotting. Additionally, this study explored MIDinduced programming of offspring thyroid gene expression through epigenetic mechanisms. Results: Maternal MID exposure led to increased gene expression of thyrotropinreleasing hormone (Trh), and gene and protein expression of thyroidstimulating hormone beta subunit (TSHB) in the hypothalamus and pituitary of the offspring animals, respectively. Thyroid gene expression of sodium iodide symporter (Slc5a5), TSH receptor (Tshr), thyroid peroxidase (Tpo), thyroglobulin (Tg), paired box 8 (Pax8), forkhead box protein E1 (Foxe1) was elevated in the offspring of MIDexposed animals. Additionally, the protein content of NIS and TPO was also increased in the thyroid of these animals. Epigenetic mechanisms alterations were observed in MIDexposed animals, such as decreased expression of Dnmt1, Hdac3 and Kdm5c, as well as increased expression of Hat1, Ezh2 and Kdm6a. Additionally, MIDexposed animals presented higher levels of acetylated histones H3 and H4, increased content of H3 trimethylated at the lysine 4, and reduced content of H3 trimethylated at the lysine 27 Conclusion: The study suggests that MID exposure during pregnancy can be as harmful as severe iodine deficiency in programming the hypothalamuspituitarythyroid (HPT) axis, leading to HPT dysfunction during adult life. Consequently, our data suggest that monitoring iodine intake throughout pregnancy is crucial to prevent the occurrence of thyroid disorders in offspring during adulthood.
Iodine is crucial in the biosynthesis of thyroid hormones and essential for proper thyroid embryonic development. While severe iodine deficiency during pregnancy and lactation has welldocumented harmful effects, the consequences of mild iodine deficiency (MID) remain not fully understood. MID during pregnancy is a reality in numerous countries, even in regions with seemingly adequate iodine supply in the diet. Previous studies have highlighted the adverse impact of MID on neurological development in offspring, but comprehensive data on thyroid function, particularly in progeny at different developmental stages, are lacking. This study aimed to investigate the repercussions of MID during pregnancy on the programming of thyroid dysfunctions during adulthood. Methods: Female CD1 mice were subjected to iodinedeficient animal chow and iodinesupplemented water, either at normal (NI; 0.18 mg/L) or mild iodine deficiency (MID; 0.08 mg/L) levels during pregnancy. Gene and protein expression in adult (PND90) male offspring animals' hypothalamus, pituitary, thyroid, and liver were evaluated using qPCR and Western blotting. Additionally, this study explored MIDinduced programming of offspring thyroid gene expression through epigenetic mechanisms. Results: Maternal MID exposure led to increased gene expression of thyrotropinreleasing hormone (Trh), and gene and protein expression of thyroidstimulating hormone beta subunit (TSHB) in the hypothalamus and pituitary of the offspring animals, respectively. Thyroid gene expression of sodium iodide symporter (Slc5a5), TSH receptor (Tshr), thyroid peroxidase (Tpo), thyroglobulin (Tg), paired box 8 (Pax8), forkhead box protein E1 (Foxe1) was elevated in the offspring of MIDexposed animals. Additionally, the protein content of NIS and TPO was also increased in the thyroid of these animals. Epigenetic mechanisms alterations were observed in MIDexposed animals, such as decreased expression of Dnmt1, Hdac3 and Kdm5c, as well as increased expression of Hat1, Ezh2 and Kdm6a. Additionally, MIDexposed animals presented higher levels of acetylated histones H3 and H4, increased content of H3 trimethylated at the lysine 4, and reduced content of H3 trimethylated at the lysine 27 Conclusion: The study suggests that MID exposure during pregnancy can be as harmful as severe iodine deficiency in programming the hypothalamuspituitarythyroid (HPT) axis, leading to HPT dysfunction during adult life. Consequently, our data suggest that monitoring iodine intake throughout pregnancy is crucial to prevent the occurrence of thyroid disorders in offspring during adulthood.
Descrição
Citação
OLIVEIRA, Mikaeli Vieira Ribeiro de. A deficiência leve de iodo durante o período intrauterino desregula o eixo hipotálamo-hipófise-tireoide dos animais da prole durante a vida adulta. 2024. 56 f. Dissertação (Mestrado em Endocrinologia e Metabologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2024.