Developmental Hypothyroxinaemia Induced by Maternal Mild Iodine Deficiency Delays Hippocampal Axonal Growth in the Rat Offspring

Abstract

Iodine is essential for the biosynthesis of thyroid hormones, including triiodothyronine and thyroxine. Thyroid hormones are important for central nervous system development. Mild maternal iodine deficiency (ID)-induced hypothyroxinaemia causes neurological deficits and mental retardation of the foetus. However, the detailed mechanism underlying these deficits is still largely unknown. Given that the growth-associated protein of 43 kDa (GAP-43), semaphorin 3A (Sema3A) and the glycogen synthase kinase 3β (GSK3β)/collapsin response mediator protein 2 (CRMP2) pathway are essential for axonal development, we hypothesise that hippocampal axonal growth-related proteins may be impaired, which may contribute to hippocampal axonal growth delay in rat offspring exposed to maternal hypothyroxinaemia. To test this hypothesis, maternal hypothyroxinaemia models were established in Wistar rats using a mild ID diet. Besides a negative control group, two maternal hypothyroidism models were created with either a severe ID diet or methimazole in the water. Our results showed that maternal hypothyroxinaemia exposure delayed offspring axonal growth on gestational day 19, postnatal day (PN) 7, PN14 and PN21. Consistent with this, the mean intensity of hippocampal CRMP2 and Tau1 immunofluorescence axonal protein was reduced in the mild ID group. Moreover, maternal hypothyroxinaemia disrupted expressions of GAP-43 and Sema3A. Furthermore, the phosphorylation of GSK3β and CRMP2 was also affected in the treated offspring, implying a potential mechanism by which hypothyroxinaemia-exposure affects neurodevelopment. Taken together, our data support the hypothesis that maternal hypothyroxinaemia may impair axonal growth of the offspring.

Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny

“…In yet another study, rodents were treated with an iodinedeficient diet and deionized water containing various doses of iodine in order to establish a mildly iodine-deficient animal model [17]. This research group found that the development of hypothyroxinemia in response to mild iodine deficiency led to impairments of long-term potentiation (LTP) induced by high-frequency stimulation, strongly suggesting irreversible injury to the hippocampus [98].…”

“…The successful establishment of rodent models of hypothyroxinemia has shown structural and functional alterations in pups' various brain regions, especially the hippocampus and cerebellum. The abnormal development of such brain regions is closely related to cognitive and psychomotor dysfunction [16][17][18]. This review summarizes the existing evidence concerning the relationship between maternal hypothyroxinemia and consequences of neurodevelopment in the offspring.…”

MANAGEMENT OF ENDOCRINE DISEASE: Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns

“…In addition to the aberrant cytoarchitecture seen in the above studies, maternal hypothyroxinemia in animal models has been associated with a number of other structural changes, including limited dendritic growth of cerebellar Purkinje cells (15), delayed hippocampal axonal development (16) and alterations of glutamergic synapses (17). Functional consequences of maternal hypothyroxinemia in the fetus have been impaired spatial learning (17), impairment of long-term potentiation in the hippocampus (17) and increased frequency of abnormal response (wild runs or seizures) to audiogenic stimuli (13).…”

“…In the rat, embryonic day 0 (E0) is the day of conception; birth occurs at E21-E22, while fetal thyroid is functional at E17. [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Neurogenesis and migration in the rat occur over 10 days, between E11 and E21, and therefore a period of 3 days in rat brain development corresponds roughly to 37-38 days in humans (13).…”

“…T 4 enters the fetal brain, where it is converted by local deiodinases to T 3 , which then acts on local thyroid receptors to affect different aspects of neurodevelopment (4). Fetal thyroid function in humans starts at 18-22 weeks gestation (16)(17)(18)(19)(20) weeks after conception), so before that time, the fetus is exclusively dependent on maternal T 4 . Inadequate supply of maternal T 4 to the fetus before the onset of fetal thyroidal maturation can significantly influence processes that occur during that neurodevelopmental window, such as neuronal migration and proliferation.…”