SAT591 Abnormal Levels Of Thyroid Hormones During Development Alters The Migration And Activity Of GnRH Reproductive Neurons

Abstract

Abstract Disclosure: C. Quignon: None. A. Backer: None. S. Wray: None. Clinical studies have shown that thyroid hormones disorders and alteration of thyroid hormone production by environmental endocrine disruptors, have deleterious effects on reproduction. By acting in the brain on the hypothalamic component of the reproductive axis, abnormal levels of thyroid hormones can disturb sex hormones production, oestrus cycles or puberty onset, possibly leading to subfertility. Moreover, in animal models, endocrine disruptors and thyroid hormones have been shown to have long-lasting transgenerational effects with the maternal hormones influencing the development of foetal reproductive functions. Despite clear evidence of an interaction between the thyroid and reproductive systems, the effect of T3, the active form of thyroid hormones, on the GnRH neurons controlling reproduction, have been poorly studied. In this work we investigated how T3 functionally interacts with GnRH neurons and how abnormal concentration of T3 alters the migration of these neurons during development. Calcium imaging was used to study the direct effect of T3 on GnRH neuronal activity in an ex vivo nasal explants model. Acute administration of T3 (30nM) was found to stimulate the activity of GnRH cells. Dual labelling of GnRH and thyroid hormone receptors (TR) showed that the GnRH neurons express both nuclear and membrane receptors. However, the use of an antagonist that specifically blocks the TR nuclear receptors (1-850), didn’t inhibit the T3 stimulatory effect. In contrast, blockage of integrin αV/β3 membrane receptors (with cilengitide), which have been shown to be activated by T3, prevented the T3-induced increase in GnRH neuronal activity. During development GnRH neurons migrate from the nasal placodes into the brain. Acute administration of T3 for 1hr significatively decreased the migration rate of the GnRH neurons in our ex vivo model. To assess the effect of thyroid disruption during pregnancy on the development of reproductive axis in utero, pregnant females mice have been treated with methimazole to induce hypothyroidism from gestational day 6 to 13. E13 embryos have been collected from treated and control dams and the distribution of migrating GnRH neurons will be compared between both groups. Together these studies are the first to report a direct effect of thyroid hormones on GnRH neuronal activity, through the integrin αV/β3 membrane receptors and show that T3 can modulate the migration of GnRH neurons during development. These results will bring new insights on how thyroid disruption by endocrine disruptor chemicals or thyroid diseases, especially during foetal development, can lead to long term reproductive defects. Presentation: Saturday, June 17, 2023