Perinatal exposure to the thyroperoxidase inhibitors methimazole and amitrole perturbs thyroid hormone system signaling and alters motor activity in rat offspring

Louise Ramhøj,Terje Svingen,Caroline Frädrich,Eddy Rijntjes,Eva K Wirth,Katrine Pedersen,Josef Köhrle,Marta Axelstad

doi:10.1016/j.toxlet.2021.10.010

Abstract

Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring’s brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.

Highlights

Brain development during fetal and early postnatal life is critically dependent on thyroid hormone action
One crucial component is the synthesis of the thyroid hormones, which exclusively takes place in the thyroid gland under the control of the enzyme thyroperoxidase (TPO) (Carvalho and Dupuy, 2017)
We recently showed that the TPO inhibiting pesticide amitrole can disrupt brain development of perinatally exposed rat offspring, causing a neuronal migration defect with heterotopia forming in the corpus callosum of 16-days old rat offspring (Ramhøj et al, 2021)

Summary

Introduction

Brain development during fetal and early postnatal life is critically dependent on thyroid hormone action. This may reduce supply of thyroid hormones to the fetal and neonatal brain and impair brain development This cause-effect relationship has been established in rodent models, which typically have induced extreme degrees of hypothyroidism by using high doses of the anti-thyroid drugs propylthiouracil (PTU) or methimazole (MMI), destruction of the thyroid gland by radioiodine treatment, thyroidectomy or a combination thereof (Akaike et al, 1991; Berbel et al, 1994; Dussault and Ruel, 1987; Gilbert et al, 2020; Goldey et al, 1995; Iniguez et al, 1996; Mohan et al, 2012; Ruiz-Marcos et al, 1979; Uchida et al, 2021). The thyroid hormone concentrations can be suppressed to below the assay’s limits of detection

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