Elsevier

Molecular and Cellular Endocrinology

Volume 474, 15 October 2018, Pages 119-126
Molecular and Cellular Endocrinology

Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat

https://doi.org/10.1016/j.mce.2018.02.017Get rights and content

Highlights

  • KI prophylaxis over many days didn't induce any modification on thyroid hormonal status (TSH –FT3 and FT4 level).

  • Repeated KI prophylaxis impacted reversibly the expression of genes involved in iodide transport, and thyroid hormone synthesis.

  • The transcriptional effect was time-dependent.

Abstract

Background

A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI.

Methods

Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days.

Results

hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (−58% and −26% respectively), followed by a delayed decrease of TPO mRNA expression (−33%) in conjunction with a stimulation of PDS mRNA expression (+62%).

Conclusion

we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones.

Introduction

The use of nuclear technology has always been accompanied by the risk of radioactivity releases into the environment, since 1990 a dramatic increase in the incidence of pediatric thyroid cancer, ensued in Belarus and Ukraine, following the Chernobyl nuclear reactor accident (Cardis et al., 2005; Jargin, 2011; Reiners et al., 2013), also four years after Fukushima accident an excess of thyroid cancer has been detected among children and adolescents in the Fukushima prefecture (Tsuda et al., 2016), these incidences are presumably due to ingestion and inhalation of radioiodine in particular 131I a gamma and beta emitter with a physical half-life of 8 days (Reiners and Schneider, 2013). To prevent radioactive contamination, the responsible authorities implement series of physical measures like sheltering, evacuation and food restriction, in addition to pharmacologic thyroid blockade by oral potassium iodide (KI) at a dose of 130 mg (2 tablets of KI at 65 mg), fractions of this quantity are used in specific population groups (130 mg in adults, pregnant and lactating women, if necessary; 65 mg in children; 32.5 mg in infant and 16.25 mg in newborn) (Zanzonico and Becker, 2000; Dreger et al., 2015). The Polish government successfully applied iodine thyroid blocking (ITB) and as result about 90% of children under the age of 16 years showed thyroid dose commitment below 50 mSv (Nauman and Wolff, 1993). In case of a single release of radioiodine, a single administration of KI is regarded as sufficient (WHO, 1999) it approximately blocks the thyroid 24 h–36 h, the blocking capacity decreases when time after administration increases (Dreger et al., 2015). Currently, in extreme situations, the responsible authorities order a second administration of KI only for adults (WHO, 1999). Based on experiences from the Chernobyl accident with the prolonged release of radioiodine over 10 days and Fukushima accident where several releases of radioactivity have occurred over many days (Reiners and Schneider, 2013), it was clear that a single dose of KI is not adequate for thyroid blocking, in similar situations repeated administration of KI may be required to ensure adequate protection, unfortunately studies regarding the effects of repeated administration of KI are scarce and consequently the scientific evidence to apply repeated prophylaxis is weak. In 1980, a clinical trial was performed using different doses of KI over 12 days, the study showed a significant level of protection without major effect on the hormonal status of participants (Sternthal et al., 1980). Since 1948, it was demonstrated that an excess of iodide may transiently disrupt thyroid function, the well-known Wolff-Chaikoff effect characterized by decreased and delayed iodide organification (Wolff and Chaikoff, 1948), this effect is complex and encompasses multiple steps including iodide entrance and organification (Eng et al., 1999), iodide efflux through the colloid (Calil-Silveira et al., 2016a), intrathyroidal iodide pool regeneration (Solis et al., 2011), and thyroid hormones transport (de Souza et al., 2015). This effect could lead to a temporary variation of thyroid hormones level (Eng et al., 1999; de Souza et al., 2015), which exert a major impact on development, growth, and metabolism (Calil-Silveira et al., 2016b). Both the Wolff- Chaikoff effect and its escape are necessary to maintain thyroid hormone synthesis under tight control (Eng et al., 1999). Recently, a new prophylactic design, implying the administration of KI at 1 mg/kg/24h over a period of 8 days, was developed (Phan et al., 2017). To go further, the present work aims to apply this design and to assess the toxic effects on the hormonal and biochemical homeostasis in adult Wistar rat, also the impact on the main steps of thyroid hormones synthesis (iodide transport, iodide organification and thyroid hormones transport) was investigated.

Section snippets

Materials

Saline solution (pH 7.4) and potassium iodide solution (0.35 g/L), were kindly provided by central pharmacy of armies (Orleans, France).

Animals

Adult male Wistar rats, aged 3 months, weighing 335 ± 17 g, were purchased from Charles River Laboratories (L'arbresle, France); and housed under controlled conditions of temperature (21 ± 2 °C), humidity (50 ± 10%) and regular dark/light cycle (12h/12h). Normal-iodized pellet diet 0.3 mg I/kg of pellet (SAFE A04-10, Augy, France) and tap water were available

Repeated administration of KI increases UIC

Urinary iodine concentration was dramatically increased in group of rats that received KI 1 mg/kg/24h for 1 day, 4 days and 8 days by a factor of 13, 14 and 15 respectively in comparison to their controls (P < 0.001). In the group d10 and d30 where the treatment was stopped for 48 h and 30 days respectively, we did not notice a significant difference between controls and treated rats (Fig. 2).

Repeated administration of KI did not affect the general health parameters and the biochemical status

Body weight was not affected by the treatment; thyroid organ coefficient judged by thyroid weight/body

Discussion

Thyroid function can be modulated by many factors, such as TSH, thyroglobulin, and availability of iodine (de Souza et al., 2015; Ishido et al., 2015). It was demonstrated that an acute excess of iodide could led to a down-regulation of thyroid hormones level, which play an important role in the regulation of body metabolism (Eng et al., 1999; Maia et al., 2011). The down-regulation of thyroxine led to the up-regulation of TSH, itself affecting thyroid genes expression (Zaballos et al., 2008).

Conflicts of interest

The authors do not report conflict of interests regarding the publication of this paper.

Acknowledgments

This study was part of the PRIODAC research program supported by ANR-RSNR. The authors thank F. VOYER, A. SACHE and R. GRANGER for animal's care; and D COHEN for grammatical correction.

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