Genetic background and window of exposure contribute to thyroid dysfunction promoted by low-dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice

Carla Reale,Nicola Antonino Russo,Filomena Russo,Maria Marotta,Concetta Ambrosino,Emanuele Carchia,Luca Roberto,Immacolata Porreca,Massimo Mallardo,Mario De Felice

doi:10.1038/s41598-018-34427-2

Abstract

Genetic and environmental factors contribute to thyroid diseases. Although still debated, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is thought to induce thyroid dysfunction in humans and rodents. The data here reported point out the contribution of the exposure window and genetic background in mediating the low-dose TCDD effects on thyroid. Indeed, early (from E0.5 to PND30) and low-dose (0,001 μg/kg/day) TCDD exposure reduced the circulating fT4 and altered the expression of thyroid specific transcripts. The role of genetic components was estimated monitoring the same markers in Pax8+/− and Nkx2-1+/− mice, susceptible to thyroid dysfunction, exposed to 0, 1 μg/kg/day TCDD from E15.5 to PND60. Haploinsufficiency of either Pax8 or Nkx2-1 genes exacerbated the effects of the exposure impairing the thyroid enriched mRNAs in sex dependent manner. Such effect was mediated by mechanisms involving the Nkx2-1/p53/p65/IĸBα pathway in vitro and in vivo. Foetal exposure to TCDD impaired both thyroid function and genes expression while thyroid development and differentiation did not appear significantly affected. In mouse, stronger effects were related to earlier exposure or specific genetic background such as either Pax8 or Nkx2-1 haploinsufficiency, both associated to hypothyroidism in humans. Furthermore, our data underline that long exposure time are needed to model in vitro and in vivo results.

Highlights

Genetic and environmental factors concur to the development of several pathologies including thyroid diseases[1]
We show that different TCDD doses, windows of exposure, genetic factors and, sex are involved in mediating the impact of foetal TCDD exposure on the thyroid function
Effects of early maternal exposure to TCDD on thyroid hormones (TH) status of dams and their offspring have not been detailed, as recently done for other chemicals[16,17], because of the stressing administration routes usually adopted for TCDD administration

Summary

Introduction

Genetic and environmental factors concur to the development of several pathologies including thyroid diseases[1]. The TCDD activity on the HPT axis observed in rodents has been only sporadically confirmed in humans[15] This might be due to the variability of the genetic background of individuals, as opposed to the homogeneous genotype of the animal strains used in laboratory, and the relevance of the exposure window clearly evaluable only in animal models. The thyroid-specific mechanisms of TCDD toxicity are not clarified yet Their investigation is complicated in vivo because TCDD exerts its effects on HPT axis by the direct activity on the pituitary, on the thyroid gland or on both by the pituitary/thyroid feedback loop. We present data obtained both in mice and in vitro (in FRTL5, rat thyroid follicular cells) suggesting that low-dose TCDD carries out a direct effect on thyrocytes by a mechanism involving NF-κB pathway. We show that different TCDD doses, windows of exposure, genetic factors and, sex are involved in mediating the impact of foetal TCDD exposure on the thyroid function

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Results

Discussion

Conclusion