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

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.

Endocrine Disruptor-Induced Bone Damage Due to Hormone Dysregulation: A Review

“…TCDD has been found to decrease TH levels, T4, and thyroid function. However, more studies are needed for better understanding of the mechanism of TCDD toxicity on bone through thyroid hormone signaling [107].…”

Peripheral T3 signaling is the target of pesticides in zebrafish larvae and adult liver

“…The small increase in tshb, which regulates the expression of the thyroid-specific genes such as scl5a5, suggests that other pathways might be involved, such as NF-kB. We have proposed it as a regulator of scl5a5 expression in mice exposed to p-dioxin and have shown that CPF reduces p65 nuclear level in rat follicular cells (Reale et al 2018(Reale et al , 2019. The results found in F2-larvae provide evidence that parental exposure might itself cause the reduction of the number of follicles and hypothyroidism, although we cannot distinguish between the impairment of the TH reserve in the yolk or germline epigenetic changes.…”

A Toxicogenomic Approach Reveals a Novel Gene Regulatory Network Active in In Vitro and In Vivo Models of Thyroid Carcinogenesis

“…The mechanisms of such activity are strongly debated, although increased thyroid-stimulating hormone (TSH) levels and oxidative stress have been described as endogenous factors contributing to the rise in thyroid cancer incidence. Notably, both are increased after exposure to EDCs such as Bisphenol A (BPA) [5] or TCDD [6]. Furthermore, signalling pathways, deeply involved in thyroid carcinogenesis, are also deregulated by the same factors [7,8].…”