Abstract
Epidemiological and experimental studies emphasize the link between environmental chemicals exposure and thyroid cancer. However, this association is strongly debated and the mechanisms of action of environmental thyroid carcinogens still need to be identified. The analysis of in vitro transcriptomic data developed to investigate the effects of chlorpyrifos on immortalized thyrocytes highlighted the impaired expression of genes involved in endodermal carcinogenesis. This endodermal carcinogenic gene-network (ECGN, including Zfp36l2, Dmbt1, Ddit4), was validated in cellular and mouse models of thyroid carcinogenesis, characterized by the constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and in immortalized thyrocytes exposed to tetrachlorodibenzo-p-dioxin (TCDD) and chlorpyrifos (CPF). The mRNA levels of Zfp36l2, Dmbt1 and Ddit4 were increased in models characterized by MAPK activation or following TCDD exposure, whereas they were inhibited by CPF exposure. Overall, the ECGN transcripts identify a novel gene-regulatory network associated with thyroid carcinogenesis promoted by genetic mutation or by environmental carcinogens. The latter have opposite effects on the modulation of the ECGN transcripts according to their mechanisms of action in promoting carcinogenesis. Therefore, the analyses of ECGN might be helpful in discriminating compounds that promote cellular survival associated or not to proliferation of thyrocytes.
Highlights
Thyroid disrupting chemicals (THDCs) are endocrine disruptor compounds (EDCs) exerting their effects on the function and regulation of the thyroid tissue, especially during the early-lifeInt
Conducted in silico toxicogenomic analyses of CPF activity, obtained by Ingenuity Pathways Analyses (IPA), revealed a gene regulatory network potentially involved in thyroid carcinogenesis
We explored the possibility that the same genes might be involved in thyroid carcinogenesis
Summary
Thyroid disrupting chemicals (THDCs) are endocrine disruptor compounds (EDCs) exerting their effects on the function and regulation of the thyroid tissue, especially during the early-lifeInt. Rodent studies have shown that environmental chemicals, such as tetrachlorodibenzo-p-dioxin (TCDD), interfere with hypothalamus-pituitary thyroid (HPT) axis and thyroid hormone (TH) signalling and have been associated with thyroid cancer [4]. The mechanisms of such activity are strongly debated, increased thyroid-stimulating hormone (TSH) levels and oxidative stress have been described as endogenous factors contributing to the rise in thyroid cancer incidence. Both are increased after exposure to EDCs such as Bisphenol A (BPA) [5] or TCDD [6]. Signalling pathways, deeply involved in thyroid carcinogenesis, are deregulated by the same factors [7,8]
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