Uma exploração multimodelo de desregulação endócrina na carcinogénese da tireoide.

Although diagnosis and therapy for several cancers have improved, we have reached a kind of plateau in terms of cancer burden reduction. The capacity to prevent cancer and to do early diagnosis are game changers to be able to decrease cancer burden, morbidity and mortality. Several risk factors have been identified (tobacco, UV radiation, HPV) and action under those factors through health education policies, eradication, or vaccines, have demonstrated effectiveness. However, this is only possible in those cancers where risk factors have been clearly demonstrated. Around 50-70% of the cancer types lack a clear etiologic factor (9), and we need to put effort in the identification of the unknown risk factors in order to be able to prevent and/or mitigate cancer. New challenges face human health, and a relevant one is the exposure to new chemical products (pollutants or manufacturing derivatives) that are increasingly produced and released to the environment. Endocrine disruptors (ED) are an example of those chemicals, known to interfere in living beings’ physiology. Exposure to EDs is already identified, in epidemiologic studies, as increasing cancer risk in humans, particularly those cancers affecting endocrine organs. TC incidence is recognizably increasing, with estimated age-standardized rates (ASR) of 15.6 for Portugal, according to the data from GLOBOCAN 2022 (10). EDs are obvious candidates as risk factors for TC, because their mimicry of thyroid hormones renders the thyroid gland particularly susceptible to them, as supported by epidemiological data. However, the precise cellular mechanism by which that risk is exerted, the characteristics of the ED-induced tumors, and the ways to prevent the transformation process remain largely unknown. Our concept proposes a multi-model approach to study EDs action in thyroid dysregulation and carcinogenesis: By using in vitro models (cancer thyroid cell lines and organoids), we aim to (Tasks 1, 2 and 3): - establish the effects of EDs on: thyroid cell differentiation; gene expression; function; in thyroid basal cell metabolism and tumorigenic potential. By using in vivo models (transgenic zebrafish), we aim to (Task 4): - establish the effects of EDs on: the complex thyrotropic feedback regulatory systems, as the HPT axis of zebrafish; in basal body metabolism; and as initiators and/or promoters of TC. By using in-silico strategies (bioinformatic analysis), we aim to (Tasks 1 and 2): - identify the effects of EDs on gene methylation and expression and identify new cellular targets of EDs. By using human samples, we aim to (Task 5): -assess the deposition of EDs in human tissues, and its relation with cancer risk By developing reporter systems of ED exposure, we aim to (Task 1, 2 and 3): - develop simple and efficient tools to evaluate the disruptor effect of compounds on thyroid cells The specific EDs to be used for our study (DEHP, BDE-28, BPAF) were selected based on our systematic review of EDs exposure and endocrine cancer risk in human cohorts (SF 2, 3) (1). Together, these investigations will establish novel models to study the effects of EDs in TC promotion and progression and elucidate mechanisms for the effect of EDs in tumorigenesis. The project results can be translated to a large number of cancers and a large number of compounds, can promote the well-being of populations, influence policymakers and contribute to prevent and reduce EDs exposure (and TC) in the general population.