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Exposição crónica de peixes-zebra juvenis aos químicos ioxinil e diethylstilbestrol leva a alterações da morfologia cardíaca e desregulação da homeostasia do eixo hipotálamo-pituitária-tiroide
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Abstract(s)
Os estudos sobre os químicos com efeitos de disrupção endócrina (EDCs) têm vindo a aumentar devido aos efeitos nocivos sobre os ecossistemas. O peixe-zebra (Danio rerio) é um modelo animal utilizado nos estudos toxicológicos quer durante o desenvolvimento como na fisiologia adulta.
Em estudos prévios foi demonstrado que os compostos químicos Ioxinil (IOX) e Diethylstilbestrol (DES), em concentração micromolares, e abaixo dos níveis mínimos de segurança, são capazes de alterar a morfologia cardíaca e desregular o eixo Hipotálamo-Pituitária-Tiroide (HPT). Neste estudo pretendemos observar se o mesmo ocorre em animais adultos. Tendo em conta que a função cardíaca é fundamental para o desenvolvimento e a homeostasia da glândula da tiroide é inquirido como o subdesenvolvimento da tiroide afeta o eixo HPT.
Foi observado que o composto químico DES em peixes-zebra juvenis não alterou a morfologia cardíaca. No entanto, a análise da expressão génica indicou uma parente alteração nos genes relacionados com a homeostasia do cálcio que poderá encontrar-se afetada. Houve uma alteração ao nível da área e dispersão dos folículos ao longo da aorta, onde foi notório um aparecimento anormal de folículos. Foi também observada uma inibição na expressão génica da tiroglobulina (Tg) e da tirotropina (TSH), mostrando que o DES tem impacto sobre a regulação do eixo HPT.
No caso do composto químico IOX, este teve um impacto ao nível da morfologia cardíaca levando a um aumento do volume do ventrículo em paralelo com um aumento da área dos folículos da tiroide. A análise génica demonstrou que houve uma aparente alteração de expressão dos genes Notch1b e Chrn3b. A expressão da Tg permaneceu igual, no entanto a expressão da TSH demonstrou uma aparente diminuição da expressão. Estas evidências sugerem que o IOX em peixe-zebra juvenil afetou o funcionamento do coração e o eixo HPT.
Em conclusão, ambos os químicos afetaram o eixo HPT, embora de modo diferente confirmando a capacidade de se comportarem como EDCs.
There is an urgency to study endocrine disruption chemicals (EDCs), due to their broad dispersion in the environment and negative effect on humans, animals, and ecosystems. The use of live vertebrate models to study the biological and structural function of the cells and tissues affected by pollutants helps to comprehend in detail the molecular and cellular events triggered by these chemicals. The zebrafish (Danio rerio) is an outstanding animal model for toxicological studies. It presents all vertebrate characteristics allowing for a detailed comprehension of the EDC may have in human health both during development and adult physiology. Chemicals such as the herbicide Ioxynil (IOX) and the steroid drug Diethylstilbestrol (DES) are commonly present in agricultural and veterinary use, and discarded as wastewater to the environment, they have a low solubility and a high bioaccumulation being important to understand the impact they have in the ecosystems. In previous studies it was reported that IOX and DES have impairment effects on the embryonic development of the heart, vasculature, and thyroid gland in zebrafish. Those studies describe that effects of these chemicals in zebrafish embryos in micromolar levels are capable of altering the cardiac and vascular physiology and have the potential to indirectly impact the endocrine regulation of the thyroid. Transcriptome analysis also observed that these low concentrations of chemicals have the capacity to alter the expression of endothelial genes. These evidences suggest that low micromolar levels are not safe and might impact the environment. The aim of this study was to understand the effect of IOX and DES in micromolar concentrations can have in juvenile cardiac morphology and function. Previous evidence shows that cardiac function is fundamental to the homeostasis of the thyroid gland. Therefore, it is interrogated how changes in cardiac morphology/function can impact in the sub-development of the thyroid that in turn affect the HPT axis. DES chronic exposition in the juvenile did not lead to an alteration of cardiac morphology and likely its function. Although gene expression analyses indicated that the calcium physiology showed some alterations. It was observed an alteration in the dispersion of thyroid follicles alongside the aorta, where is evident an abnormal development of the follicles in areas far posterior and anterior of the normal development area. It was also observed an apparent decrease in Tg and TSH gene expression, suggesting that this steroid chemical might have direct impact on HPT-axis homeostasis. In case of IOX this had an impact on the juvenile zebrafish cardiac morphology, leading to increased ventricle volume in parallel with an increase of the thyroid follicles. Analysis of gene expression demonstrates that IOX exposition leads to an alteration on the cardiac genes. Likewise, thyroglobulin (Tg) expression was in even levels though there is a low expression of thyrotropin (TSH). This evidence suggests that IOX in juvenile zebrafish had impact on the heart and consequently on the HPT system. To summarize: (1) micromolar levels of IOX affect the cardiac system, increasing ventricle volume and indirectly impacted the thyroid follicles morphology and HPT axis; (2) the mechanism by which DES acts was not so clear. Nonetheless, it affected the thyroid field size, thus being capable of interfering with the HPT axis homeostasis; (3) these chemicals are capable of disrupting the endocrine function of the thyroid in juvenile zebrafish, in micromolecular levels, lower concentrations than those permitted by law. Overall, both chemicals have EDC potential albeit with different mechanisms.
There is an urgency to study endocrine disruption chemicals (EDCs), due to their broad dispersion in the environment and negative effect on humans, animals, and ecosystems. The use of live vertebrate models to study the biological and structural function of the cells and tissues affected by pollutants helps to comprehend in detail the molecular and cellular events triggered by these chemicals. The zebrafish (Danio rerio) is an outstanding animal model for toxicological studies. It presents all vertebrate characteristics allowing for a detailed comprehension of the EDC may have in human health both during development and adult physiology. Chemicals such as the herbicide Ioxynil (IOX) and the steroid drug Diethylstilbestrol (DES) are commonly present in agricultural and veterinary use, and discarded as wastewater to the environment, they have a low solubility and a high bioaccumulation being important to understand the impact they have in the ecosystems. In previous studies it was reported that IOX and DES have impairment effects on the embryonic development of the heart, vasculature, and thyroid gland in zebrafish. Those studies describe that effects of these chemicals in zebrafish embryos in micromolar levels are capable of altering the cardiac and vascular physiology and have the potential to indirectly impact the endocrine regulation of the thyroid. Transcriptome analysis also observed that these low concentrations of chemicals have the capacity to alter the expression of endothelial genes. These evidences suggest that low micromolar levels are not safe and might impact the environment. The aim of this study was to understand the effect of IOX and DES in micromolar concentrations can have in juvenile cardiac morphology and function. Previous evidence shows that cardiac function is fundamental to the homeostasis of the thyroid gland. Therefore, it is interrogated how changes in cardiac morphology/function can impact in the sub-development of the thyroid that in turn affect the HPT axis. DES chronic exposition in the juvenile did not lead to an alteration of cardiac morphology and likely its function. Although gene expression analyses indicated that the calcium physiology showed some alterations. It was observed an alteration in the dispersion of thyroid follicles alongside the aorta, where is evident an abnormal development of the follicles in areas far posterior and anterior of the normal development area. It was also observed an apparent decrease in Tg and TSH gene expression, suggesting that this steroid chemical might have direct impact on HPT-axis homeostasis. In case of IOX this had an impact on the juvenile zebrafish cardiac morphology, leading to increased ventricle volume in parallel with an increase of the thyroid follicles. Analysis of gene expression demonstrates that IOX exposition leads to an alteration on the cardiac genes. Likewise, thyroglobulin (Tg) expression was in even levels though there is a low expression of thyrotropin (TSH). This evidence suggests that IOX in juvenile zebrafish had impact on the heart and consequently on the HPT system. To summarize: (1) micromolar levels of IOX affect the cardiac system, increasing ventricle volume and indirectly impacted the thyroid follicles morphology and HPT axis; (2) the mechanism by which DES acts was not so clear. Nonetheless, it affected the thyroid field size, thus being capable of interfering with the HPT axis homeostasis; (3) these chemicals are capable of disrupting the endocrine function of the thyroid in juvenile zebrafish, in micromolecular levels, lower concentrations than those permitted by law. Overall, both chemicals have EDC potential albeit with different mechanisms.
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Keywords
Ioxynil Diesthylstilbestrol Peixe-zebra Tiroide Eixo hpt EDC