Hypothyroidism induces oxidative stress and DNA damage in breast

Abstract

Breast cancer and thyroid dysfunctions have been associated for decades. Although many studies suggest a biological correlation, the mechanisms linking these two pathologies have not been elucidated. Reactive oxygen species (ROS) can oxidize lipids, proteins, and DNA molecules and may promote tumor initiation. Hence, we aimed at evaluating the mammary redox balance and genomic instability in a model of experimental hypothyroidism. Female Wistar rats were treated with 0.03% methimazole for 7 or 21 days to evaluate ROS generation, antioxidant enzyme activities, and oxidative stress biomarkers, as well as genomic instability. After 7 days, lower catalase, GPx, and DUOX activities were detected in the breast of hypothyroid group compared to the control while the levels of 4-hydroxynonenal (HNE) were higher. In addition, hypothyroid group showed an increase in γH2Ax/H2Ax ratio. 21-days hypothyroid group had increased catalase and SOD activities, without significant differences between groups in the levels of oxidative stress biomarkers and DNA damage. TSH-treated MCF10A cells showed a higher extracellular, intracellular, and mitochondrial ROS production. Additionally, greater DNA damage was observed in these cells, demonstrated by a higher comet tail DNA percentage and increased 53BP1 foci. Finally, we found that TSH treatment was not able to alter cell viability. The Genome Cancer Atlas (TGCA) data showed that high TSHR expression is associated with more invasive breast cancer types. In conclusion, we demonstrate that oxidative stress and DNA damage in breast are early events of experimental hypothyroidism. Moreover, high TSH levels induce oxidative stress and genomic instability in mammary cells.

Oxidative stress in thyroid dysfunction

“…In both hyperthyroidism and hypothyroidism, investigations revealed a misbalance of the oxidative/ anti-oxidative system. 7,8,18 That imbalance may be due to changes in metabolic rates leading to excessive production of hydrogen peroxide and nitric oxide. 19 Owing to the excess production of free radicals, there are several tissues damages and inflammation 20 leading to instigation of associated diseases such as diabetes, hypertension and cancer.…”

“…19 Owing to the excess production of free radicals, there are several tissues damages and inflammation 20 leading to instigation of associated diseases such as diabetes, hypertension and cancer. 7,8,18 Accordingly, the recent work revealed a misbalance of the oxidative stress status in peripheral blood in thyroiditis. There was significant increase in lipid peroxidation metabolites in hypothyroidism (1.14 ±0.631 µmol.…”

“…6 Obviously, the oxidative stress misbalance is conceived as a cross-linking mechanism leading to the development of many associated diseases. 7,8 In this work, the oxidative stress condition was investigated in a sample of population with thyroidal disorder.…”

Thyroid function and epilepsy: a two-sample Mendelian randomization study

“…During the fetal and neonatal periods, THs can influence neuronal proliferation, migration, synaptogenesis, myelination, and dendritic cell differentiation ( Remaud et al, 2014 ). Both hyperthyroidism and hypothyroidism have the potential to disrupt mitochondrial function through genetic and nongenetic pathways, leading to oxidative/antioxidative imbalance (oxidative stress) and the generation of reactive oxygen species (ROS) ( Maity et al, 2013 ; Peixoto et al, 2021 ). As a common and challenging neurological disorder, the etiology of epilepsy is heterogenous and gaining widespread attention.…”

Consequências do hipotireoidismo na doença de Chagas experimental

“…O estudo do hipotireoidismo em modelos animais possibilitou grandes descobertas sobre as consequências da hipofunção tireoidiana em processos celulares, metabólicos e infecciosos (MISHRA et al, 2021;PEIXOTO et al, 2021;VAREDI et al, 2014) sonda gástrica ou pela adição do medicamento em água de beber dos animais, promoveu efeitos similares no que se refere a quantificação de parâmetros tireoidianos associados a hipofunção, além disso, as doses de 0,02% ou 0,04% do medicamento diluídos em água de beber, também apresentaram a mesma eficácia para a instalação do hipotireoidismo (ZHOU et al, 2015b). Baseado nesses achados, nós e outros autores (SAMPAIO et al, 2020;SARATI et al, 2012;VAREDI et al, 2014), temos optado pelo uso de menor dose do medicamento e pela via de administração menos invasiva.…”