Estrogens counteract tributyltin-induced toxicity in the rat islets of Langerhans

Abstract

Background: Tributyltin (TBT) is known as an endocrine disruptor able to interfere with estrogen receptors (ERs) leading to toxic effects on the related endocrine pathways. TBT is an obesogen, reported to disrupt glucose homeostasis leading to diabetes. The aim of this study was to assess the influence of TBT and β-estradiol on the pancreatic islets of Langerhans in simultaneous exposures.Experimental: Pancreatic islets of 15 male rat were isolated and exposed to TBT (10 μM), β-estradiol, and TBT plus β-estradiol for 24 h. Therewith, cellular viability, oxidative stress, apoptosis, and insulin secretion markers were investigated. Results: TBT decreased the viability and increased the apoptosis, reactive oxygen species, and insulin secretion TBT led to increased amounts of apaptosis, reactive oxygen species (ROS), and insulin secretion in pancreatic islets; however, cellular viability was reduced. Co-exposure with β-estradiol ameliorated the entire mentioned variables near to the control level. Conclusion: These results showed that β-estradiol protect pancreatic islets of Langerhans against TBT-induced toxicity by counteracting oxidative stress and apoptosis as well as insulin secretion. In this way, it is postulated that pancreatic ER pathways particularly in β-cells might be the determinant target of toxic effects of xenoestrogens like TBT. Hence, evaluation of xenoestrogens-induced ER dysfunction in the endocrine pancreas can be helpful in diabetic risk assessment of these contaminants. Pharmacological modifications of ER pathway in the β-cells seems promising for better management of diabetes.

Screening of metabolism-disrupting chemicals on pancreatic α-cells using in vitro methods

“…Contrary to β-cells, where TBT increases glucose-stimulated insulin secretion in a variety of models [20–22,43], here we did not observe a clear effect on glucagon secretion. However, as a clear trend is seen at both glucose concentrations, it may be that higher TBT doses result in augmented glucagon release.…”

“…It has been reported that in vivo and in vitro exposure to TBT results in β-cell death [21,22,42,43]. Here we show for the first time that TBT also induces α-cell apoptosis at doses as low as 1 nM.…”

Development of in vitro test methods in a model of human pancreatic β-cells to identify metabolism disrupting chemicals with diabetogenic activity

“…Yet, exposure to 500 nM TBT for 24 h markedly increased the number of apoptotic cells in the RINm5F cell line [22]. In line with the results observed in mouse [50] and rat islets [27], here we show that doses from 1 to 200 nM reduced cell viability by inducing apoptosis in two cell lines, EndoC-βH1 and INS-1E, and in dispersed mouse islets. TBT is an agonist of PPARγ and RXR [34,35] and our results indicate that the apoptotic effect of TBT in β-cells is mediated by these receptors because it is abolished by a PPARγ antagonist.…”

“…In rats, TBT effects on cell viability varied depending on the model studied. A TBT dose as low as 10 nM decreased cell viability by 20% in isolated rat islets [27], whereas doses up to 200 nM did not affect viability in the rat insulinoma cell line RINm5F [22,29]. Yet, exposure to 500 nM TBT for 24 h markedly increased the number of apoptotic cells in the RINm5F cell line [22].…”

“…BPA and TBT decreased β-cell viability in different β-cell models, namely INS-1E cells [21] and RINm5F cells [22]. Moreover, both chemicals have been characterized as MDCs that alter insulin secretion in primary mouse islets/β-cells [22][23][24], rat islets and insulinomas [25][26][27], and human islets [28,29]. Therefore, we used these two chemicals as positive controls to evaluate our human β-cell model.…”