Elsevier

Toxicology

Volume 425, 1 September 2019, 152242
Toxicology

Tributyltin exposure disturbs hepatic glucose metabolism in male mice

https://doi.org/10.1016/j.tox.2019.152242Get rights and content

Highlights

Abstract

Some previous studies showed that organotin compounds induced diabetes in animal models. The underlying mechanisms should be further revealed. In this study, male KM mice were exposed to tributyltin (TBT) at 0.5, 5 and 50 μg/kg once every three days for 45 days. The TBT-treated mice exhibited an elevation of fasting blood glucose level and glucose intolerance. The fasting serum insulin levels were increased and reached a significant difference in the 50 μg/kg group; the glucagon levels were significantly decreased in all the treatments. Pancreatic β-cell mass was significantly decreased in all the treatments; α-cell mass showed a significant decrease in the 5 and 50 ug/kg groups. The transcription of pancreatic insulin gene (Ins2) showed an up-regulation and reached a significant difference in the 5 and 50 μg/kg groups, which would be responsible for the increased serum insulin levels. The transcription of glucagon gene (Gcg) in the pancreas was significantly down-regulated in the 5 and 50 ug/kg groups. The protein expression of hepatic glucagon receptor was down-regulated, while the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase was up-regulated accompanied by increased hepatic glycogen content. These results indicated that hepatic gluconeogenesis was enhanced during insulin resistance stage caused by TBT exposure, which would exert a potential risk inducing the development of diabetes mellitus.

Introduction

The prevalence of diabetes mellitus (DM) is increasing worldwide, which causes extensive financial burden and increased mortality risk (American Diabetes Association, 2013; Baena-Díez et al., 2016). Besides the effects of genetic factors and life style, environmental pollutants, especially persistent organic pollutants, are thought to play an important part in the incidence of DM (Lee et al., 2014; Taylor et al., 2013). Among environmental pollutants, exposure to organotin compounds such as tributyltin (TBT) and triphenyltin (TPT) is related with the development of DM in experimental animal research. A single administration of TPT fluoride (100 mg/kg) caused diabetes in rabbits (Manabe and Wada, 1981). The treatment with a single dose of TPT hydroxide led marked hyperglycemia in rabbits and hamsters (Matsui et al., 1984); Rabbits and hamsters treated with TPTCl (60 mg/kg) exhibited diabetes with decreased insulin secretion (Miura et al., 1997); TBT exposure can induce obesity trough the activation of both PPARγ and RXRα which are the master regulator of adipogenesis and promote lipid storage (Grün et al., 2006; Grün and Blumberg, 2006). In young male mice, repeatedly exposure to TBT (0.5, 5, 50 μg/kg) for 45 days caused obesity, hepatic steatosis, elevated plasma insulin levels (Zuo et al., 2011), and reduced plasma glucagon levels (Li et al., 2017), and inhibited the expression of the insulin receptor (IR) signaling cascade, including IR, IR substrate, phosphatidylinositol 3-kinase, Akt, and glucose transporter 4 both in the liver and the skeletal muscle, which might be responsible for the insulin resistance and hyperglycemia (Li et al., 2017). TBT increased the apoptosis and reduced the proliferation of islet cells, resulting in the reduction of relative area of pancreatic islets (Zuo et al., 2014). However, the mass and function of pancreatic α-cell and β-cell needs to be further investigated; whether hepatic glucose metabolism was influenced should be studied.

Glucagon plays a key role in the regulation of glucose homeostasis (Wu et al., 2018). Glucagon is secreted from islet α-cells and increases blood glucose levels through increased hepatic glucose production in the fasting state (Campbell and Drucker, 2015). Glucagon stimulates the transcription of genes encoding gluconeogeneic enzymes such as glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PCK) via glucagon receptor (GCGR) (Miller and Birnbaum, 2016; Ravnskjaer et al., 2015). GCGR is emerging as a key molecule involved in glucose metabolism (Albrechtsen, 2018). Liver glycogenolysis is another means by which glucose homeostasis is maintained during fasting. But there are few studies investigating the hepatic glucose metabolism response to TBT exposure.

The aim of the present study were to (1) investigate the changes of pancreatic β-cell and α-cell mass and their function in mice exposed to TBT; (2) explore the possible reason for the elevated serum insulin levels; and (3) analyze the alteration of serum glucagon levels and its relation with hepatic glucose metabolism.

Section snippets

Animal treatment

All animal experiments were performed following the guides of the Institutional Animal Care and Use Committee of Xiamen University. KM male mice, 21 days old and weighing 21–22 g, were housed at 22 ± 1 °C under a 12:12 h light-dark cycle and were given ad libitum access to food and water. After acclimation for 3 days, twenty four mice were divided randomly into four groups for treatment, without statistically significant differences in body weights among groups. Tributyltin chloride (purity

TBT increased body weight and visceral fat mass

After exposure to TBT for 45 days, mice’s body weight and visceral fat mass were increased and reached a significant difference in the 50 μg/kg group (1.07-fold and 1.4-fold respectively) compared to the control (Fig. 1).

TBT resulted in hyperglycaemia and glucose intolerance

Fasting plasma glucose concentration was increased in the TBT-treated mice and reached a significant difference (by 1.30-fold) in the 50 ug/kg group (Fig. 2A). The area under the GTT curve (AUC) were significantly elevated (1.28, 1.29 and 1.32-fold) in the 0.5, 5, 50 μg/kg

Discussion

Organotin compounds are widely used as biocides in agriculture, paint pesticides, wood preservatives, and as a PVC plastic heat stabilizer. General population may be exposed to TBT through drinking water and contaminated dietary sources that are mainly fish and fish products. The concentrations of total butyltins in the liver sample form Danish men ranged from 1.1 to 33.0 ng/g wet weight (Nielsen and Strand, 2002). The concentrations of butyltins including monobutyltin, dibutyltin and TBT in

Declaration of Competing Interest

None.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (21577113).

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    These authors contributed equally to this work.

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