Low-dose tributyltin exposure induces an oxidative stress-triggered JNK-related pancreatic \u03b2-cell apoptosis and a reversible hypoinsulinemic hyperglycemia in mice

Chun-Fa Huang,Jing-Ren Tsai,Kuo-Cheng Lan,Ching-Yao Yang,Cheng-Tien Wu,Shing-Hwa Liu

doi:10.1038/s41598-018-24076-w

Abstract

Tributyltin (TBT), an endocrine disrupting chemical, can be found in food (particular in fish and seafood) and drinking water by contamination. Here, we elucidated the effects and possible mechanisms of low-dose TBT on the growth and function of pancreatic β-cells and glucose metabolism in mice. Submicromolar-concentration of TBT significantly induced β-cell cytotoxicity and apoptosis, which were accompanied by poly (ADP-ribose) polymerase cleavage and mitogen-activated protein kinases-JNK and ERK1/2 phosphorylation. TBT could also suppress the glucose-stimulated insulin secretion in β-cells and isolated mouse islets. TBT increased reactive oxygen species production. TBT-induced β-cell cytotoxicity and apoptosis were significantly prevented by antioxidant N-acetylcysteine (NAC) and JNK inhibitor SP600125, but not ERK1/2 inhibitor PD98059 and p38 inhibitor SB203580. Both NAC and SP600125 inhibited JNK phosphorylation and reduced cell viability in TBT-treated β-cells. Four-week exposure of TBT (0.25 mg/kg) to mice revealed the decreased plasma insulin, increased blood glucose and plasma malondialdehyde, suppressed islet insulin secretion, and increased islet caspase-3 activity, which could be reversed by NAC treatment. After removing the TBT exposure for 2 weeks, the TBT-induced glucose metabolism alteration was significantly reversed. These results suggest that low-dose TBT can induce β-cell apoptosis and interfere with glucose homeostasis via an oxidative stress-related pathway.

Highlights

Endocrine disrupting chemicals (EDCs) are chemical compounds that mimic or interfere with the synthesis, secretion, transport, function, or metabolism of natural hormones, causing a wide range and deleterious effects in physiological systems including reproductive, neurological, cardiovascular, metabolic and immune systems[1,2]
We further investigated the effects of TBT on β-cell function determined by glucose-stimulated insulin secretion assay
EDCs are discharged into the environment and remain to be introduced into organisms and act as hormones, and more than 100 species of EDCs have been identified including TBT6,7

Summary

Introduction

Endocrine disrupting chemicals (EDCs) are chemical compounds that mimic or interfere with the synthesis, secretion, transport, function, or metabolism of natural hormones, causing a wide range and deleterious effects in physiological systems including reproductive, neurological, cardiovascular, metabolic and immune systems[1,2]. The increased presence of EDCs in the life environment of humans has been reported playing an important role in the disruption of pancreatic β-cells function and the development of diabetes-related diseases[4,5]. The effect of TBT exposure on the alteration of insulin secretion in mammalian may contribute to an environment risk factor in the development of diabetes. Pancreatic islet β-cell cells are vulnerable to oxidative stress, which may induce β-cell apoptosis and β-cell mass reduction, resulting in the dysfunction of insulin secretion and the pathogenesis of diabetes[17]. We aimed to examine the effects of TBT on islet β-cell dysfunction and apoptosis in vitro and in vivo and investigate the involvement of ROS-mediated molecular signals in these TBT-induced effects

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Conclusion