Tributyltin exposure at noncytotoxic doses dysregulates pancreatic β-cell function in vitro and in vivo.
Tributyltin (TBT) is an endocrine disruptor. TBT can be found in food and in human tissues and blood. Several animal studies revealed that organotins induced diabetes with decreased insulin secretion. The detailed effect and mechanism of TBT on pancreatic β-cell function still remain unclear. We investigated the effect and mechanism of TBT exposure at noncytotoxic doses relevant to human exposure on β-cell function in vitro and in vivo. The β-cell-derived RIN-m5F cells and pancreatic islets from mouse and human were treated with TBT (0.05-0.2 μM) for 0.5-4 h. Adult male mice were orally exposed to TBT (25 μg/kg/day) with or without antioxidant N-acetylcysteine (NAC) for 1-3 weeks. Assays for insulin secretion and glucose metabolism were carried out. Unlike previous studies, TBT at noncytotoxic concentrations significantly increased glucose-stimulated insulin secretion and intracellular Ca2+([Ca2+]i) in β-cells. The reactive oxygen species (ROS) production and phosphorylation of protein kinase C (PKC-pan) and extracellular signal-regulated kinase (ERK)1/2 were also increased. These TBT-triggered effects could be reversed by antiestrogen ICI182780 and inhibitors of ROS, [Ca2+]i, and PKC, but not ERK. Similarly, islets treated with TBT significantly increased glucose-stimulated insulin secretion, which could be reversed by ICI182780, NAC, and PKC inhibitor. Mice exposed to TBT for 3 weeks significantly increased blood glucose and plasma insulin and induced glucose intolerance and insulin resistance, which could be reversed by NAC. These findings suggest that low/noncytotoxic doses of TBT induce insulin dysregulation and disturb glucose homeostasis, which may be mediated through the estrogen receptor-regulated and/or oxidative stress-related signaling pathways.
Department of Physiology and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, Republic of China.
Ya-Wen
YW
Chen
Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Kuo-Cheng
KC
Lan
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
Jing-Ren
JR
Tsai
Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
Te-I
TI
Weng
Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan, Republic of China.
Ching-Yao
CY
Yang
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China. shinghwaliu@ntu.edu.tw.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan, Republic of China. shinghwaliu@ntu.edu.tw.|Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan, Republic of China. shinghwaliu@ntu.edu.tw.
Shing-Hwa
SH
Liu
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D008813:Mice, Inbred ICR; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000008:administration & dosage* / Q000633:toxicity*
D001786:Blood Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D014220:Trialkyltin Compounds; C011559:tributyltin; D005947:Glucose; D002118:Calcium
Insulin dysregulation; Islets; Oxidative stress; Tributyltin; β-Cells