|Title:||Tributyltin exposure at noncytotoxic doses dysregulates pancreatic β-cell function in vitro and in vivo||Authors:||Chen Y.-W.
|Issue Date:||2017||Journal Volume:||91||Journal Issue:||9||Start page/Pages:||3135-3144||Source:||Archives of Toxicology||Abstract:||
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. ? 2017, Springer-Verlag Berlin Heidelberg.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/508542||ISSN:||0340-5761||DOI:||10.1007/s00204-017-1940-y||SDG/Keyword:||acetylcysteine; alpha tubulin; calcium ion; estrogen receptor; fulvestrant; glucose; insulin; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein kinase B; protein kinase C; reactive oxygen metabolite; tributyltin; calcium; glucose; insulin; organotin compound; reactive oxygen metabolite; tributyltin; adult; animal cell; animal experiment; Article; calcium cell level; controlled study; enzyme phosphorylation; exposure; glucose blood level; glucose homeostasis; glucose intolerance; glucose metabolism; glucose tolerance; human; human cell; in vitro study; in vivo study; insulin blood level; insulin release; insulin resistance; male; mouse; nonhuman; oxidative stress; pancreas islet beta cell; priority journal; signal transduction; animal; blood; cell survival; dose response; drug effect; environmental exposure; glucose tolerance test; Institute for Cancer Research mouse; metabolism; pancreas islet beta cell; pathology; physiology; rat; secretion (process); Animals; Blood Glucose; Calcium; Cell Survival; Dose-Response Relationship, Drug; Environmental Exposure; Glucose; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred ICR; Rats; Reactive Oxygen Species; Trialkyltin Compounds
|Appears in Collections:||法醫學科所|
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