Archives of Toxicology

, Volume 91, Issue 9, pp 3135–3144 | Cite as

Tributyltin exposure at noncytotoxic doses dysregulates pancreatic β-cell function in vitro and in vivo

  • Ya-Wen Chen
  • Kuo-Cheng Lan
  • Jing-Ren Tsai
  • Te-I Weng
  • Ching-Yao Yang
  • Shing-Hwa Liu
Organ Toxicity and Mechanisms

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.

Keywords

Tributyltin β-Cells Islets Oxidative stress Insulin dysregulation 

References

  1. Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A (2006) The estrogenic effect of bisphenol A disrupts pancreatic β-cell function in vivo and induces insulin resistance. Environ Health Perspect 114:106–112CrossRefPubMedGoogle Scholar
  2. Alonso-Magdalena P, Ropero AB, Carrera MP, Cederroth CR, Baquié M, Gauthier BR et al (2008) Pancreatic insulin content regulation by the estrogen receptor ERα. PLoS One 3:e2069CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alonso-Magdalena P, Quesada I, Nadal A (2011) Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol 7:346–353CrossRefPubMedGoogle Scholar
  4. Antizar-Ladislao B (2008) Environmental levels, toxicity and human exposure to tributyltin (TBT)-contaminated marine environment. Environ Int 34:292–308CrossRefPubMedGoogle Scholar
  5. Casals-Casas C, Desvergne B (2011) Endocrine disruptors: From endocrine to metabolic disruption. Annu Rev Physiol 73:135–162CrossRefPubMedGoogle Scholar
  6. Chamorro-Garcia R, Sahu M, Abbey RJ, Laude J, Pham N, Blumberg B (2013) Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice. Environ Health Perspect 121:359–366CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen YW, Huang CF, Tsai KS, Yang RS, Yen CC, Yang CY et al (2006) The role of phosphoinositide 3-kinase/Akt signaling in low-dose mercury-induced mouse pancreatic β-cell dysfunction in vitro and in vivo. Diabetes 55:1614–1624CrossRefPubMedGoogle Scholar
  8. Chien LC, Hung TC, Choang KY, Yeh CY, Meng PJ, Shieh MJ et al (2002) Daily intake of TBT, Cu, Zn, Cd and As for fishermen in Taiwan. Sci Total Environ 285:177–185CrossRefPubMedGoogle Scholar
  9. Clapham DE (2007) Calcium signaling. Cell 131:1047–1058CrossRefPubMedGoogle Scholar
  10. Fernandez-Millan E, Ramos S, Alvarez C, Bravo L, Goya L, Martin MA (2014) Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic β-cells against tert-butyl hydroperoxide-induced toxicity via ERKs and PKC pathways. Food Chem Toxicol 66:245–253CrossRefPubMedGoogle Scholar
  11. Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic β-cell dysfunction in diabetes. Curr Diabetes Rev 9:25–53CrossRefPubMedPubMedCentralGoogle Scholar
  12. Görlach A, Bertram K, Hudecova S, Krizanova O (2015) Calcium and ROS: a mutual interplay. Redox Biol 6:260–271CrossRefPubMedPubMedCentralGoogle Scholar
  13. Grandjean P (2011) Exposure to environmental chemicals as a risk factor for diabetes development. In: Bourguignon JP, Jégou B, Kerdelhué B, Toppari J, Christen Y (eds) Multi-system endocrine disruption. Springer, Berlin, pp 91–99CrossRefGoogle Scholar
  14. Gupte AA, Pownall HJ, Hamilton DJ (2015) Estrogen: an emerging regulator of insulin action and mitochondrial function. J Diabetes Res 2015:916585CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hectors TL, Vanparys C, van der Ven K, Martens GA, Jorens PG, Van Gaal LF et al (2011) Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function. Diabetologia 54:1273–1290CrossRefPubMedGoogle Scholar
  16. Huang CF, Chen YW, Yang CY, Lin HY, Way TD, Chiang W et al (2011) Extract of lotus leaf (Nelumbo nucifera) and its active constituent catechin with insulin secretagogue activity. J Agric Food Chem 59:1087–1094CrossRefPubMedGoogle Scholar
  17. Kannan K, Senthilkumar K, Giesy JP (1999) Occurrence of butyltin compounds in human blood. Environ Sci Technol 33:1776–1779CrossRefGoogle Scholar
  18. Le May C, Chu K, Hu M, Ortega CS, Simpson ER, Korach KS et al (2006) Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci USA 103:9232–9237CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lee CC, Hsieh CY, Tien CJ (2006) Factors influencing organotin distribution in different marine environmental compartments, and their potential health risk. Chemosphere 65:547–559CrossRefPubMedGoogle Scholar
  20. Manabe S, Wada O (1981) Triphenyltin fluoride (TPTF) as a diabetogenic agent. TPTF induces diabetic lipemia by inhibiting insulin secretion from morphologically intact rabbit β-cell. Diabetes 30:1013–1021CrossRefPubMedGoogle Scholar
  21. Mauvais-Jarvis F, Clegg DJ, Hevener AL (2013) The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 34:309–338CrossRefPubMedPubMedCentralGoogle Scholar
  22. Mbaya E, Oules B, Caspersen C, Tacine R, Massinet H, Pennuto M et al (2010) Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain complex II deficiency. Cell Death Differ 17:1855–1866CrossRefPubMedGoogle Scholar
  23. Mitra S, Gera R, Siddiqui WA, Khandelwal S (2013) Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood-brain barrier and metal homeostasis in cerebral cortex of rat brain: an in vivo and in vitro study. Toxicology 310:39–52CrossRefPubMedGoogle Scholar
  24. Miura Y, Matsui H (1987) The effects of triphenyltin on insulin release from pancreatic islets in hamsters. J Japan Diab Soc 30:895–900Google Scholar
  25. Miura Y, Kato M, Ogino K, Matsui H (1997) Impaired cytosolic Ca2+ response to glucose and gastric inhibitory polypeptide in pancreatic β-cells from triphenyltin-induced diabetic hamster. Endocrinology 138:2769–2775CrossRefPubMedGoogle Scholar
  26. Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB (2009) The pancreatic β-cell as a target of estrogens and xenoestrogens: implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol 304:63–68CrossRefPubMedGoogle Scholar
  27. Nakatsu Y, Kotake Y, Ohta S (2007) Concentration dependence of the mechanisms of tributyltin-induced apoptosis. Toxicol Sci 97:438–447CrossRefPubMedGoogle Scholar
  28. Nielsen JB, Strand J (2002) Butyltin compounds in human liver. Environ Res 88:129–133CrossRefPubMedGoogle Scholar
  29. Ovalle F, Azziz R (2002) Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril 77:1095–1105CrossRefPubMedGoogle Scholar
  30. Penninks AH (1993) The evaluation of data-derived safety factors for bis(tri-n-butyltin)oxide. Food Addit Contam 10:351–361CrossRefPubMedGoogle Scholar
  31. Quesada I, Fuentes E, Viso-León MC, Soria B, Ripoll C, Nadal A (2002) Low doses of the endocrine disruptor bisphenol-A and the native hormone 17β-estradiol rapidly activate transcription factor CREB. FASEB J 16:1671–1673PubMedGoogle Scholar
  32. Ramadan JW, Steiner SR, O’Neill CM, Nunemaker CS (2011) The central role of calcium in the effects of cytokines on β-cell function: Implications for type 1 and type 2 diabetes. Cell Calcium 50:481–490CrossRefPubMedPubMedCentralGoogle Scholar
  33. Sharma N, Kumar A (2014) Mechanism of immunotoxicological effects of tributyltin chloride on murine thymocytes. Cell Biol Toxicol 30:101–112CrossRefPubMedGoogle Scholar
  34. Sternberg RM, Gooding MP, Hotchkiss AK, LeBlanc GA (2010) Environmental-endocrine control of reproductive maturation in gastropods: Implications for the mechanism of tributyltin-induced imposex in prosobranchs. Ecotoxicology 19:4–23CrossRefPubMedGoogle Scholar
  35. Thayer KA, Heindel JJ, Bucher JR, Gallo MA (2012) Role of environmental chemicals in diabetes and obesity: a national toxicology program workshop review. Environ Health Perspect 120:779–789CrossRefPubMedPubMedCentralGoogle Scholar
  36. Wang J, Chakravarthy BR, Morley P, Whitfield JF, Durkin JP, Begin-Heick N (1996) Glucose, potassium, and CCK-8 induce increases in membrane-associated PKC activity that correspond to increases in [Ca2+]i in islet cells from neonatal rats. Cell Signal 8:305–311CrossRefPubMedGoogle Scholar
  37. Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G, Wheeler MB (2010) Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic β-cell apoptosis and increases insulin gene expression and secretion. J Biol Chem 285:33623–33631CrossRefPubMedPubMedCentralGoogle Scholar
  38. World Health Organization (2016) Global report on diabetes. Geneva:WHO. Available: http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf. Accessed 8 September 2016]
  39. Youl E, Bardy G, Magous R, Cros G, Sejalon F, Virsolvy A et al (2010) Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway. Br J Pharmacol 161:799–814CrossRefPubMedPubMedCentralGoogle Scholar
  40. Yu WJ, Lee BJ, Nam SY, Kim YC, Lee YS, Yun YW (2003) Spermatogenetic disorders in adult rats exposed to tributyltin chloride during puberty. J Vet. Med Sci 65:1331–1335Google Scholar
  41. Zhang Y, Chen Y, Sun L, Liang J, Guo Z, Xu L (2014) Protein phosphatases 2a as well as reactive oxygen species involved in tributyltin-induced apoptosis in mouse livers. Environ Toxicol 29:234–242CrossRefPubMedGoogle Scholar
  42. Zhivotovsky B, Orrenius S (2011) Calcium and cell death mechanisms: A perspective from the cell death community. Cell Calcium 50:211–221CrossRefPubMedGoogle Scholar
  43. Zuo Z, Wu T, Lin M, Zhang S, Yan F, Yang Z et al (2014) Chronic exposure to tributyltin chloride induces pancreatic islet cell apoptosis and disrupts glucose homeostasis in male mice. Environ Sci Technol 48:5179–5186CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Ya-Wen Chen
    • 1
  • Kuo-Cheng Lan
    • 2
  • Jing-Ren Tsai
    • 3
  • Te-I Weng
    • 4
  • Ching-Yao Yang
    • 5
  • Shing-Hwa Liu
    • 3
    • 6
    • 7
  1. 1.Department of Physiology and Graduate Institute of Basic Medical Science, College of MedicineChina Medical UniversityTaichungTaiwan, Republic of China
  2. 2.Department of Emergency Medicine, Tri-Service General HospitalNational Defense Medical CenterTaipeiTaiwan, Republic of China
  3. 3.Institute of Toxicology, College of MedicineNational Taiwan UniversityTaipeiTaiwan, Republic of China
  4. 4.Department of Forensic Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan, Republic of China
  5. 5.Department of Surgery, College of Medicine and HospitalNational Taiwan UniversityTaipeiTaiwan, Republic of China
  6. 6.Department of Medical Research, China Medical University HospitalChina Medical UniversityTaichungTaiwan, Republic of China
  7. 7.Department of Pediatrics, College of Medicine and HospitalNational Taiwan UniversityTaipeiTaiwan, Republic of China

Personalised recommendations