Abstract
Tributyltin (TBT), an antifouling agent found in boat paints, is a common contaminant of marine and freshwater ecosystems. It is rapidly absorbed by organic materials and accumulated in many aquatic animals. Human exposure may depend on ingestion of contaminated food or by indirect exposure from household items containing organotin compounds. TBT is defined as an endocrine disruptor compound (EDC) because it binds to androgen receptors. Moreover, it is also included on the list of metabolic disruptors. The brain is a known target of TBT and this compound interferes with the orexigenic system, inducing a strong decrease in NPY expression in the hypothalamus. In the present experiment, we investigated the effect of a chronic treatment with TBT on the mouse anorexigenic system in both sexes, to look at the pro-opiomelanocortin (POMC) expression in the paraventricular (PVN), dorsomedial (DMN), ventromedial (VMN), and arcuate (ARC) hypothalamic nuclei. The results show a sexually dimorphic effect of TBT on both systems. TBT induced a significant decrease of POMC-positive structures only in female mice in DMN, ARC, and in PVN for both sexes. Apparently, these results show that TBT may interfere with the anorexigenic system in hypothalamic areas involved in the control of food intake, by inhibiting POMC in a sexually dimorphic way. In conclusion, in addition to having a direct effect on fat tissue, the effects of TBT as metabolic disruptor, may be due to gender-specific actions on both orexigenic and anorexigenic hypothalamic systems.
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References
Antizar-Ladislao B (2008) Environmental levels, toxicity and human exposure to tributyltin (TBT)-contaminated marine environment. A review. Environ Int 34:292–308
Bagnol D, Lu XY, Kaelin CB, Day HE, Ollmann M, Gantz I, Akil H, Barsh GS, Watson SJ (1999) Anatomy of an endogenous antagonist: relationship between agouti-related protein and proopiomelanocortin in brain. J Neurosci 19:RC26
Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK, Lowell BB (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42:983–991
Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, Vianna CR, Williams KW, Xu Y, Elmquist JK (2013) Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest 123:5061–5070
Bicknell AB (2008) The tissue-specific processing of pro-opiomelanocortin. J Neuroendocrinol 20:692–699
Bo E, Farinetti A, Marraudino M, Sterchele D, Eva C, Gotti S, Panzica G (2016) Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice. Andrology 4:723–734
Bo E, Viglietti-Panzica C, Panzica GC (2011) Acute exposure to tributyltin induces c-fos activation in the hypothalamic arcuate nucleus of adult male mice. Neurotoxicology 32:277–280
Clegg DJ (2012) Minireview: the year in review of estrogen regulation of metabolism. Mol Endocrinol 26:1957–1960
Cong WN, Golden E, Pantaleo N, White CM, Maudsley S, Martin B (2010) Ghrelin receptor signaling: a promising therapeutic target for metabolic syndrome and cognitive dysfunction. CNS Neurol Disord Drug Targets 9:557–563
Decherf S, Seugnet I, Fini JB, Clerget-Froidevaux MS, Demeneix BA (2010) Disruption of thyroid hormone-dependent hypothalamic set-points by environmental contaminants. Mol Cell Endocrinol 323:172–182
Elmquist JK (2001) Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Int J Obes Relat Metab Disord 25(Suppl 5):S78–S82
Frank A, Brown LM, Clegg DJ (2014) The role of hypothalamic estrogen receptors in metabolic regulation. Front Neuroendocrinol 35:550–557
Gouaze A, Brenachot X, Rigault C, Krezymon A, Rauch C, Nedelec E, Lemoine A, Gascuel J, Bauer S, Penicaud L, Benani A (2013) Cerebral cell renewal in adult mice controls the onset of obesity. PLoS One 8:e72029
Grun F (2014) The obesogen tributyltin. Vitam Horm 94:277–325
Grun F, Blumberg B (2009) Endocrine disrupters as obesogens. Mol Cell Endocrinol 304:19–29
He K, Zhang J, Chen Z (2014) Effect of tributyltin on the food intake and brain neuropeptide expression in rats. Endokrynol Pol 65:485–490
Heindel JJ, Blumberg B, Cave M, Machtinger R, Mantovani A, Mendez MA, Nadal A, Palanza P, Panzica G, Sargis R, Vandenberg LN, Vom Saal F (2017) Metabolism disrupting chemicals and metabolic disorders. Reprod Toxicol 68:3–33
Heindel JJ, Vom Saal FS, Blumberg B, Bovolin P, Calamandrei G, Ceresini G, Cohn BA, Fabbri E, Gioiosa L, Kassotis C, Legler J, La Merrill M, Rizzir L, Machtinger R, Mantovani A, Mendez MA, Montanini L, Molteni L, Nagel SC, Parmigiani S, Panzica G, Paterlini S, Pomatto V, Ruzzin J, Sartor G, Schug TT, Street ME, Suvorov A, Volpi R, Zoeller RT, Palanza P (2015) Parma consensus statement on metabolic disruptors. Environ Health 14:54
Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS (2000) Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A 97:12729–12734
Hill JW (2012) PVN pathways controlling energy homeostasis. Indian J Endocrinol Metab 16:S627–S636
International Program on Chemical Safety (IPCS) (1999) Concise International Chemical Assessment Documents No. 14, Tributyltin oxide. World Organization of Health, Geneva. http://www.who.int/ipcs/publications/cicad/en
Kabra DG, Pfuhlmann K, Garcia-Caceres C, Schriever SC, Casquero Garcia V, Kebede AF, Fuente-Martin E, Trivedi C, Heppner K, Uhlenhaut NH, Legutko B, Kabra UD, Gao Y, Yi CX, Quarta C, Clemmensen C, Finan B, Muller TD, Meyer CW, Paez-Pereda M, Stemmer K, Woods SC, Perez-Tilve D, Schneider R, Olson EN, Tschop MH, Pfluger PT (2016) Hypothalamic leptin action is mediated by histone deacetylase 5. Nat Commun 7:10782
Kim JD, Leyva S, Diano S (2014) Hormonal regulation of the hypothalamic melanocortin system. Front Physiol 5:480
Konner AC, Klockener T, Bruning JC (2009) Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiol Behav 97:632–638
Kuwada M, Kawashima R, Nakamura K, Kojima H, Hasumi H, Maki J (2006) Study of neonatal exposure to androgenic endocrine disruptors, testosterone and dihydrotestosterone by normal-phase HPLC. Biomed Chromatogr 20:1237–1241
Meador JP, Sommers FC, Cooper KA, Yanagida G (2011) Tributyltin and the obesogen metabolic syndrome in a salmonid. Environ Res 111:50–56
Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P (1996) Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 387:113–116
Michel C, Levin BE, Dunn-Meynell AA (2003) Stress facilitates body weight gain in genetically predisposed rats on medium-fat diet. Am J Physiol Regul Integr Comp Physiol 285:R791–R799
Munzberg H, Huo L, Nillni EA, Hollenberg AN, Bjorbaek C (2003) Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144:2121–2131
Myers MG Jr, Munzberg H, Leinninger GM, Leshan RL (2009) The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab 9:117–123
Nohara K, Zhang Y, Waraich RS, Laque A, Tiano JP, Tong J, Munzberg H, Mauvais-Jarvis F (2011) Early-life exposure to testosterone programs the hypothalamic melanocortin system. Endocrinology 152:1661–1669
Olofsson L, Pierce A, Xu A (2009) Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake. Proc Natl Acad Sci U S A 106:15932–15937
Palanza PL, Howdeshell KL, Parmigiani S, vom Saal, FS (2002) Exposure to a low dose of bisphenol a during fetal life or in adulthood alters maternal behavior in mice. Environ Health Perspect 110 Suppl 3:415–422
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic Press, San Diego
Puri P, Rattan A, Bijlani RL, Mahapatra SC, Nath I (1996) Splenic and intestinal lymphocyte proliferation response in mice fed milk or yogurt and challenged with Salmonella typhimurium. Int J Food Sci Nutr 47:391–398
Qiu J, Zhang C, Borgquist A, Nestor CC, Smith AW, Bosch MA, Ku S, Wagner EJ, Ronnekleiv OK, Kelly MJ (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682–693
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671
Shimasaki Y, Kitano T, Oshima Y, Inoue S, Imada N, Honjo T (2003) Tributyltin causes masculinization in fish. Environ Toxicol Chem / SETAC 22:141–144
Si J, Wu X, Wan C, Zeng T, Zhang M, Xie K, Li J (2011) Peripubertal exposure to low doses of tributyltin chloride affects the homeostasis of serum T, E2, LH, and body weight of male mice. Environ Toxicol 26:307–314
Sohn JW (2015) Network of hypothalamic neurons that control appetite. BMB Rep 48:229–233
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 19:4–23
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271
Titley-O’Neal CP, Munkittrick KR, Macdonald BA (2011) The effects of organotin on female gastropods. J Environ Monit 13:2360–2388
Toda C, Santoro A, Kim JD, Diano S (2017) POMC neurons: from birth to death. Annu Rev Physiol 79:209–236
Urban JH, Bauer-Dantoin AC, Levine JE (1993) Neuropeptide Y gene expression in the arcuate nucleus: sexual dimorphism and modulation by testosterone. Endocrinology 132:139–145
Valassi E, Scacchi M, Cavagnini F (2008) Neuroendocrine control of food intake. Nut Metab Cardiovasc Dis 18:158–168
Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, Zhang X, Zou F, Gent LM, Hahner LD, Khan SA, Elias CF, Elmquist JK, Clegg DJ (2011) Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 14:453–465
Yan F, Chen Y, Zuo Z, Chen Y, Yang Z, Wang C (2009) Effects of tributyltin on epididymal function and sperm maturation in mice. Environ Toxicol Pharmacol 28:19–24
Zammaretti F, Panzica G, Eva C (2007) Sex-dependent regulation of hypothalamic neuropeptide Y-Y1 receptor gene expression in moderate/high fat, high-energy diet-fed mice. J Physiol 583:445–454
Zhang J, Zuo Z, Zhu W, Sun P, Wang C (2013) Sex-different effects of tributyltin on brain aromatase, estrogen receptor and retinoid X receptor gene expression in rockfish (Sebastiscus marmoratus). Mar Enviro Res 90:113–118
Zhang X, van den Pol AN (2016) Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat Neurosci 19:1341–1347
Acknowledgements
This study was supported by Ministero dell’Istruzione, dell’Università e della Ricerca–MIUR project “Dipartimenti di Eccellenza 2018–2022” to Dept. of Neuroscience “Rita Levi Montalcini,” University of Torino and Cavalieri-Ottolenghi Foundation, Orbassano, Italy. We are very grateful to Maria Schimenti for her technical help. We would like to thank Alzbeta Talarovicova and Christina Lee, North Carolina State University, Raleigh (NC), USA, for the proofreading of this manuscript.
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Animal care and handling was carried out according to the European Union Council Directive of 22th September 2010 (2010/63/UE); the Italian Ministry of Health and the Ethical Committee of the University of Torino approved all the procedures reported in the present study.
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Farinetti, A., Marraudino, M., Ponti, G. et al. Chronic treatment with tributyltin induces sexually dimorphic alterations in the hypothalamic POMC system of adult mice. Cell Tissue Res 374, 587–594 (2018). https://doi.org/10.1007/s00441-018-2896-9
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DOI: https://doi.org/10.1007/s00441-018-2896-9