Fish Physiology and Biochemistry

, Volume 45, Issue 1, pp 33–42 | Cite as

Modulation of brain kisspeptin expression after bisphenol-A exposure in a teleost fish, Catla catla

  • Mehwish FaheemEmail author
  • Nusrat Jahan
  • Saba Khaliq
  • Khalid Parvez Lone


Endocrine-disrupting chemicals (EDCs) affect the neuroendocrine system which in turn influences the reproductive regulation. Neuronal genes disrupted by EDCs are the gonadotropin-releasing hormone (gnrh2), the Kiss/GPR54 system that regulates gonadotropin release and cyp19b gene encoding brain aromatase. In the present study, pubertal Catla catla expected to spawn for first the time in the coming season were exposed to graded concentration of bisphenol-A (10, 100, 1000 μg/l) for 14 days. Messenger RNA (mRNA) levels of neuroendocrine genes, i.e., kisspeptins and their receptors, gonadotropin-releasing hormone type II and brain aromatase were studied after 14 days exposure. Results showed that bisphenol-A (BPA) strongly upregulated expression of kiss1, kiss2, gpr54a, and gnrh2 in fish exposed to 10 μg/l BPA. Fish exposed to 1000 μg/l BPA, expression of kiss1 and gnrh2 were comparable to control while kiss2 mRNA increased compared to controls. Brain aromatase (cyp19b) mRNA expression increased in fish exposed to both 10 and 1000 μg/l BPA. These results indicate that BPA exposure can disrupt organization of the kisspeptin signaling pathways. This neuroendocrine disruption may be the underlying mechanism by which a suite of reproductive abnormalities are induced.


Kisspeptins Gonadotropin releasing hormone Brain aromatase Kisspeptin receptors Bisphenol-A (BPA) Catla catla 


  1. Angle BM, Do RP, Ponzi D, Stahlhut RW, Drury BE, Nagel SC, Welshons WV, Besch-Williford CL, Palanza P, Parmigiani S, vom Saal FS, Taylor JA (2013) Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol a (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reprod Toxicol 42:256–268. CrossRefGoogle Scholar
  2. Adewale HB, Jefferson WN, Newbold RR, Patisaul HB (2009) Neonatal bisphenol-A (2009) exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin releasing hormone neurons. Biol Reprod 81(4):690–699. CrossRefGoogle Scholar
  3. Bai Y, Chang F, Zhou R, Jin PP, Matsumoto H, Sokabe M, Chen L (2011) Increase of anteroventral periventricular kisspeptin neurons and generation of E2-induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol. Endocrinology 152:1562–1571. CrossRefGoogle Scholar
  4. Bergman A, Heindel JJ, Jobling S, Kidd KA, Zoeller RT. (2013) State of the science of endocrine disrupting chemicals 2012: an assessment of the state of the science of endocrine disruptors prepared by a group of experts for the United Nations Environment Programme and World Health Organization. WHO.
  5. Biran J, Ben-Dor S, Levavi-Sivan B (2008) Molecular identification and functional characterization of the kisspeptin/ kisspeptin receptor system in lower vertebrates. Biol Reprod 79:776–786. CrossRefGoogle Scholar
  6. Biran J, Palevitch O, Ben-Dor S, Levavi-Sivan B (2012) Neurokinin Bs and neurokinin B receptors in zebrafish-potential role in controlling fish reproduction. Proc Natl Acad Sci U S A 109:10269–10274CrossRefGoogle Scholar
  7. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622. CrossRefGoogle Scholar
  8. Calafat AM, Ye X, Wong L, Reidy JA, Needham LL (2008) Exposure of the U.S. Population to bisphenol A and 4-tertiary-octylphenol : 2003–2004. Environ Health Perspect 116:39–44. CrossRefGoogle Scholar
  9. Chung E, Genco MC, Megrelis L, Ruderman JV (2011) Effects of bisphenol A and triclocarban on brain-specific expression of aromatase in early zebrafish embryos. Proc Natl Acad Sci U S A 108:17732–17737. CrossRefGoogle Scholar
  10. Colledge WH (2009) Kisspeptins and GnRH neuronal signalling. Trends Endocrinol Metab 20:115–121. CrossRefGoogle Scholar
  11. Corrales J, Kristofco LA, Baylor SW, Yates BS, Breed CS, Spencer WE, Brooks BW (2015) Global assessment of bisphenol A in the environment: review and analysis of its occurrence and bioaccumulation. Dose Response 13(3):1–29. CrossRefGoogle Scholar
  12. de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1- derived peptide receptor GPR54. PNAS 100:10972–10976. CrossRefGoogle Scholar
  13. Diotel N, Le Page Y, Mouriec K, Tong S, Pellegrini E, Vaillant C, Anglade I, Brion F, Pakdel F, Chung B, Kah O (2010) Aromatase in the brain of teleost fish: expression, regulation and putative functions. Front Neuroendocrinol 31:172–192. CrossRefGoogle Scholar
  14. Elizur A (2009) The Kiss1/GPR54 system in fish. Peptides 30:164–170. CrossRefGoogle Scholar
  15. Faheem M, Jahan N, Lone KP (2016) Histopathological effects of bisphenol-A on liver, kidneys and gills of Indian major carp, Catla catla (Hamilton, 1822). J Anim Plant Sci 26(2):514–522Google Scholar
  16. Faheem M, Khaliq S, Lone KP (2017a) Non-monotonic endocrine-disrupting effects of bisphenol-a on vitellogenin expression in juvenile freshwater cyprinid, Catla catla. Pakistan J Zoo 49(4):1531–1534. CrossRefGoogle Scholar
  17. Faheem M, Khaliq S, Lone KP (2017c) Disruption of the reproductive axis in freshwater fish, Catla catla, after bisphenol-A exposure. Zool Sci 34(5):438–444. CrossRefGoogle Scholar
  18. Faheem M, Jahan N, Khaliq S, Lone KP (2018) Validation of reference genes for expression analysis in a teleost fish (Catla catla Hamilton) exposed to an endocrine-disrupting chemical, bisphenol-A. Rendiconti Lincei 29:13–22. CrossRefGoogle Scholar
  19. Felip A, Zanuy S, Pineda R, Pinilla L, Carrillo M, TenaSempere M, Gomez A (2009) Evidence for two distinct KiSS genes in non-placental vertebrates that encode kisspeptins with different gonadotropin-releasing activities in fish and mammals. Mol Cell Endocrinol 312(1–2):61–71. CrossRefGoogle Scholar
  20. Filby AL, van Aerle R, Duitman TCR (2008) The kisspeptin/gonadotropin-releasing hormone pathway and molecular signaling of puberty in fish. Biol Reprod 78:278–289. CrossRefGoogle Scholar
  21. Frye C, Bo E, Calamandrei G, Calzà L, Dessì-Fulgheri F, Fernández M, Fusani L, Kah O, Kajta M, Le Page Y, Patisaul HB, Venerosi A, Wojtowicz AK, Panzica GC (2012) Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behavior and neuroendocrine systems. J Neuroendocrinol 24(1):144–159. CrossRefGoogle Scholar
  22. Hameed S, Jayasena CN, Dhillo WS (2011) Kisspeptin and fertility. J Endocrinol 208:97–105. CrossRefGoogle Scholar
  23. Herbison AE (2009) Rapid actions of oestrogen on gonadotropin-releasing hormone neurons; from fantasy to physiology? J Physiol Lond 587:5025–5030. CrossRefGoogle Scholar
  24. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA (2004) Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinol 80:264–272. CrossRefGoogle Scholar
  25. Jenkins S, Wang J, Eltoum I, Desmond R, Lamartiniere CA (2011) Chronic oral exposure to bisphenol A results in a nonmonotonic dose response in mammary carcinogenesis and metastasis in MMTV-erbB2 mice. Environ Health Perspect 119:1604–1609. CrossRefGoogle Scholar
  26. Kah O, Lethimonier C, Somoza G, Guilgur LG, Vaillant C, Lareyre JJ (2007) GnRH and GnRH receptors in metazoa: a historical, comparative, and evolutionary perspective. Gen Comp Endocrinol 153(1–3):346–364. CrossRefGoogle Scholar
  27. Kaiser UB, Kuohung W (2005) KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty. Endocrine 26:277–284. CrossRefGoogle Scholar
  28. Kanda S, Akazome Y, Matsunaga T, Yamamoto N, Yamada S, Tsukamura H, Maeda K, Oka Y (2008) Identification of KiSS-1 product kisspeptin and steroidsensitive sexually dimorphic kisspeptin neurons in medaka (Oryzias latipes). Endocrinology 149:2467–2476. CrossRefGoogle Scholar
  29. Kanda S, Karigo T, Oka Y (2012) Steroid sensitive kiss2 neurones in the goldfish: evolutionary insights into the duplicate kisspeptin gene-expressing neurones. J Neuroendocrinol 24:897–906. CrossRefGoogle Scholar
  30. Kinch CD, Ibhazehiebo K, Jeong JH, Habibi HR, Kurrasch DM (2015) Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish. Proc Natl Acad Sci U S A 112:1475–1480CrossRefGoogle Scholar
  31. Kitahashi T, Ogawa S, Parhar IS (2009) Cloning and expression of kiss2 in the zebrafish and medaka. Endocrinology 150:821–831. CrossRefGoogle Scholar
  32. Kurian JR, Keen KL, Kenealy BP, Garcia JP, Hedman CJ, Terasawa E (2015) Acute influences of bisphenol A exposure on hypothalamic release of gonadotropin-releasing hormone and kisspeptin in female rhesus monkeys. Endocrinology 156:2563–2570. CrossRefGoogle Scholar
  33. Lee YM, Seo JS, Kim IC, Yoon YD, Lee JS (2006) Endocrine disrupting chemicals (bisphenol A, 4-nonylphenol, 4-tert-octylphenol) modulate expression of two distinct cytochrome P450 aromatase genes differently in gender types of the hermaphroditic fish Rivulus marmoratus. Biochem Biophys Res Commun 345:894–903. CrossRefGoogle Scholar
  34. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2–∆∆Ct method. Methods 25(4):402–408. CrossRefGoogle Scholar
  35. Lone KP, Sahar S, Fatima S (2012) Age-related changes in ovarian gross and histological characteristics during pubertal development in captive Catla catla (Hamilton, 1822) of age 18-29 months. Pakistan J Zool 44(1):159–172Google Scholar
  36. Myers DE, Hutz RJ (2011) Current status of potential bisphenol toxicity in dentistry. Gen Dent 59(4):262–265Google Scholar
  37. Mitani Y, Kanda S, Akazome Y, Zempo B, Oka Y (2010) Hypothalamic Kiss1 but not Kiss2 neurons are involved in estrogen feedback in medaka (Oryzias latipes). Endocrinology 151:1751–1759. CrossRefGoogle Scholar
  38. Mohamed JS, Benninghoff AD, Holt GJ, Khan IA (2007) Developmental expression of the G protein-coupled receptor 54 and three GnRH mRNAs in the teleost fish cobia. J Mol Endocrinol 38:235–244. CrossRefGoogle Scholar
  39. Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla T-SM (2004) Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor. GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145:4565–4574. CrossRefGoogle Scholar
  40. Nocillado JN, Levavi-Sivan B, Carrick F, Elizur A (2007) Temporal expression of G-protein-coupled receptor 54 (GPR54), gonadotropin-releasing hormones (GnRH), and dopamine receptor D2 (drd2) in pubertal female grey mullet, Mugil cephalus. Gen Comp Endocrinol 150:278–287. CrossRefGoogle Scholar
  41. Organization for Economic Cooperation and Development (1992) Fish acute toxicity test. Test guideline 203. OECD guidelines for the testing of chemicals. Paris, FranceGoogle Scholar
  42. Page YL, Vosges M, Servili A, Brion F, Kah O (2011) Neuroendocrine effects of endocrine disruptors in teleost fish. J Toxicol Environ Health 14(5–7):370–386. CrossRefGoogle Scholar
  43. Parhar IS, Ogawa S, Sakuma Y (2004) Laser-captured single digoxigenin-labeled neurons of gonadotropin-releasing hormone types reveal a novel G protein-coupled receptor (Gpr54) during maturation in cichlid fish. Endocrinology 145:3613–3618. CrossRefGoogle Scholar
  44. Patisaul HB (2013) Effects of environmental endocrine disruptors and phytoestrogens on the kisspeptin system. Adv Exp Med Biol 784:455–479. CrossRefGoogle Scholar
  45. Qin F, Wang L, Wang X, Liu S, Xu P, Wang H, Wu T, Zhang Y, Zheng Y, Li M, Zhang X, Yuan C, Hu G, Wang Z (2013) Bisphenol A affects gene expression of gonadotropin-releasing hormones and type I GnRH receptors in brains of adult rare minnow Gobiocypris rarus. Comp Biochem Physiol 157:192–202. Google Scholar
  46. Qiu W, Zhao Y, Yang M, Farajzadeh M, Pan C, Wayne NL (2016) Actions of bisphenol A and bisphenol S on the reproductive neuroendocrine system during early development in zebrafish. Endocrinology 157(2):636–647. CrossRefGoogle Scholar
  47. Rather MA, Bhat IA, Gireesh-babu P, Chaudhari A, Sundaray JK (2016) Molecular characterization of kisspeptin gene and effect of nano–encapsulted kisspeptin-10 on reproductive maturation in Catla catla. Domest Anim Endocrinol 56:36–47. CrossRefGoogle Scholar
  48. Revel FG, Ansel L, Klosen P, Saboureau M, Pevet P, Mikkelsen JD, Simonneaux V (2007) Kisspeptin: a key link to seasonal breeding. Rev Endocr Metab Disord 8:57–65. CrossRefGoogle Scholar
  49. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1162. CrossRefGoogle Scholar
  50. Servili A, Le Page Y, Leprince J, Caraty A, Escobar S, Parha IS, Seong JY, Vaudry H, Kah O (2011) Organization of two independent kisspeptin systems derived from evolutionary-ancient kiss genes in the brain of zebrafish. Endocrinology 152(4):1527–1540. CrossRefGoogle Scholar
  51. Taranger GL, Carrillo M, Schulz RW, Fontaine P, Zanuy S, Felip A, Weltzien F-A, Dufour S, Karlsen O, Norberg B, Andersson E, Hansen T (2010) Control of puberty in farmed fish. Gen Comp Endocrinol 165:483–515. CrossRefGoogle Scholar
  52. Taylor SC, Mrkusich EM (2013) The state of RT-quantitative PCR: first hand observations of implementation of minimum information for the publication of quantitative real-time PCR experiments (MIQE). J Mol Microbiol Biotechnol 24:46–52. CrossRefGoogle Scholar
  53. USEPA (2010) Bisphenol A action plan (CASRN 80–05-7). Released March 29, 2010. action_plan.pdf, 2010
  54. Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM (2009) Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocrinol Rev 30:75–95. CrossRefGoogle Scholar
  55. Vandenberg LN (2014) Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol A as a case study. Dose Response 12:259–227. CrossRefGoogle Scholar
  56. Vandesompele J, Preter DK, Pattyn F, Poppe B, Roy VN, Paepe DA, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:34CrossRefGoogle Scholar
  57. Vetillard A, Bailhache T (2005) Cadmium: an endocrine disrupter that affects gene expression in the liver and brain of juvenile rainbow trout. Biol Reprod 72:119–126. CrossRefGoogle Scholar
  58. Vetillard A, Bailhache T (2006) Effects of 4-n-nonylphenol and tamoxifen on salmon gonadotropin-releasing hormone, estrogen receptor, and vitellogenin gene expression in juvenile rainbow trout. Toxicol Sci 92(2):537–544. CrossRefGoogle Scholar
  59. vom Saal FS, Akingbemi BT, Belcher SM, Birnbaum LS, Crain DA et al (2007) Chapel Hill bisphenol a expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol 24(2):131–138. CrossRefGoogle Scholar
  60. vom Saal FS, Welshons WV (2006) Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A. Environ Res 100:50–76. CrossRefGoogle Scholar
  61. vom Saal FS, Nagel SC, Coe BL, Angle BM, Taylor JA (2012) The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. Mol Cell Endocrinol 354(1–2):74–84. CrossRefGoogle Scholar
  62. Vosges M, Le Page Y, Chung BC, Combarnous Y, Porcher JM, Kah O, Brion F (2010) 17alpha-ethinylestradiol disrupts the ontogeny of the forebrain GnRH system and the expression of brain aromatase during early development of zebrafish. Aquat Toxicol 99:479–491. CrossRefGoogle Scholar
  63. Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM, vom Saal FS (2003) Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environ Health Perspect 111(8):994–1006CrossRefGoogle Scholar
  64. Xi W, Lee CKF, Yeung WSB, Giesy JP, Wong MH, Zhang X, Hecker M, Wong CKC (2011) Effect of perinatal and postnatal bisphenol A exposure to the regulatory circuits at the hypothalamus–pituitary–gonadal axis of CD-1 mice. Reprod Toxiocol 31(4):409–417. CrossRefGoogle Scholar
  65. Yang Y, Gao J, Yuan C, Zhang Y, Guan Y, Wang Z (2016) Molecular identification of kiss/GPR54 and function analysis with mRNA expression profiles exposure to 17a-ethinylestradiol in rare minnow Gobiocypris rarus. Mol Biol Rep 43(7):737–749. CrossRefGoogle Scholar
  66. Xu XH, Zhang J, Wang YM, Ye YP, Luo QQ (2010) Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-D-aspartate receptors of hippocampus in male offspring mice. Horm Behav 58:326–333. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Mehwish Faheem
    • 1
    Email author
  • Nusrat Jahan
    • 1
  • Saba Khaliq
    • 2
  • Khalid Parvez Lone
    • 2
  1. 1.Department of ZoologyGovernment College UniversityLahorePakistan
  2. 2.Department of Physiology and Cell biologyUniversity of Health SciencesLahorePakistan

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