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Characterisation of vitamin D-related molecules and calcium-sensing receptor in human Fallopian tube during the menstrual cycle and in ectopic pregnancy

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Abstract

This is a prospective observational study that measures the expression of vitamin D (VD) metabolising and signalling molecules and Ca2+ sensing receptor (CaSR) in human Fallopian tube (FT) during the menstrual cycle and ectopic pregnancy (EP). Fresh FTs were obtained during total abdominal hysterectomy at the follicular (n = 16) and midluteal (n = 16) phases. Specimens from remote and implantation sites as well as trophoblastic tissues were also freshly collected from each FT with EP (n = 10). All women had normal serum VD and ionised Ca2+. The expression of VD synthesising (CYP27B1) and catalysing (CYP24A1) enzymes, binding protein (VDBP), receptor (VDR), retinoid X receptor (RXR) and CaSR was measured by immunohistochemistry and quantitative RT-PCR. All molecules, except VDBP, were significantly increased (P < 0.05) in midluteal compared with follicular samples. Remote EP sites showed significantly (P < 0.05) lower expression of CYP27B1, CYP24A1, VDR and RXR and a higher expression of VDBP and CaSR (P < 0.05) compared with midluteal samples. Significant differences were observed by immunohistochemistry between implantation and remote sites from EP for all molecules, which were also localised in the trophoblastic tissues. In conclusion, VD and calcium are under cycle-dependent regulations within human FT and they appear to play a role in tubal biology through paracrine/autocrine mode of signalling. Furthermore, EP was associated with alterations in the expression of all the studied molecules by the tubal epithelium. Further studies are needed to explore the roles of VD in tubal biology and pathogenesis of EP.

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References

  • Aquila S, Guido C, Middea E, Perrotta I, Bruno R, Pellegrino M, Ando S (2009) Human male gamete endocrinology: 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates different aspects of human sperm biology and metabolism. Reprod Biol Endocrinol 7:140

    Article  PubMed  PubMed Central  Google Scholar 

  • Archibong EI, Sobande AA (2000) Ectopic pregnancy in Abha, Saudi Arabia. A continuing conundrum. Saudi Med J 21:330–334

    CAS  PubMed  Google Scholar 

  • Barrera D, Avila E, Hernandez G, Mendez I, Gonzalez L, Halhali A, Larrea F, Morales A, Diaz L (2008) Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts. Reprod Biol Endocrinol 6:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Becker S, Cordes T, Diesing D, Diedrich K, Friedrich M (2007) Expression of 25 hydroxyvitamin D3-1alpha-hydroxylase in human endometrial tissue. J Steroid Biochem Mol Biol 103:771–775

    Article  CAS  PubMed  Google Scholar 

  • Breitbart H (2002) Intracellular calcium regulation in sperm capacitation and acrosomal reaction. Mol Cell Endocrinol 187:139–144

    Article  CAS  PubMed  Google Scholar 

  • Brennan SC, Wilkinson WJ, Tseng HE, Finney B, Monk B, Dibble H, Quilliam S, Warburton D, Galietta LJ, Kemp PJ, Riccardi D (2016) The extracellular calcium-sensing receptor regulates human fetal lung development via CFTR. Sci Rep 6:21975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown EM, Chattopadhyay N, Vassilev PM, Hebert SC (1998) The calcium-sensing receptor (CaR) permits Ca2+ to function as a versatile extracellular first messenger. Recent Prog Horm Res 53:257–280, discussion 280-251

    CAS  PubMed  Google Scholar 

  • Cagnacci A, Landi S, Volpe A (1999) Rhythmic variation in the rate of ectopic pregnancy throughout the year. Am J Obstet Gynecol 180:1067–1071

    Article  CAS  PubMed  Google Scholar 

  • Capasso G, Geibel PJ, Damiano S, Jaeger P, Richards WG, Geibel JP (2013) The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule. Kidney Int 84:277–284

    Article  CAS  PubMed  Google Scholar 

  • Carlberg C (2014) The physiology of vitamin D-far more than calcium and bone. Front Physiol 5:335

    PubMed  PubMed Central  Google Scholar 

  • Chan SY, Susarla R, Canovas D, Vasilopoulou E, Ohizua O, McCabe CJ, Hewison M, Kilby MD (2015) Vitamin D promotes human extravillous trophoblast invasion in vitro. Placenta 36:403–409

    Article  CAS  PubMed  Google Scholar 

  • Chow EC, Quach HP, Vieth R, Pang KS (2013) Temporal changes in tissue 1alpha,25-dihydroxyvitamin D3, vitamin D receptor target genes, and calcium and PTH levels after 1,25(OH)2D3 treatment in mice. Am J Physiol Endocrinol Metab 304:E977–E989

    Article  CAS  PubMed  Google Scholar 

  • Coste J, Job-Spira N, Aublet-Cuvelier B, Germain E, Glowaczower E, Fernandez H, Pouly JL (1994) Incidence of ectopic pregnancy. First results of a population-based register in France. Hum Reprod 9:742–745

    Article  CAS  PubMed  Google Scholar 

  • Dell’Aquila ME, De Santis T, Cho YS, Reshkin SJ, Caroli AM, Maritato F, Minoia P, Casavola V (2006) Localization and quantitative expression of the calcium-sensing receptor protein in human oocytes. Fertil Steril 85 (Suppl 1):1240–1247

    Google Scholar 

  • Dicken CL, Israel DD, Davis JB, Sun Y, Shu J, Hardin J, Neal-Perry G (2012) Peripubertal vitamin D(3) deficiency delays puberty and disrupts the estrous cycle in adult female mice. Biol Reprod 87:51

    Article  PubMed  PubMed Central  Google Scholar 

  • Dickens CJ, Comer MT, Southgate J, Leese HJ (1996) Human Fallopian tubal epithelial cells in vitro: establishment of polarity and potential role of intracellular calcium and extracellular ATP in fluid secretion. Hum Reprod 11:212–217

    Article  CAS  PubMed  Google Scholar 

  • Dixon RE, Britton FC, Baker SA, Hennig GW, Rollings CM, Sanders KM, Ward SM (2011) Electrical slow waves in the mouse oviduct are dependent on extracellular and intracellular calcium sources. Am J Physiol Cell Physiol 301:C1458–C1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Downing SJ, Maguiness SD, Watson A, Leese HJ (1997) Electrophysiological basis of human fallopian tubal fluid formation. J Reprod Fertil 111:29–34

    Article  CAS  PubMed  Google Scholar 

  • Du H, Daftary GS, Lalwani SI, Taylor HS (2005) Direct regulation of HOXA10 by 1,25-(OH)2D3 in human myelomonocytic cells and human endometrial stromal cells. Mol Endocrinol 19:2222–2233

    Article  CAS  PubMed  Google Scholar 

  • Evans KN, Nguyen L, Chan J, Innes BA, Bulmer JN, Kilby MD, Hewison M (2006) Effects of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on cytokine production by human decidual cells. Biol Reprod 75:816–822

    Article  CAS  PubMed  Google Scholar 

  • Goldenberg M, Bider D, Seidman DS, Lipitz S, Mashiach S, Oelsner G (1993) Seasonal patterns in tubal pregnancy. Gynecol Obstet Invest 35:149–151

    Article  CAS  PubMed  Google Scholar 

  • Grundmann M, von Versen-Hoynck F (2011) Vitamin D - roles in women’s reproductive health? Reprod Biol Endocrinol 9:146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henry HL (2011) Regulation of vitamin D metabolism. Best Pract Res Clin Endocrinol Metab 25:531–541

    Article  CAS  PubMed  Google Scholar 

  • Johnson JA, Grande JP, Roche PC, Kumar R (1996) Immunohistochemical detection and distribution of the 1,25-dihydroxyvitamin D3 receptor in rat reproductive tissues. Histochem Cell Biol 105:7–15

    Article  CAS  PubMed  Google Scholar 

  • Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF (2006) WHO analysis of causes of maternal death: a systematic review. Lancet 367:1066–1074

    Article  PubMed  Google Scholar 

  • Lee LR, Teng PN, Nguyen H, Hood BL, Kavandi L, Wang G, Turbov JM, Thaete LG, Hamilton CA, Maxwell GL, Rodriguez GC, Conrads TP, Syed V (2013) Progesterone enhances calcitriol antitumor activity by upregulating vitamin D receptor expression and promoting apoptosis in endometrial cancer cells. Cancer Prev Res (Phila) 6:731–743

    Article  CAS  Google Scholar 

  • Lindenbaum ES, Peretz BA, Beach D (1983) Menstrual-cycle-dependent and -independent features of the human Fallopian tube fimbrial epithelium: an ultrastructural and cytochemical study. Gynecol Obstet Invest 16:76–85

    Article  CAS  PubMed  Google Scholar 

  • Lippes J, Enders RG, Pragay DA, Bartholomew WR (1972) The collection and analysis of human fallopian tubal fluid. Contraception 5:85–103

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Wu GQ, Fu XW, Mo XH, Zhao LH, Hu HM, Zhu SE, Hou YP (2015) The Extracellular Calcium-Sensing Receptor (CASR) regulates gonadotropins-induced meiotic maturation of porcine oocytes. Biol Reprod 93:131

    PubMed  Google Scholar 

  • Loot AE, Pierson I, Syzonenko T, Elgheznawy A, Randriamboavonjy V, Zivkovic A, Stark H, Fleming I (2013) Ca2+-sensing receptor cleavage by calpain partially accounts for altered vascular reactivity in mice fed a high-fat diet. J Cardiovasc Pharmacol 61:528–535

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Fernandez I, Schepelmann M, Brennan SC, Yarova PL, Riccardi D (2015) The calcium-sensing receptor: one of a kind. Exp Physiol 100:1392–1399

    Article  CAS  PubMed  Google Scholar 

  • Luk J, Torrealday S, Neal Perry G, Pal L (2012) Relevance of vitamin D in reproduction. Hum Reprod 27:3015–3027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyons RA, Djahanbakhch O, Mahmood T, Saridogan E, Sattar S, Sheaff MT, Naftalin AA, Chenoy R (2002) Fallopian tube ciliary beat frequency in relation to the stage of menstrual cycle and anatomical site. Hum Reprod 17:584–588

    Article  CAS  PubMed  Google Scholar 

  • Ma R, Gu Y, Zhao S, Sun J, Groome LJ, Wang Y (2012) Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies. Am J Physiol Endocrinol Metab 303:E928–E935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Macias-Garcia B, Rocha A, Gonzalez-Fernandez L (2016) Extracellular calcium regulates protein tyrosine phosphorylation through calcium-sensing receptor (CaSR) in stallion sperm. Mol Reprod Dev 83:236–245

    Article  CAS  PubMed  Google Scholar 

  • Mendoza FJ, Perez-Marin CC, Garcia-Marin L, Madueno JA, Henley C, Aguilera-Tejero E, Rodriguez M (2012) Localization, distribution, and function of the calcium-sensing receptor in sperm. J Androl 33:96–104

    Article  CAS  PubMed  Google Scholar 

  • Mizwicki MT, Norman AW (2009) The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci Signal 2:re4

    Article  PubMed  Google Scholar 

  • Noyes RW, Hertig AT and Rock J (1950) Dating the endometrial biopsy. Fertil Steril 1:3–25

  • Pojednic RM, Ceglia L, Lichtenstein AH, Dawson-Hughes B, Fielding RA (2015) Vitamin D receptor protein is associated with interleukin-6 in human skeletal muscle. Endocrine 49:512–520

    Article  CAS  PubMed  Google Scholar 

  • Popescu LM, Ciontea SM, Cretoiu D (2007) Interstitial Cajal-like cells in human uterus and fallopian tube. Ann N Y Acad Sci 1101:139–165

    Article  CAS  PubMed  Google Scholar 

  • Rajaei S, Mirahmadian M, Jeddi-Tehrani M, Tavakoli M, Zonoobi M, Dabbagh A, Zarnani AH (2012) Effect of 1,25(OH)2 vitamin D3 on cytokine production by endometrial cells of women with repeated implantation failure. Gynecol Endocrinol 28:906–911

    Article  CAS  PubMed  Google Scholar 

  • Refaat B (2014) Role of activins in embryo implantation and diagnosis of ectopic pregnancy: a review. Reprod Biol Endocrinol 12:116

    Article  PubMed  PubMed Central  Google Scholar 

  • Refaat B, Ledger W (2011) The expression of activins, their type II receptors and follistatin in human Fallopian tube during the menstrual cycle and in pseudo-pregnancy. Hum Reprod 26:3346–3354

    Article  CAS  PubMed  Google Scholar 

  • Refaat B, Simpson H, Britton E, Biswas J, Wells M, Aplin JD, Ledger W (2012) Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation. Fertil Steril 97:1115–1123

    Article  CAS  PubMed  Google Scholar 

  • Refaat B, Dalton E, Ledger WL (2015) Ectopic pregnancy secondary to in vitro fertilisation-embryo transfer: pathogenic mechanisms and management strategies. Reprod Biol Endocrinol 13:30

    Article  PubMed  PubMed Central  Google Scholar 

  • Refaat B, Ashshi AM, Batwa SA, Ahmad J, Idris S, Kutbi SY, Malibary FA, Kamfar FF (2016) The prevalence of Chlamydia trachomatis and Mycoplasma genitalium tubal infections and their effects on the expression of IL-6 and leukaemia inhibitory factor in Fallopian tubes with and without an ectopic pregnancy. Innate Immun. doi:10.1177/1753425916662326

    PubMed  Google Scholar 

  • Rios M, Parada-Bustamante A, Velasquez LA, Croxatto HB, Orihuela PA (2011) Participation of the oviductal s100 calcium binding protein G in the genomic effect of estradiol that accelerates oviductal embryo transport in mated rats. Reprod Biol Endocrinol 9:69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ, Aggarwal A, Graca J, Rietdorf K, Matchkov V, Fenton RA, Chang W, Krssak M, Stewart A, Broadley KJ, Ward DT, Price SA, Edwards DH, Kemp PJ, Riccardi D (2016) The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure. Am J Physiol Cell Physiol 310:C193–C204

    Article  CAS  PubMed  Google Scholar 

  • Schmid A, Salathe M (2011) Ciliary beat co-ordination by calcium. Biol Cell 103:159–169

    Article  CAS  PubMed  Google Scholar 

  • Tang L, Peng M, Liu L, Chang W, Binder HJ, Cheng SX (2015) Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon. Am J Physiol Gastrointest Liver Physiol 308:G874–G883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tavakoli M, Jeddi-Tehrani M, Salek-Moghaddam A, Rajaei S, Mohammadzadeh A, Sheikhhasani S, Kazemi-Sefat GE, Zarnani AH (2011) Effects of 1,25(OH)2 vitamin D3 on cytokine production by endometrial cells of women with recurrent spontaneous abortion. Fertil Steril 96:751–757

    Article  CAS  PubMed  Google Scholar 

  • Tavakoli M, Salek-Moghaddam A, Jeddi-Tehrani M, Talebi S, Kazemi-Sefat GE, Vafaei S, Mohammadzadeh A, Sheikhhassani S, Zarnani AH (2015) Comparable vitamin D3 metabolism in the endometrium of patients with recurrent spontaneous abortion and fertile controls. Mol Reprod Dev 82:356–364

    Article  CAS  PubMed  Google Scholar 

  • Thangamani S, Kim M, Son Y, Huang X, Kim H, Lee JH, Cho J, Ulrich B, Broxmeyer HE, Kim CH (2015) Cutting edge: progesterone directly upregulates vitamin d receptor gene expression for efficient regulation of T cells by calcitriol. J Immunol 194:883–886

    Article  CAS  PubMed  Google Scholar 

  • Thota C, Laknaur A, Farmer T, Ladson G, Al-Hendy A, Ismail N (2014) Vitamin D regulates contractile profile in human uterine myometrial cells via NF-kappaB pathway. Am J Obstet Gynecol 210:347.e1–347.e10

    Article  CAS  Google Scholar 

  • Vigano P, Lattuada D, Mangioni S, Ermellino L, Vignali M, Caporizzo E, Panina-Bordignon P, Besozzi M, Di Blasio AM (2006) Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol 36:415–424

    Article  CAS  PubMed  Google Scholar 

  • Woeckel VJ, van der Eerden BC, Schreuders-Koedam M, Eijken M, Van Leeuwen JP (2013) 1alpha,25-dihydroxyvitamin D3 stimulates activin A production to fine-tune osteoblast-induced mineralization. J Cell Physiol 228:2167–2174

    Article  CAS  PubMed  Google Scholar 

  • Xiao LJ, Yuan JX, Li YC, Wang R, Hu ZY, Liu YX (2005) Extracellular Ca2+-sensing receptor expression and hormonal regulation in rat uterus during the peri-implantation period. Reproduction 129:779–788

    Article  CAS  PubMed  Google Scholar 

  • Yarova PL, Stewart AL, Sathish V, Britt RD Jr, Thompson MA APPL, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ JPTW, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D (2015) Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med 7:284ra260

    Article  Google Scholar 

  • Zarnani AH, Shahbazi M, Salek-Moghaddam A, Zareie M, Tavakoli M, Ghasemi J, Rezania S, Moravej A, Torkabadi E, Rabbani H, Jeddi-Tehrani M (2010) Vitamin D3 receptor is expressed in the endometrium of cycling mice throughout the estrous cycle. Fertil Steril 93:2738–2743

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Bassem Refaat.

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This project was funded by the National Science, Technology and Innovation Plan (MARRIFAH), King Abdul Aziz City for Science and Technology (KACST), the Kingdom of Saudi Arabia, Award Number (11-MED2067-10).

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The authors declare that they have no competing interests.

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Refaat, B., Ahmad, J., Idris, S. et al. Characterisation of vitamin D-related molecules and calcium-sensing receptor in human Fallopian tube during the menstrual cycle and in ectopic pregnancy. Cell Tissue Res 368, 201–213 (2017). https://doi.org/10.1007/s00441-016-2519-2

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