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Valproic Acid Exposure of Pregnant Rats During Organogenesis Disturbs Pancreas Development in Insulin Synthesis and Secretion of the Offspring

  • Komariah, Komariah (Department of Histology, Faculty of Dentistry, Trisakti University) ;
  • Manalu, Wasmen (Department of Anatomy, Physiology, and Pharmacology, Faculty of Veterinary Medicine, Bogor Agricultural University) ;
  • Kiranadi, Bambang (Department of Anatomy, Physiology, and Pharmacology, Faculty of Veterinary Medicine, Bogor Agricultural University) ;
  • Winarto, Adi (Department of Anatomy, Physiology, and Pharmacology, Faculty of Veterinary Medicine, Bogor Agricultural University) ;
  • Handharyani, Ekowati (Department of Clinic, Reproduction, and Pathology, Faculty of Veterinary Medicine, Bogor Agricultural University) ;
  • Roeslan, M. Orliando (Department of Biology Oral, Faculty of Dentistry, Trisakti University)
  • Received : 2017.08.17
  • Accepted : 2018.03.09
  • Published : 2018.04.15

Abstract

Valproic acid (VPA) plays a role in histone modifications that eventually inhibit the activity of histone deacetylase (HDAC), and will affect the expressions of genes Pdx1, Nkx6.1, and Ngn3 during pancreatic organogenesis. This experiment was designed to study the effect of VPA exposure in pregnant rats on the activity of HDAC that controls the expression of genes regulating the development of beta cells in the pancreas to synthesize and secrete insulin. This study used 30 pregnant Sprague-Dawley rats, divided into 4 groups, as follows: (1) a control group of pregnant rats without VPA administration, (2) pregnant rats administered with 250 mg VPA on day 10 of pregnancy, (3) pregnant rats administered with 250 mg VPA on day 13 of pregnancy, and (4) pregnant rats administered with 250 mg VPA on day 16 of pregnancy. Eighty-four newborn rats born to control rats and rats administered with VPA on days 10, 13, and 16 of pregnancy were used to measure serum glucose, insulin, DNA, RNA, and ratio of RNA/DNA concentrations in the pancreas and to observe the microscopical condition of the pancreas at the ages of 4 to 32 weeks postpartum with 4-week intervals. The results showed that at the age of 32 weeks, the offspring of pregnant rats administered with 250 mg VPA on days 10, 13, and 16 of pregnancy had higher serum glucose concentrations and lower serum insulin concentrations, followed by decreased concentrations of RNA, and the ratio of RNA/DNA in the pancreas. Microscopical observations showed that the pancreas of the rats born to pregnant rats administered with VPA during pregnancy had low immunoreaction to insulin. The exposure of pregnant rats to VPA during pregnancy disturbs organogenesis of the pancreas of the embryos that eventually disturb the insulin production in the beta cells indicated by the decreased insulin secretion during postnatal life.

Keywords

References

  1. Yong, J., Ansari, P.I. and Kaufman, R.J. (2016) When less is better: ER stress and beta cell proliferation. Dev. Cell, 36, 4-6. https://doi.org/10.1016/j.devcel.2015.12.030
  2. Aguirre, A.M.L., Aguirre, A.A.C., Camberos, E.P., Solis, H.E. and Martinez, N.E.D. (2015) Development of the endocrine pancreas and novel strategies for b-cell mass restoration and diabetes therapy. Braz. J. Med. Biol. Res., 48, 765-776. https://doi.org/10.1590/1414-431X20154363
  3. Gerace, D., Wilks, M.R., O'Brien, B.A. and Simpson, A.M. (2015) The use of ${\beta}$-cell transcription factors in engineering artificial ${\beta}$ cells from non-pancreatic tissue. Gene Ther., 22, 1-8. https://doi.org/10.1038/gt.2014.93
  4. Pagliuca, F.W., Millman, J.R., Gurtler, M., Segel, M., Dervort, A.D., Ryu, J.H., Peterson, Q.P., Greiner, D. and Melton, D.A. (2014) Generation of functional human pancreatic ${\beta}$ cells in vitro. J. Cell, 159, 428-439. https://doi.org/10.1016/j.cell.2014.09.040
  5. Baynest, H.W. (2015) Classification, pathophysiology, diagnosis and management of diabetes mellitus. J. Diabetes Metab., 6, 541.
  6. Henquin, J.C. and Rahier, J. (2011) Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia, 54, 1720-1725. https://doi.org/10.1007/s00125-011-2118-4
  7. Pan, F.C. and Wright, C. (2011) Pancreas organogenesis: from bud to plexus to gland. Dev. Dyn., 240, 530-565. https://doi.org/10.1002/dvdy.22584
  8. Shih, H.P. and Sander, W.M. (2013) Pancreas organogenesis: from lineage determination to morphogenesis. Annu. Rev. Cell Dev. Biol., 29, 81-105. https://doi.org/10.1146/annurev-cellbio-101512-122405
  9. Wang, X., Wei, X., Pang, Q. and Yia, F. (2012) Histone deacetylases and their inhibitors: molecular mechanisms and therapeutic implications indiabetes mellitus. Acta Pharm. Sin., 2, 387-395. https://doi.org/10.1016/j.apsb.2012.06.005
  10. Sostrup, B., Gaarn, L.W., Nalla, A., Billestrup, N. and Nielsen, J.N. (2014) Co-ordinated regulation of neurogenin-3 expression in the maternal and fetal pancreas during pregnancy. Acta Obstet. Gynecol. Scand., 93, 1190-1197. https://doi.org/10.1111/aogs.12495
  11. Ornoy, A. and Ergaz, Z. (2010) Alcohol abuse in pregnant women: Effects on the fetus and newborn, mode of action and maternal treatment. Int. J. Environ. Res. Public Health, 7, 364-379. https://doi.org/10.3390/ijerph7020364
  12. da Costa, R.F.M., Kormann, M.L., Galina, A. and Rehen, S.K. (2015) Valproate disturbs morphology and mitochondrial membrane potential in human neural cells. Appl. In Vitro Toxicol., 1, 254-261. https://doi.org/10.1089/aivt.2015.0016
  13. Ximenes, J.C.M., Verde, E.C.L., Mazzacoratti, M.G.N. and Viana, G.S.B. (2012) Valproic acid, a drug with multiple molecular targets related to its potential neuroprotective action. Neurosci. Med., 3, 107-123. https://doi.org/10.4236/nm.2012.31016
  14. Ververis, K., Alison, H., Karagiannis, T.C. and Licciardi, P.V. (2013) Histone deacetylase inhibitors (HDACIS): multitargeted anticancer agents. Biologics, 7, 47-60.
  15. Halsall, J.A. and Turner, B.M. (2016) Histone deacetylase inhibitors for cancer therapy: an evolutionarily ancient resistance response may explain their limited success. Bioessays, 38, 1102-1110. https://doi.org/10.1002/bies.201600070
  16. Dahlan, M.S. (2014) Statistics for medicine and health; descriptive, bivariate, and multivariate. Epidemiology Indonesia, Jakarta, Indonesia, pp. 110-117.
  17. Maksoud, H.M.A., El-Shazly, S.M. and El Saied, M.H. (2016) Effect of antiepileptic drug (valproic acid) on children growth. Gaz. Egypt Paediatr. Assoc., 64, 69-73. https://doi.org/10.1016/j.epag.2016.04.001
  18. Vajda, F. and O'Brien, T. (2010) Valproic acid use in pregnancy and congenital malformations. N. Engl. J. Med., 363, 1771-1772. https://doi.org/10.1056/NEJMc1008255
  19. Guerrini, R. (2006) Valproate as a mainstay of therapy for pediatric epilepsy. Paediatr. Drugs, 2, 113-29.
  20. De Felice, A., Ricceri, L., Venerosi, A., Chiarotti, F. and Calamandrei, G. (2015) Multifactorial origin of neurodevelopmental disorders: approaches to understanding complex etiologies. Toxics, 3, 89-129. https://doi.org/10.3390/toxics3010089
  21. Kokate, P. and Bang, R. (2017) Study of congenital malformation in tertiary care centre, Mumbai, Maharashtra, India. Int. J. Reprod. Contracept. Obstet. Gynecol., 6, 89-93.
  22. Tang, O.S., Danielsson, K.G. and Ho, P.C. (2007) Misoprostol: pharmacokinetic profiles, effects on the uterus and sideeffects. Int. J. Gynaecol. Obstet., 99, 160-167. https://doi.org/10.1016/j.ijgo.2007.09.004
  23. Wlodarczyk, B.J., Palacios, A.M., Chapa, C.J., Zhu, H., George, T.M. and Finnell, R.H. (2011) Genetic basis of susceptibility to teratogen induced birth defects. Am. J. Med. Genet., 157, 215-226. https://doi.org/10.1002/ajmg.c.30314
  24. Berridge, M.J. (2014) Cell cycle and proliferation. Cell Signalling Biology, 901-943.
  25. Bertoli, C., Skotheim, J.M. and De Bruin, R.A.M. (2013) Control of cell cycle transcription during G1 and S phases. Nat. Rev. Mol. Cell Biol., 14, 518-528. https://doi.org/10.1038/nrm3629
  26. Li, Q., Foote, M. and Chen, J. (2014) Effects of histone deacetylase inhibitor valproic acid on skeletal myocyte development. Sci. Rep., 4, 1-4.
  27. Gallagher, S.J., Tiffen, J.C. and Hersey, P. (2015) Histone modifications, modifiers and readers in melanoma resistance to targeted and immune therapy. Cancers, 7, 1959-1982. https://doi.org/10.3390/cancers7040870
  28. Kurihara, Y., Suzuki, T., Sakaue, M., Murayama, O., Miyazaki, Y. and Onuki, A. (2014) Valproic acid, a histone deacetylase inhibitor, decreases proliferation of and induces pecific neurogenic differentiation of canine adipose tissuederived stem cells. J. Vet. Med. Sci., 76, 15-23. https://doi.org/10.1292/jvms.13-0219
  29. Schulpen, S.H.W., Pennings, J.L.A. and Piersma, A.H. (2015) Gene expression regulation and pathway analysis after valproic acid and carbamazepine exposure in a human embryonic stem cell-based neurodevelopmental toxicity assay. Toxicol. Sci., 146, 311-320. https://doi.org/10.1093/toxsci/kfv094
  30. Giavini, E. and Menegola, E. (2014) Teratogenic activity of HDAC inhibitors. Curr. Pharm. Des., 20, 1-6.
  31. Xu, W., Wang, Y., Li, Y., Wang, L., Xiong, X., Su, J. and Zhang, Y. (2012) Valproic acid improves the in vitro development competence of bovine somatic cell nuclear transfer embryos. Cell. Reprogram., 14, 138-145. https://doi.org/10.1089/cell.2011.0084
  32. Rajendran, P., Kidane, A.I., Yu, T.W., Dashwood, W.M., Bisson, W.H., Lohr, C.V., Ho, E., Williams, D.E. and Dashwood, R.H. (2013) HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics, 8, 612-623. https://doi.org/10.4161/epi.24710
  33. Shi, D. and Gu, W. (2012) Dual roles of MDM2 in the regulation of p53: ubiquitination dependent and ubiquitination independent mechanisms of MDM2 repression of p53 activity. Genes Cancer, 3, 240-248. https://doi.org/10.1177/1947601912455199
  34. Garner, E. and Raj, K. (2008) Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle, 7, 1-6.
  35. Shkreta, L. and Chabot, B. (2015) The RNA splicing response to DNA damage. Biomolecules, 5, 2935-2977. https://doi.org/10.3390/biom5042935
  36. Foleya, C.J., Bradleyc, D.L. and Hook, T.O. (2016) A review and assessment of the potential use of RNA:DNA ratios to assess the condition of entrained fish larvae. Ecol. Indic., 60, 346-357. https://doi.org/10.1016/j.ecolind.2015.07.005
  37. Reef, R., Ball, M.C., Feller, I.C. and Lovelock, C.E. (2010) Relationships among RNA : DNA ratio, growth and elemental stoichiometry in mangrove trees. Funct. Ecol., 24, 1064-1072. https://doi.org/10.1111/j.1365-2435.2010.01722.x
  38. Chicharo, M.A. and Chicharo, L. (2008) RNA:DNA ratio and other nucleic acid derived indices in marine ecology. Int. J. Mol. Sci., 9, 1453-1471. https://doi.org/10.3390/ijms9081453
  39. Olivar, M.P., Diaz, M.V. and Chicharo, M.A. (2009) Tissue effect on RNA:DNA ratios of marine fish larvae. Sci. Mar., 171-182.
  40. Pscherer, S., Larbig, M., Stritsky, B., Pfutzner, A. and Forst, T. (2012) In type 2 diabetes patients insulin glargine is associated with lower postprandial release of intact proinsulin compared with sulfonylurea treatment. J. Diabetes Sci. Technol., 6, 634-640. https://doi.org/10.1177/193229681200600318
  41. FizeIova, M., Cederberg, H., Stancakova, A., Jauhiainen, R., Vangipurapu, J., Kuusisto, J. and Laakso, M. (2014) Markers of tissue-specific insulin resistance predict the worsening of hyperglycemia, incident type 2 diabetes and cardiovascular disease. PLoS ONE, 10, e109772.
  42. Ali, S.F. and Padhi, R. (2009) Optimal blood glucose regulation of diabetic patients using single network adaptive critics. Optimal Control Applications & Methods, 32, 196-214.
  43. Cerf, M.E. (2013) Beta cell dysfunction and insulin resistance. Front. Endocrinol., 37, 1-12.
  44. Arystarkhova, E., Liu, Y.B., Salazar, C., Stanojevic, V., Clifford, R.J., Kaplan, J.H., Kidder, G.M. and Weadner, K.J. (2013) Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase. J. Biol. Chem., 288, 7077-7085. https://doi.org/10.1074/jbc.M112.401190
  45. Yoon, K.H., Ko, S.H., Cho, J.H., Lee, J.M., Ahn, Y.B., Song, K.H., Yoo, S.J., Kang, M.L., Cha, B.Y. and Lee, K.W. (2003) Selective ${\beta}$-cell loss and ${\alpha}$-cell expansion in patients with type 2 diabetes mellitus in Korea. J. Clin. Endocrinol. Metab., 88, 2300-2308. https://doi.org/10.1210/jc.2002-020735
  46. Deng, S., Vatamaniuk, M., Huang, X., Doliba, N., Lian, M., Frank, A., Velidedeoglu, E., Desai, N.M., Koeberlein, B., Wolf, B., Clyde, F.B., Ali, N., Franz, M.M. and James, F.M. (2004) Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes, 53, 624-632. https://doi.org/10.2337/diabetes.53.3.624
  47. Otsuka, T., Tsukahara, T. and Takeda, H. (2015) Development of the pancreas in medaka, Oryzias latipes, from embryo to adult. Dev. Growth Differ., 57, 557-569. https://doi.org/10.1111/dgd.12237
  48. Schwartz, M.W., Guyenet, S.J. and Cirulli, V. (2010) The hypothalamus and beta-cell connection in the gene-targeting era. Diabetes, 59, 2991-2993. https://doi.org/10.2337/db10-1149
  49. Gomez, D.L., O'Driscoll, M., Sheets, T.P., Hruban, R.H., Oberholzer, J., McGarrigle, J.J. and Shamblott, M.J. (2015) Neurogenin 3 expressing cells in the human exocrine pancreas have the capacity for endocrine cell fate. PLoS ONE, 10, e0133862. https://doi.org/10.1371/journal.pone.0133862
  50. Sanchez, A.M., Rutter, G.A. and Latreille, M. (2017) MiRNAs in ${\beta}$-cell development, identity, and disease. Front. Genet., 7, 226.