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Congenital Malformations in a VPA-Induced Rat Model of Autism Spectrum Disorder

Yıl 2019, , 151 - 156, 01.08.2019
https://doi.org/10.32708/uutfd.547540

Öz

Autism is a disorder with a spectrum of behavioral,
developmental and neurological symptoms and has genetic and environmental
etiology. Prenatal exposure to valproic acid (VPA) induces autism like symptoms
in rodents and it is a favored model because of its similar aspects in humans.
8 pregnant Wistar albino rats were used in this study. 5 of them received 400
mg/kg/ml VPA and 3 of them received same volume of vehicle on E12,5. 79
offsprings (nVPA: 48, nctrl: 31) were grossly examined on P22. Among 48 of the
VPA exposed pups, 30 of them showed physical malformations whereas there were
no malformations observed in the control group. Displayed malformations are as
follows; tail bends in 22 out of 48 (45,83%), extra digit-like paw
malformations in 8 out of 48 (16,66%) and position deformity with motor
strength loss in foot in 1 out of 48 (2,08%). Distribution of the malformations
among sexes was insignificant. Bends in tails were characterized by location
and severity. Proximal tail bends were more common than middle and distal
locations. Our results support the teratogenic effects of in utero VPA exposure
which were seen as physical malformations. Further studies are required to
unreveal possible correlations of malformations with behavioral symptoms. Our
findings enhance the facial validity of VPA induced models of autism and
broaden model’s symptomatic spectrum.

Kaynakça

  • Kaynaklar1. American Psychiatry Association (2013) Diagnostic and Statistical Manual of Mental Disorders, DSM-5®, American Psychiatric Publishing, Arlington, VA.
  • 2. Auyeung B, Baron-Cohen S, Ashwin E, Knickmeyer R, Taylor K, & Hackett G. Fetal testosterone and autistic traits. British Journal of Psychology 2009; 100(1), 1-22.
  • 3. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, et al. Prevalence of autism spectrum disorders in a total population sample. American Journal of Psychiatry 2011; 168(9): 904-12.
  • 4. Volkmar FR ve Klin A. Issues in the classification of autism and related conditions. Handbook of Autism and Pervasive Developmental Disorders 2005; Volume 1, Third Edition, 5-41.
  • 5. Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism, Exp. Neurol. 2017; 299:217-27
  • 6. Lancaster K, Dietz DM, Moran TH, Pletnikov MV. Abnormal social behaviors in young and adult rats neonatally infected with borna disease virus. Behav. Brain Res. 2007; 176: 141-8.
  • 7. Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y. et al. Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 2009; 137(7): 1235-46.
  • 8. Schneider T, Ziòlkowska B, Gieryk A, Tyminska A, Przewlocki R. Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology 2007; 193: 547- 55.
  • 9. Wolterink G, Daenen LE, Dubbeldam S, Gerrits MA, van Rijn R, Kruse CG, Van Der Heijden AM, et al. Early amygdala damage in the rat as a model for neurodevelopmental psychopathological disorders. European Neuropsychopharmacology 2001; 11: 51- 9.
  • 10. Favre MR, Barkat TR, Mendola DL, Khazen G, Markram H, Markram K. General developmental health in the VPA-rat model of autism. Frontiers in Behavioral Neuroscience 2013; 7: 1-11.
  • 11. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 2008; 33(4): 901-12.
  • 12. Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005; 30(1): 80-9.
  • 13. Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus?. Reproductive Toxicology 2009; 28(1): 1-10.
  • 14. Dufour-Rainfray D, Vourc’h P, Tourlet S, Guilloteau D, Chalon S, Andres CR. Fetal exposure to teratogens: evidence of genes involved in autism. Neuroscience & Biobehavioral Reviews 2011; 35(5): 1254-65.
  • 15. Kim KC, Choi CS, Kim JW, Han SH, Cheong JH, Ryu JH, Shin CY. MeCP2 modulates sex differences in the postsynaptic development of the valproate animal model of autism. Mol Neurobiol. 2014; 53(1): 40-56.
  • 16. Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci. 2005; 23: 287-97.
  • 17. Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, et al. Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism. PLoS One. 2014; 9:e104927.
  • 18. Schneider T, Turczak J, Przewłocki R. Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology 2006;31:36-46
  • 19. Clayton-Smith J, Donnai D. Fetal valproate syndrome. Journal of Medical Genetics 1995; 32(9): 724-7.
  • 20. Stadelmaier R, Nasri H, Deutsch CK, Bauman M, Hun A, Stodgell CJ, Adams J, Holmes LB. Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism. Birth Defects Research 2017; 109(14): 1134-43.
  • 21. Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental Health Perspectives 2000; 108(suppl 3): 511-33.
  • 22. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. & EURAP Study Group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. The Lancet Neurology 2011; 10(7): 609-17.
  • 23. Weston J, Bromley R, Jackson CF, Adab N, Clayton‐Smith J, Greenhalgh J, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. The Cochrane Library 2016; 1-348.
  • 24. Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 1992; 42(4 Suppl 5):17-24.
  • 25. Ruhela RK, Sarma P, Soni S, Prakash A, Medhi B. Congenital malformation and autism spectrum disorder: Insight from a rat model of autism spectrum disorder. Indian Journal of Pharmacology 2017; 49(3): 243-9.
  • 26. Saft P, Toledo-Cardenas R, Coria-Avila GA, Perez-Pouchoulen M, Brug B, Hernandez ME, Manzo J. Characterization of four types of tail abnormalities in rats treated prenatally with valproic acid. Revista Eneurobiología 2014; 5(9): 070714.
  • 27. Kim KC, Kim P, Go HS, Choi CS, Yang SI, Cheong JH, Shin CH, Ko KH. The critical period of valproate exposure to induce autistic symptoms in Sprague–Dawley rats. Toxicology Letters 2011; 201(2): 137-42.
  • 28. Menegola E, Broccia ML, Nau H, Prati M, Ricolfi R, Giavini E. Teratogenic effects of sodium valproate in mice and rats at midgestation and at term. Teratogenesis, Carcinogenesis, and Mutagenesis 1996; 16(2): 97-108.
  • 29. Paradis FH, Hales BF. Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. Toxicological Sciences 2012; 131(1): 234-41.
  • 30. Scott Jr WJ, Schreiner CM, Nau H, Vorhees CV, Beliles RP, Colvin J, McCandless D. Valproate-induced limb malformations in mice associated with reduction of intracellular pH. Reproductive Toxicology 1997; 11(4): 483-93.
  • 31. Gajovic S, Kostovic-Knezevic L, Svajger A. Origin of the notochord in the rat embryo tail. Anat Embryol (Berl) 1989;179:305-10.
  • 32. Menegola E, Broccia ML, Prati M, Giavini E. Stage-dependent skeletal malformations induced by valproic acid in rat. International Journal of Developmental Biology 2003; 42(1), 99-102.
  • 33. Vorhees CV. Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats. Psychopharmacology (Berl.) 1987; 92, 173-9.

Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar

Yıl 2019, , 151 - 156, 01.08.2019
https://doi.org/10.32708/uutfd.547540

Öz

Otizm genetik ve çevresel bir etiolojiye sahip davranışsal,
gelişimsel ve nörolojik semptomlarla görülen bir spektrum bozukluğudur.
Prenatal dönemde valproik asit (VPA) maruziyeti sıçanlarda otizm benzeri
semptomlara neden olur ve insanlarda da benzer etkiler göstermesi nedeniyle
tercih edilen bir modeldir. Çalışmamızda 8 gebe Wistar albino sıçan
kullanılmıştır. E12,5’de 5 anne sıçan 400 mg/kg/ml VPA’e, 3 anne sıçan ise aynı
volümde serum fizyolojiğe maruz kalmıştır. Doğan 79 yavru (nVPA: 48,
nctrl
: 31) P22’de muayene edilmiştir. VPA’e maruz kalmış 48 yavrudan
30’u malformasyonlara sahipken, kontrol grubu yavrularda herhangi bir
malformasyon görülmemiştir. Görülen malformasyonlar; 48 hayvanın 22’sinde
(%45,83) kuyruk kırılması, 8’inde (%16,66) ekstra parmak benzeri pati
deformasyonu, ve 1’inde (%2,08) ayak duruş deformitesi ve motor kuvvet kaybı
şeklindedir. Cinsiyetler arasında malformasyon dağılımı bakımından bir fark
yoktur. Kuyruk kırılmaları lokasyon ve ciddiyet bakımından karakterize
edilmiştir. Kuyruğun proksimal kısmında orta ve distal kısma göre daha fazla
kırılma görülmüştür. Sonuçlarımız fiziksel malformasyonlar şeklinde karşımıza
çıkan VPA’in teratojenik etkilerini doğrular niteliktedir. Malformasyonlar ve
davranışsal semptomlar arasındaki muhtemel ilişki için ek çalışmalar
gerekmektedir. Bulgularımız VPA maruziyetiyle oluşturulan otizm modelinin
semptomatik geçerliliğini artırmakta ve modelin semptomatik spektrumunu
genişletmektedir. 

Kaynakça

  • Kaynaklar1. American Psychiatry Association (2013) Diagnostic and Statistical Manual of Mental Disorders, DSM-5®, American Psychiatric Publishing, Arlington, VA.
  • 2. Auyeung B, Baron-Cohen S, Ashwin E, Knickmeyer R, Taylor K, & Hackett G. Fetal testosterone and autistic traits. British Journal of Psychology 2009; 100(1), 1-22.
  • 3. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, et al. Prevalence of autism spectrum disorders in a total population sample. American Journal of Psychiatry 2011; 168(9): 904-12.
  • 4. Volkmar FR ve Klin A. Issues in the classification of autism and related conditions. Handbook of Autism and Pervasive Developmental Disorders 2005; Volume 1, Third Edition, 5-41.
  • 5. Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism, Exp. Neurol. 2017; 299:217-27
  • 6. Lancaster K, Dietz DM, Moran TH, Pletnikov MV. Abnormal social behaviors in young and adult rats neonatally infected with borna disease virus. Behav. Brain Res. 2007; 176: 141-8.
  • 7. Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y. et al. Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell 2009; 137(7): 1235-46.
  • 8. Schneider T, Ziòlkowska B, Gieryk A, Tyminska A, Przewlocki R. Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology 2007; 193: 547- 55.
  • 9. Wolterink G, Daenen LE, Dubbeldam S, Gerrits MA, van Rijn R, Kruse CG, Van Der Heijden AM, et al. Early amygdala damage in the rat as a model for neurodevelopmental psychopathological disorders. European Neuropsychopharmacology 2001; 11: 51- 9.
  • 10. Favre MR, Barkat TR, Mendola DL, Khazen G, Markram H, Markram K. General developmental health in the VPA-rat model of autism. Frontiers in Behavioral Neuroscience 2013; 7: 1-11.
  • 11. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 2008; 33(4): 901-12.
  • 12. Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005; 30(1): 80-9.
  • 13. Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus?. Reproductive Toxicology 2009; 28(1): 1-10.
  • 14. Dufour-Rainfray D, Vourc’h P, Tourlet S, Guilloteau D, Chalon S, Andres CR. Fetal exposure to teratogens: evidence of genes involved in autism. Neuroscience & Biobehavioral Reviews 2011; 35(5): 1254-65.
  • 15. Kim KC, Choi CS, Kim JW, Han SH, Cheong JH, Ryu JH, Shin CY. MeCP2 modulates sex differences in the postsynaptic development of the valproate animal model of autism. Mol Neurobiol. 2014; 53(1): 40-56.
  • 16. Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci. 2005; 23: 287-97.
  • 17. Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, et al. Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism. PLoS One. 2014; 9:e104927.
  • 18. Schneider T, Turczak J, Przewłocki R. Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology 2006;31:36-46
  • 19. Clayton-Smith J, Donnai D. Fetal valproate syndrome. Journal of Medical Genetics 1995; 32(9): 724-7.
  • 20. Stadelmaier R, Nasri H, Deutsch CK, Bauman M, Hun A, Stodgell CJ, Adams J, Holmes LB. Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism. Birth Defects Research 2017; 109(14): 1134-43.
  • 21. Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental Health Perspectives 2000; 108(suppl 3): 511-33.
  • 22. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. & EURAP Study Group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. The Lancet Neurology 2011; 10(7): 609-17.
  • 23. Weston J, Bromley R, Jackson CF, Adab N, Clayton‐Smith J, Greenhalgh J, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. The Cochrane Library 2016; 1-348.
  • 24. Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 1992; 42(4 Suppl 5):17-24.
  • 25. Ruhela RK, Sarma P, Soni S, Prakash A, Medhi B. Congenital malformation and autism spectrum disorder: Insight from a rat model of autism spectrum disorder. Indian Journal of Pharmacology 2017; 49(3): 243-9.
  • 26. Saft P, Toledo-Cardenas R, Coria-Avila GA, Perez-Pouchoulen M, Brug B, Hernandez ME, Manzo J. Characterization of four types of tail abnormalities in rats treated prenatally with valproic acid. Revista Eneurobiología 2014; 5(9): 070714.
  • 27. Kim KC, Kim P, Go HS, Choi CS, Yang SI, Cheong JH, Shin CH, Ko KH. The critical period of valproate exposure to induce autistic symptoms in Sprague–Dawley rats. Toxicology Letters 2011; 201(2): 137-42.
  • 28. Menegola E, Broccia ML, Nau H, Prati M, Ricolfi R, Giavini E. Teratogenic effects of sodium valproate in mice and rats at midgestation and at term. Teratogenesis, Carcinogenesis, and Mutagenesis 1996; 16(2): 97-108.
  • 29. Paradis FH, Hales BF. Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. Toxicological Sciences 2012; 131(1): 234-41.
  • 30. Scott Jr WJ, Schreiner CM, Nau H, Vorhees CV, Beliles RP, Colvin J, McCandless D. Valproate-induced limb malformations in mice associated with reduction of intracellular pH. Reproductive Toxicology 1997; 11(4): 483-93.
  • 31. Gajovic S, Kostovic-Knezevic L, Svajger A. Origin of the notochord in the rat embryo tail. Anat Embryol (Berl) 1989;179:305-10.
  • 32. Menegola E, Broccia ML, Prati M, Giavini E. Stage-dependent skeletal malformations induced by valproic acid in rat. International Journal of Developmental Biology 2003; 42(1), 99-102.
  • 33. Vorhees CV. Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats. Psychopharmacology (Berl.) 1987; 92, 173-9.
Toplam 33 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Tıbbi Fizyoloji
Bölüm Özgün Araştırma Makaleleri
Yazarlar

Süeda Tunçak 0000-0002-5723-0769

Bülent Gören Bu kişi benim

Tayfun Uzbay Bu kişi benim

Pınar Öz

Yayımlanma Tarihi 1 Ağustos 2019
Kabul Tarihi 7 Mayıs 2019
Yayımlandığı Sayı Yıl 2019

Kaynak Göster

APA Tunçak, S., Gören, B., Uzbay, T., Öz, P. (2019). Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar. Uludağ Üniversitesi Tıp Fakültesi Dergisi, 45(2), 151-156. https://doi.org/10.32708/uutfd.547540
AMA Tunçak S, Gören B, Uzbay T, Öz P. Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar. Uludağ Tıp Derg. Ağustos 2019;45(2):151-156. doi:10.32708/uutfd.547540
Chicago Tunçak, Süeda, Bülent Gören, Tayfun Uzbay, ve Pınar Öz. “Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar”. Uludağ Üniversitesi Tıp Fakültesi Dergisi 45, sy. 2 (Ağustos 2019): 151-56. https://doi.org/10.32708/uutfd.547540.
EndNote Tunçak S, Gören B, Uzbay T, Öz P (01 Ağustos 2019) Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar. Uludağ Üniversitesi Tıp Fakültesi Dergisi 45 2 151–156.
IEEE S. Tunçak, B. Gören, T. Uzbay, ve P. Öz, “Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar”, Uludağ Tıp Derg, c. 45, sy. 2, ss. 151–156, 2019, doi: 10.32708/uutfd.547540.
ISNAD Tunçak, Süeda vd. “Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar”. Uludağ Üniversitesi Tıp Fakültesi Dergisi 45/2 (Ağustos 2019), 151-156. https://doi.org/10.32708/uutfd.547540.
JAMA Tunçak S, Gören B, Uzbay T, Öz P. Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar. Uludağ Tıp Derg. 2019;45:151–156.
MLA Tunçak, Süeda vd. “Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar”. Uludağ Üniversitesi Tıp Fakültesi Dergisi, c. 45, sy. 2, 2019, ss. 151-6, doi:10.32708/uutfd.547540.
Vancouver Tunçak S, Gören B, Uzbay T, Öz P. Valproik Asitle İndüklenmiş Otizm Spektrum Bozukluğu Sıçan Modelinde Doğumsal Malformasyonlar. Uludağ Tıp Derg. 2019;45(2):151-6.

ISSN: 1300-414X, e-ISSN: 2645-9027

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