Anti-epileptic drug topiramate upregulates TGFβ1 and SOX9 expression in primary embryonic palatal mesenchyme cells: Implications for teratogenicity

Autor: Nicholas J. Ernst, Everett G. Hall, Jeremy P. Goering, Syed K. Rafi, Lauren A. Hipp, Sumedha Gunewardena, Nathan R. Wilson, Irfan Saadi, Adam J. Olm-Shipman
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cell signaling
Maternal Health
Protein Expression
Cancer Treatment
Cleft Lip and Palate
Signal transduction
Biochemistry
Mice
Medical Conditions
Pregnancy
Medicine and Health Sciences
Morphogenesis
Receptor
Cells
Cultured
Multidisciplinary
Gene Expression Regulation
Developmental
Signaling cascades
Obstetrics and Gynecology
SOX9 Transcription Factor
Neurochemistry
Neurotransmitters
Up-Regulation
Cleft Palate
medicine.anatomical_structure
Teratogens
Oncology
Medicine
Anticonvulsants
Anatomy
medicine.drug
Research Article
Topiramate
medicine.medical_specialty
Cell biology
Mesenchyme
Cleft Lip
Science
Immunology
SOX9
Research and Analysis Methods
gamma-Aminobutyric acid
Cell Line
Transforming Growth Factor beta1
Downregulation and upregulation
Antibody Therapy
Internal medicine
medicine
Gene Expression and Vector Techniques
Congenital Disorders
Animals
Humans
Birth Defects
Molecular Biology Techniques
Molecular Biology
Mouth
Molecular Biology Assays and Analysis Techniques
Biology and life sciences
business.industry
Palate
Gamma-Aminobutyric Acid
medicine.disease
Endocrinology
Migraine
TGF-beta signaling cascade
Otorhinolaryngology
Women's Health
Clinical Immunology
Clinical Medicine
business
Digestive System
Neuroscience
Developmental Biology
Zdroj: PLoS ONE, Vol 16, Iss 2, p e0246989 (2021)
PLoS ONE
ISSN: 1932-6203
Popis: Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFβ1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFβ1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFβ1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFβ1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.
Databáze: OpenAIRE
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