A rat model of valproate teratogenicity from chronic oral treatment during pregnancy
Dana Jazayeri
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
La Trobe Centre for Sport and Exercise Medicine Research, School of Allied Health, Human Services, and Sport, La Trobe University, Bundoora, Victoria, Australia
Search for more papers by this authorEmma Braine
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorStuart McDonald
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Department of Physiology, Anatomy, and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
Search for more papers by this authorSebastian Dworkin
Department of Physiology, Anatomy, and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
Search for more papers by this authorKim L. Powell
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorKaren Griggs
Department of Physiology, Anatomy, and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
Search for more papers by this authorFrank J. E. Vajda
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorTerence J. O’Brien
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorCorresponding Author
Nigel C. Jones
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Correspondence
Nigel C. Jones, Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Vic, 3004, Australia.
Email: [email protected]
Search for more papers by this authorDana Jazayeri
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
La Trobe Centre for Sport and Exercise Medicine Research, School of Allied Health, Human Services, and Sport, La Trobe University, Bundoora, Victoria, Australia
Search for more papers by this authorEmma Braine
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorStuart McDonald
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Department of Physiology, Anatomy, and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
Search for more papers by this authorSebastian Dworkin
Department of Physiology, Anatomy, and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
Search for more papers by this authorKim L. Powell
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorKaren Griggs
Department of Physiology, Anatomy, and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
Search for more papers by this authorFrank J. E. Vajda
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorTerence J. O’Brien
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Search for more papers by this authorCorresponding Author
Nigel C. Jones
Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Neurology, Alfred Hospital, Melbourne, Victoria, Australia
Correspondence
Nigel C. Jones, Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Vic, 3004, Australia.
Email: [email protected]
Search for more papers by this authorAbstract
Objective
Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects.
Methods
We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures; inbred Non-Epileptic Controls (NEC); and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same-strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements.
Results
VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls of all three strains (P < .0001). Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100%; NEC, 95%; Wistar, 80%), more frequently than in controls (9%, 13%, 19%).
Significance
Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug–induced birth defects.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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