Spinal nerve defects in mouse embryos prenatally exposed to valproic acid

Abstract

To examine in detail spinal nerve defects induced by prenatal exposure to valproic acid in mice, pregnant ICR mice were subcutaneously injected with a single dose of 400 mg/kg valproic acid on gestational day 6, 7, 8, or 9, and their embryos were observed on gestational day 10. The whole-mount immunostaining using an anti-neurofilament antibody allowed us to identify spinal nerve defects, such as a loss of bundle, anastomosis among bundles arising from adjacent segment, and a disrupted segmental pattern of the dorsal root ganglia, in valproic acid-exposed embryos. The prevalence of spinal nerve defects was the highest in the embryos exposed to valproic acid on gestational day 8 among the experimental groups. Then, effects of the administration dose of valproic acid on the prevalence of spinal nerve defects were examined on gestational day 10 and found to be dose-dependently increased. It was noteworthy that all embryos exposed to 600 mg/kg of valproic acid on gestational day 8 suffered spinal nerve defects. Folic acid (3 mg/kg/day) supplementation during gestational day 6-10 suppressed the prevalence of valproic acid-induced neural tube defects, which are common malformations in offspring prenatally exposed to valproic acid, but not that of spinal nerve defects. Thus, the spinal nerve defects due to prenatal valproic acid exposure might be induced by mechanisms different from those of neural tube defects. Because spinal nerve defects were predicted to be caused by the disrupted segmental arrangement of the somites and/or that of neural crest cells, which was the origin of the dorsal root ganglia and/or abnormal polarity of the somite, this mouse model with spinal nerve defects at high incidence would be useful to examine the effects of valproic acid on the somitogenesis and morphogenesis of somite-associated structures.

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

“…The preventive effect of maternal folic acid supplementation was recapitulated in rodents with regard to neural tube defects. VPA administration in pregnant ICR mice on E8 caused neural tube defects, which were prevented by oral folic acid administration prior to the VPA injection ( 110 ). A recent study investigated the effect of folic acid supplementation on VPA-induced ASD.…”

Peripheral Somatosensory Neuron Dysfunction: Emerging Roles in Autism Spectrum Disorders

“…In vitro application of VPA to DRG neurons inhibited the collapse of sensory neuron growth cones, increased growth cone area and increased total neurite outgrowth (Shaltiel et al, 2007;Williams et al, 2002). Furthermore, embryonic treatment with VPA leads to alterations in DRG neuron anatomy, including abnormal branching patterns in vivo (Bold et al, 2018). While additional experiments are needed to ascertain whether VPA-induced changes in DRG neurons cause somatosensory alterations in mammals, these studies indicate that non-genetic models for ASD also exhibit abnormalities in somatosensory behaviors and alterations in DRG neuron properties.…”

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

“…Since the confirmation of VPA as a potent human teratogen, many studies employing different laboratory animal species (mice, rats, zebra fish, hamsters, drosophila, chicken, calf, rabbits and monkeys) of various strains have made extensive efforts to recapitulate the adverse effects of VPA reported in humans, in order to understand the mechanisms by which this drug mediates teratogenicity [ 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ].…”