Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats

Binkerd, Pamela E.; Rowland, Jon M.; Nau, Heinz; Hendrickx, Andrew G.

doi:10.1016/0272-0590(88)90112-1

Cited by 120 publications

(44 citation statements)

References 29 publications

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“…VPA is a known inducer of NTD and causes crooked tail phenotypes, a mild form of NTD, and autistic-like behavioral abnormalities in mice and rats2425. It was shown that crooked-tail phenotype occurs in the VPA-exposed F1 group26.…”

Section: Resultsmentioning

confidence: 99%

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

Choi

Gonzales

Kim

et al. 2016

Sci Rep

106

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Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.

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Section: Resultsmentioning

confidence: 99%

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

Choi

Gonzales

Kim

et al. 2016

Sci Rep

106

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“…For instance, VPA bioavailability in humans (70–100%) is about twice of that in rodents (34–47%;Loscher, 1999, 2002; Haddad et al, 2009; Roullet et al, 2013). Furthermore, in utero toxicant exposure is also likely to vary across species, but to date, few studies have focused on the issue (Binkerd et al, 1988; Hendrickx et al, 1988). As a consequence, it is difficult today to estimate how the model doses compare to humans.…”

Section: Discussionmentioning

confidence: 99%

General developmental health in the VPA-rat model of autism

Favre¹,

Barkat²,

LaMendola³

et al. 2013

Front. Behav. Neurosci.

106

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Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.

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“…A human population study revealed a significant relationship between the dosage of VPA and human teratogenicity, with higher doses associated with greater risk for birth defects (Vajda et al, 2004). Anatomical defects were also observed in progeny of VPA exposed dams to be dose dependent (Binkerd et al, 1988). Collectively, these results are consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

Banerjee

Sauls

Morales

et al. 2014

Front. Behav. Neurosci.

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Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.

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Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats

Cited by 120 publications

References 29 publications

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy

General developmental health in the VPA-rat model of autism

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

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