Paternal valproic acid exposure in mice triggers behavioral alterations in offspring

Ibi, Daisuke; Fujiki, Yu; Koide, Nayu; Nakasai, Genki; Takaba, Rika; Hiramatsu, Masayuki

doi:10.1016/j.ntt.2019.106837

Cited by 24 publications

(11 citation statements)

References 57 publications

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“…In recent times, it has been seen that maternal exposure to VPA throughout gestation is capable of increasing the risk of behavioural disorders such as autism spectrum disorder in children, demonstrating similar phenotypes at the molecular, cellular and behavioural in animal models (Nicolini & Fahnestock, 2018; Schiavi et al., 2019). It has also been seen that paternal exposure to VPA can alter the histone acetylation balance in the brain of the offspring, this due to modifications in the germline epigenome, which leads to behavioural alterations in the offspring (Ibi et al., 2019), being projections of research in this type of models, to evaluate the possible applications of VE in this type of epigenetic alterations.…”

Section: Discussionmentioning

confidence: 99%

Protective role of vitamin E in testicular development of mice exposed to valproic acid

et al. 2021

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Valproic acid (VPA) is a teratogenic antiepileptic, causing alterations in oxidative stress in prenatal development, being altered the development of the male reproductive system. The purpose of this study was to determine the protective effect of vitamin E (VE) on the testicular development in embryos, foetuses and pubertal mice exposed to VPA, VPA+VE and only VE. Sixty pregnant adult female mice were used, to which they were administered 600 mg/kg of VPA (VPA groups), 600 mg/kg of VPA and 200 IU of VE (VPA+VE groups), 200 IU VE (VE groups) and 0.3 ml of 0.9% physiological solution (control groups), showing at 12.5 days post‐coital (dpc), 17.5 dpc and 6 weeks postnatal testicular development, and proliferative and apoptotic indices. The groups treated with VPA presented a smaller testicular volume, with greater interstitial space and a delay in the conformation of the testicular cords, shorter lengths and diameters of the germinal epithelium, a smaller number of germline and somatic cells, an increase in cells apoptotic and less proliferation, with significant differences. VE‐treated groups behaved similarly to controls. In conclusion, VE reduces the effects caused by VPA throughout testicular development, from embryonic stages, continuing until pubertal stages.

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Section: Discussionmentioning

confidence: 99%

Protective role of vitamin E in testicular development of mice exposed to valproic acid

et al. 2021

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“…However, sensorimotor gating was only disturbed in female offspring. Brain histone H3 concentration was down-regulated [83].…”

Section: Neurodevelopmental Risksmentioning

confidence: 98%

“…Considering that maternal exposition to VPA may be responsible for neurodevelopmental disorders, an intriguing question arises whether paternal VPA exposure may induce comparable alterations in offspring [83]. Male mice (8 weeks old) were given VPA at daily doses of 30 or 100 mg/kg) for 4 weeks.…”

Section: Neurodevelopmental Risksmentioning

confidence: 99%

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Epilepsy in Pregnancy—Management Principles and Focus on Valproate

Błaszczyk¹,

Miziak

Pluta

et al. 2022

IJMS

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An estimated 60 million people worldwide suffer from epilepsy, half of whom are women. About one-third of women with epilepsy are of childbearing age. The childbirth rate in women with epilepsy is about 20–40% lower compared to that of the general population, which may be partly due to a lower number of these women being in relationships. Lower fertility in women with epilepsy may be linked to the disease itself, but it is mainly a result of the treatment provided. Valproate, as an antiepileptic drug inhibiting histone deacetylases, may affect the expression of genes associated with cell cycle control and cellular differentiation. Evidently, this drug is associated with the risk of malformations although other antiepileptic drugs (AEDs) may also trigger birth defects, however, to a lower degree. Valproate (and to a certain degree other AEDs) may induce autism spectrum disorders and attention deficit hyperactivity disorder. The main mechanism responsible for all negative effects of prenatal exposure to valproate seems inhibition of histone deacetylases. Animal studies show a reduction in the expression of genes involved in social behavior and an increase in hippocampal cytokines. Valproate-induced oxidative stress may also contribute to neural tube defects. Interestingly, paternal exposure to this AED in mice may trigger neurodevelopmental disorders as well although a population-based cohort study does not confirm this effect. To lower the risk of congenital malformations and neurodevelopmental disorders, a single AED at the optimal dose and supplementation with folic acid is recommended. VPA should be avoided in women of childbearing age and especially during pregnancy.

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“…Based on these clinical ndings, rodents exposed in utero to VPA have been used as animal models of autism spectrum disorder (ASD) [11][12][13]. There are few reports on the transgenerational effects of paternal VPA ingestion, although a recent study reported that VPA triggers behavioral alterations in mice [14]. The effects of intrauterine exposure to VPA are thought to be mediated by various pharmacological effects of VPA acting directly on the fetus.…”

Section: Introductionmentioning

confidence: 99%

Testicular Histone Hyperacetylation in Mice by Valproic Acid Administration Affects the Next Generation by Changes in Sperm DNA Methylation

Sakai

Hara

Tanemura

2022

Preprint

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Various reports have described epigenetic transgenerational inheritance through sperm. However, the detailed mechanism remains unclear. In this study, we focused on DNA methylation and analyzed the effects on the next generation of sperm from mice treated with valproic acid (VPA) as an inducer of epigenomic changes. Administration of 200 mg/kg/day VPA to mice for 4 weeks caused transient histone hyperacetylation in the testes and DNA methylation changes in sperm, including promoter CpGs of genes related to brain function. Oocytes fertilized by VPA-treated mouse sperm showed some methylation fluctuations at the morula stage. Pups fathered by these mice also showed behavioral changes in the light/dark transition test after maturation. Brain RNA-seq of these mice showed decreased expression of many genes related to brain and neural function. Comparison of the sperm DNA methylation status of the next generation of mice with that of the parental generation revealed the disappearance of the methylation changes observed in the sperm of the parental generation. These findings suggest that VPA-treated mice may be a useful simple epigenetic transgenerational inheritance model for histone hyperacetylation.

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Paternal valproic acid exposure in mice triggers behavioral alterations in offspring

Cited by 24 publications

References 57 publications

Protective role of vitamin E in testicular development of mice exposed to valproic acid

Protective role of vitamin E in testicular development of mice exposed to valproic acid

Epilepsy in Pregnancy—Management Principles and Focus on Valproate

Testicular Histone Hyperacetylation in Mice by Valproic Acid Administration Affects the Next Generation by Changes in Sperm DNA Methylation

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