Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation

Sakai, Kazuya; Hara, Kenshiro; Tanemura, Kentaro

doi:10.1371/journal.pone.0282898

Cited by 5 publications

(3 citation statements)

References 41 publications

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“…In fact, oxcarbazepine improved sperm motility and survival rate [78]. In 26 men taking levetiracetam, total sperm count, percentage of normal morphology and functional sperm count tested after treatment were significantly lower compared with pre-treatment values (p < 0.05), but there were no effects on hormone levels [79]. There is little data on the newest ASMs.…”

Section: Valproate and Male Fertility-spermmentioning

confidence: 97%

“…Epigenetic mechanisms for example via DNA methylation have been postulated as a mechanism for transgenerational passage of autism [79,80]. A rodent study proposed it as a potential mechanism for teratogenic effects of valproate in second and third generation and increased levels of autism [80].…”

Section: Genetic and Transgenic Effectsmentioning

confidence: 99%

“…Another study failed to replicate transgenerational effects in mice [79]. Valproate administration induced histone hyperacetylation in testes, but this effect was transient and did not translate to the next generation.…”

Section: Genetic and Transgenic Effectsmentioning

confidence: 99%

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New valproate regulations, informed choice and seizure risk

Angus-Leppan,

Arkell,

Watkins

et al. 2024

J Neurol

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Valproate is the most effective medication for generalised epilepsies, and several specific epilepsy syndromes. For some people, it will be the only medication to establish seizure remission, and withdrawing it carries risks of seizure recurrence and Sudden Unexpected Death in Epilepsy (SUDEP). It is also of proven efficacy for bipolar disorder and migraine prevention. Guidelines based on observational and epidemiological studies stress that maternal valproate related teratogenicity and neurodevelopmental effects are significantly higher than for other antiseizure medications (ASMs). It should, therefore, only be used if other medications are ineffective and after balancing the teratogenicity risk. Regulatory restrictions have changed prescribing practices and reduced valproate use. The number of other medications that must be trialled in the different conditions for which valproate has effectiveness and the consequences of the lack of efficacy of those drugs leading to significant harm including death remains unexplored. Risk minimisation measures (RMMs) for valproate, chiefly Pregnancy Prevention practices (PPP), consider foetal risk and not risk to people living with epilepsy. In the United Kingdom (UK), limitations relating to valproate use in all people < 55 years commenced in January 2024. While the evidence in child-bearing women is not disputed, the data in males are based on animal models, case reports, and one commissioned, unpublished, non-peer reviewed report unavailable to the UK public, stakeholder charities or professionals. Evidence suggests that 30–40% of people switching from valproate have breakthrough seizures. Thus, an estimated 21,000–28000 people in the UK will imminently be exposed to the potential hazards of breakthrough seizures, including death. There is little government investment in monitoring the effects of these changes to valproate prescribing on patient health and quality of life. This review summarises the history of valproate regulation, evidence underpinning it and argues how the latest regulations in the UK do not align with the country’s medical regulatory bodies ethical principles nor with the Montgomery principles of informed patient choice and autonomy. It dissects how such regulations infringe Common Law principles, nor give due regard for patient outcomes beyond reproduction. The paper looks to provide recommendations to redress these concerns while appreciating the core need for such governance to emerge in the first place.

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Section: Valproate and Male Fertility-spermmentioning

confidence: 97%

Section: Genetic and Transgenic Effectsmentioning

confidence: 99%

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New valproate regulations, informed choice and seizure risk

Angus-Leppan,

Arkell,

Watkins

et al. 2024

J Neurol

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Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated

Garey,

Damkier,

Scialli

et al. 2024

Birth Defects Research

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On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far‐reaching recommendations.

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The prescription of valproate: risk of harm

Rugg-Gunn,

Hunt

2024

The Lancet Neurology

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Testicular histone hyperacetylation in mice by valproic acid administration affects the next generation by changes in sperm DNA methylation

Cited by 5 publications

References 41 publications

New valproate regulations, informed choice and seizure risk

New valproate regulations, informed choice and seizure risk

Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated

The prescription of valproate: risk of harm

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