Transplacental genotoxicity of antiepileptic drugs: Animal model and pilot study on mother/newborn cohort

Fučić, Aleksandra; Stojković, Ranko; Miškov, Snježana; Želježić, Davor; Marković, Darko; Gjergja, Romana; Katic, Jelena; Jazbec, Ana Marija; Bakulić, Tomislav Ivičević; Demarin, Vida

doi:10.1016/j.reprotox.2010.08.008

Cited by 17 publications

(5 citation statements)

References 87 publications

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“…In order to assess the effect of genetic background on the results of prenatal exposure to valproate in the current study, we compared C57BL/6 and BALB/c strains of mice. Both strains were previously reported to exhibit prenatal-valproate-exposure-related behavioral impairments (Wagner et al, 2006; Fucic et al, 2010; Gandal et al, 2010; Roullet et al, 2010; Moldrich et al, 2013). Moreover, they are known for their diverse, innate tendency to exhibit stereotypic behaviors (Moy et al, 2008), their diverse sociability (Chen et al, 2009) and social motivation (Kennedy et al, 2012).…”

Section: Introductionmentioning

confidence: 92%

A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

Puścian

Łęski

Górkiewicz

et al. 2014

Front. Behav. Neurosci.

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Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repetitive behaviors during reversal learning in mice in the automated IntelliCage system. During the reward-motivated place preference reversal learning, designed to assess cognitive abilities of mice, visits to the previously rewarded places were recorded to measure cognitive flexibility. Thereafter, emotional flexibility was assessed by measuring conditioned fear extinction. Additionally, to look for neuronal correlates of cognitive impairments, we measured CA3-CA1 hippocampal long term potentiation (LTP). To standardize the designed tests we used C57BL/6 and BALB/c mice, representing two genetic backgrounds, for induction of autism by prenatal exposure to the sodium valproate. We found impairments of place learning related to perseveration and no LTP impairments in C57BL/6 valproate-treated mice. In contrast, BALB/c valproate-treated mice displayed severe deficits of place learning not associated with perseverative behaviors and accompanied by hippocampal LTP impairments. Alterations of cognitive flexibility observed in C57BL/6 valproate-treated mice were related to neither restricted exploration pattern nor to emotional flexibility. Altogether, we showed that the designed tests of cognitive performance and perseverative behaviors are efficient and highly replicable. Moreover, the results suggest that genetic background is crucial for the behavioral effects of prenatal valproate treatment.

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Section: Introductionmentioning

confidence: 92%

A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

Puścian

Łęski

Górkiewicz

et al. 2014

Front. Behav. Neurosci.

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“…This hypothesis was based on 3 observations: (1) congenital malformations develop only in a minority of AED‐exposed fetuses 3,4 ; (2) there is considerable phenotypic overlap across congenital malformations associated with different AEDs, suggesting that AED‐associated birth defects possibly arise from dysregulation of a shared mechanism or pathway critical to fetal development; and (3) several teratogens, including drugs, have genotoxic or mutagenic effects . Although there is no conclusive evidence for AEDs being mutagenic, chromosomal/DNA damaging effects in vitro or in vivo have been reported for several AEDs, including VPA, phenytoin, barbiturates, carbamazepine, oxcarbazepine, and possibly lamotrigine . At least for VPA, the suggestion has been made that increased DNA damage may result from chronic inhibition of histone deacetylase .…”

Section: Discussionmentioning

confidence: 99%

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Perucca

Anderson

Jazayeri

et al. 2020

Annals of Neurology

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Objective: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. Methods: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. Results: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed View this article online at wileyonlinelibrary.com.Additional supporting information can be found in the online version of this article.

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“…Genome damage studies in newborns can predict health status in later life. Detected genome damage in newborns does not automatically imply genome damage in their mothers or the presence of higher susceptibility during intrauterine development 30,32,33 . The current increase in childhood cancer incidence, neurodevelopmental disorders (autism and attention deficit, hyperactivity disorder), testicular cancer in young men and breast cancer in younger age groups 34–36 are inferred to have their origin in intrauterine gene–environment interactions of nongenome mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Nuclear abnormalities in umbilical cord blood lymphocytes of newborns from the Ahome and Guasave municipalities in Sinaloa, Mexico

Martínez-Valenzuela

Huichapan

Martínez

et al. 2020

J of Obstet and Gynaecol

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Aim We measured the frequency of nuclear abnormalities of 210 blood samples from the umbilical cord, since human fetuses are exposed to environmental mixtures of pesticides that induce DNA damage. Methods The determinations were made through the micronucleus assay test in lymphocytes from the umbilical cord blood of newborns whose mothers live in Ahome (n = 105) and Guasave (n = 105), Sinaloa, Mexico. Results The average frequency of anomalies in 1000 cells were, respectively: micronucleus 0.4 vs. 2.9, pyknotic cells 18.3 vs. 109.2, chromatin condensation 7.7 vs. 150.1, karyolitic cells 1.8 vs. 24.4, and binucleated cells 4.9 vs. 74.6. The calculated Pearson correlation factors of nuclear abnormality frequencies between both municipalities were low and negative, suggesting that they did not correlate between the Ahome and Guasave newborns and indicating a higher number of mothers exposed in Guasave. Conclusion Our data suggest that monitoring nuclear abnormalities in umbilical cord blood samples could be a useful tool to identify transplacental mutagens perfusion that is being discharged into the local environment.

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Transplacental genotoxicity of antiepileptic drugs: Animal model and pilot study on mother/newborn cohort

Cited by 17 publications

References 87 publications

A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism

Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Nuclear abnormalities in umbilical cord blood lymphocytes of newborns from the Ahome and Guasave municipalities in Sinaloa, Mexico

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