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

Choi, Chang Soon; Gonzales, Edson Luck; Kim, Ki Chan; Yang, Sung Min; Mabunga, Darine Froy N.; Cheong, Jae Hoon; Han, Seol‐Heui; Bahn, Geon Ho; Shin, Chan Young

doi:10.1038/srep36250

Cited by 97 publications

(74 citation statements)

References 58 publications

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“…VPA is also used for the treatment of bipolar disorder, anxiety, and migraine (Loscher, 2002). Studies showed that the exposure to VPA during pregnancy induces neurobehavioral abnormalities similar to autism traits in both rodents and humans (Bertelsen et al., 2016; Choi et al., 2016; Mony, Lee, Dreyfus, DiCicco‐Bloom, & Lee, 2016). In fact, VPA treatment of postnatal rats was shown to affect DNA synthesis and astrocyte proliferation and was associated with autistic behavior (Mony et al., 2016).…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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“…VPA, a histone deacetylase (HDAC) inhibiting compound used in the treatment of epilepsy and depression, has been demonstrated to have adverse F2 effects in animal models. Pregnancy VPA induced epigenetic inheritance of an autism‐like neurobehavioral phenotype in both F1 and F2 mice (Choi et al ). Also in mice, F0 VPA resulted in altered transcriptional activity in whole embryos, blood, and brain samples of F2, and higher proinflammatory cytokines, with more marked transcriptional effects in offspring from F1 females (Cipriani et al ).…”

Section: A Growing Body Of Empirical Evidencementioning

confidence: 99%

Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Escher

Robotti²

2019

Environ and Mol Mutagen

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Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long‐term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the “missing heritability” of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445–454, 2019. © 2019 Wiley Periodicals, Inc.

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“…In humans, prenatal exposure to valproic acid (VPA) has been shown to increase the risk of developing ASD (Christensen et al, 2013) and embryonic exposure to it has been widely used to model the ASD syndrome in rodents (Choi et al, 2016;Morris et al, 2010;Nagode et al, 2017;Schneider and Przewłocki, 2005). Embryonic exposure to VPA has been shown to induce impairments in chicks' aggregative behavior (Nishigori et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Embryonic Exposure to Valproic Acid impairs Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

Lorenzi

Pross

Rosa‐Salva

et al. 2018

Preprint

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Predispositions to preferentially orient towards cues associated with social partners, such as face-like stimuli or biological and animate motion, appear to guide social behavior from the onset of life. These predispositions have been documented in several vertebrate species including human neonates, young monkeys and newly-hatched domestic chicks. Human newborns at high familiar risk of Autism Spectrum Disorder (ASD) show a remarkable deficit in their attention toward these predisposed stimuli, either static and dynamic, compared to newborns at low risk. A previous study showed that prenatal exposure to valproic acid (VPA) (that in humans increases the risk of developing ASD) impairs the chicks' predisposition to approach naturalistic social stimuli that convey static configurations of features (a stuffed hen), without impairing general cognitive and learning abilities. Here we investigated the effect of VPA exposure on another class of social predispositions, i.e. the spontaneous preference to approach self-propelled objects, namely objects that display autonomous changes in speed. We observed that the preference for stimuli displaying autonomous changes in speed was impaired in VPA-compared to vehicle-injected chicks. Our results indicate an effect of VPA on the development of predisposed orienting mechanisms towards dynamic stimuli, that could be used to investigate the molecular and neurobiological mechanisms underlying ASD early symptoms.

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

Cited by 97 publications

References 58 publications

Autism throughout genetics: Perusal of the implication of ion channels

Autism throughout genetics: Perusal of the implication of ion channels

Pregnancy drugs, fetal germline epigenome, and risks for next‐generation pathology: A call to action

Embryonic Exposure to Valproic Acid impairs Social Predispositions for Dynamic Cues of Animate Motion in Newly-Hatched Chicks

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