In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven

Harden, Cynthia L.

doi:10.5698/1535-7597-13.6.282

Cited by 9 publications

(10 citation statements)

References 15 publications

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“…Other transcriptome studies from our laboratory in human neuronal cells examined whether valproate at clinical dosage can induce changes in the expression of genes associated with neurological disorders including autism [27]. Valproate, an anticonvulsant with similar properties to carbamazepine [28], has been previously found linked to ASD by inducing autism-like phenotypes in mice [29]. Furthermore, studies in humans have found that in utero exposure to valproate is associated with higher risk of ASD [29].…”

Section: Discussionmentioning

confidence: 99%

“…Valproate, an anticonvulsant with similar properties to carbamazepine [28], has been previously found linked to ASD by inducing autism-like phenotypes in mice [29]. Furthermore, studies in humans have found that in utero exposure to valproate is associated with higher risk of ASD [29]. Taken together, these studies suggest that exposure to carbamazepine during pregnancy, even at very low concentrations, may pose a liability to the embryo/fetus towards the development of ASD.…”

Section: Discussionmentioning

confidence: 99%

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Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers

Kaushik

Huber

Aho

et al. 2016

Biochemical and Biophysical Research Communications

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Psychoactive pharmaceuticals have been found as teratogens at clinical dosage during pregnancy. These pharmaceuticals have also been detected in minute (ppb) concentrations in drinking water in the US, and are environmental contaminants that may be complicit in triggering neurological disorders in genetically susceptible individuals. Previous studies have determined that psychoactive pharmaceuticals (fluoxetine, venlafaxine and carbamazepine) at environmentally relevant concentrations enriched sets of genes regulating development and function of the nervous system in fathead minnows. Altered gene sets were also associated with potential neurological disorders, including autism spectrum disorders (ASD). Subsequent in vitro studies indicated that psychoactive pharmaceuticals altered ASD-associated synaptic protein expression and gene expression in human neuronal cells. However, it is unknown if environmentally relevant concentrations of these pharmaceuticals are able to cross biological barriers from mother to fetus, thus potentially posing risks to nervous system development. The main objective of this study was to test whether psychoactive pharmaceuticals (fluoxetine, venlafaxine, and carbamazepine) administered through the drinking water at environmental concentrations to pregnant mice could reach the brain of the developing embryo by crossing intestinal and placental barriers. We addressed this question by adding 2H-isotope labeled pharmaceuticals to the drinking water of female mice for 20 days (10 pre-and 10 post-conception days), and quantifying 2H-isotope enrichment signals in the dam liver and brain of developing embryos using isotope ratio mass spectrometry. Significant levels of 2H enrichment was detected in the brain of embryos and livers of carbamazepine-treated mice but not in those of control dams, or for fluoxetine or venlafaxine application. These results provide the first evidence that carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo. Our results, combined with previous evidence that carbamazepine may be associated with ASD in infants, warrant the closer examination of psychoactive pharmaceuticals in drinking water and their potential association with neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers

Kaushik

Huber

Aho

et al. 2016

Biochemical and Biophysical Research Communications

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“…When the cohort was restricted to children born to women with epilepsy ( n = 6584), the absolute risk of ASD in the 432 infants exposed to valproate was 4.15% (95%CI, 2.20%–7.81%). In 6125 non‐exposed children, the risk for ASD was 2.44% (95%CI, 1.88%–3.16%) . Thus, there appears to be a definite risk of neurobehavioral issues, including risk of ASD, in those with an in utero exposure to valproate.…”

Section: Prenatal Medication Exposurementioning

confidence: 99%

“…In 6125 non-exposed children, the risk for ASD was 2.44% (95%CI, 1.88%-3.16%). 44 Thus, there appears to be a definite risk of neurobehavioral issues, including risk of ASD, in those with an in utero exposure to valproate.…”

Section: Prenatal Medication Exposurementioning

confidence: 99%

Autism spectrum disorder: Trends in research exploring etiopathogenesis

Gyawali

Patra

2019

Psychiatry Clin Neurosci

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Autism spectrum disorder is a neurodevelopmental condition in which affected individuals have difficulties while interacting and communicating socially, and repetitive behaviors. It has a multifactorial etiology. Various risk factors, including genetic and environmental influences, have been explored while trying to understand its causation. As older evidence was suggestive of a high heritability, a majority of research focused on finding the underlying genetic causes of autism. Due to these efforts, there have been advances in the knowledge of some of the genetic factors associated with autism. But a recent trend also shows an increasing interest in exploration of various potential environmental triggers. These efforts have brought us closer to understanding the elusive disorder more so than ever before. The current review discusses the recent trends in research exploring the etiopathogenesis of autism spectrum disorder.

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“…Also, as studying autism only in humans is a difficult task that implies a lot of ethical issues, lately there were created some rodent model of this disorder, which are replicating most of its autistic pathophysiological features. In this way, one of the classical models of autism in rodents is based on the observation that valproic acid (VPA), an antiepileptic treatment, when applied to pregnant women results in an increased teratogenic risk of autism [10]. Following the same rationale, the Rodier et al [11] research group induced an animal model of autism, based on the perinatal administration of VPA in an increased dosage (usually 500 or 600 mg/kg), in the 12.5 day of gestation, resulting in a complex range of behavioral and anatomical modifications of autistic-like features in the new-born rats (e.g.…”

mentioning

confidence: 99%

The Effect of Exercising on Oxidative Stress Status and Pain in a Valproic-acid Induced Model of Autism Possible relevance of oxytocin

Antioch¹,

Ababei²,

Lefter³

et al. 2017

Rev. Chim.

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In this report we will describe the effect of exercising (6 days, each day 3 separate training phases of 5 minutes each, on an adapted treadmill at 1.0 m/s) on oxidative stress status from the temporal lobe (expressed through 3 main parameters: superoxide dismutase (SOD), glutathione peroxidase (GPX) and malondialdehyde (MDA), as a marker of lipid peroxidation) and pain (as determined through 2 specific behavioural tasks such as hot plate test for the supraspinal acute thermal pain and the intra abdominal Zymosan administration for eliciting a local inflammatory reaction following responses to inflammatory visceral pain) in a rat valproic-acid induced perinatal model of autism, also trying to emphasize a possible implication of oxytocin in this complex pathological picture. We demonstrated here an increased oxidative stress status, as a result of treadmill exercising, in a VPA rat induced model of autism, as demonstrated mainly by a significant decrease in the specific activity of SOD (for the exercised VPA female rats), as well as a significant decrease of GPX specific activity in the male VPA exercised rats, when compared to nonexercised VPA groups, as well as the fact that the aforementioned series of exercises did not resulted in any changes of the pain perception of this rat models of autism, as studied in 2 pain-related behavioural tasks, independent to the gender of the rats with VPA model of autism.

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In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven

Cited by 9 publications

References 15 publications

Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers

Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers

Autism spectrum disorder: Trends in research exploring etiopathogenesis

The Effect of Exercising on Oxidative Stress Status and Pain in a Valproic-acid Induced Model of Autism Possible relevance of oxytocin

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