Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis

Rojas-Mayorquín, Argelia E.; Padilla-Velarde, Edgar; Ortuño-Sahagún, Daniel

doi:10.3389/fnins.2016.00565

Cited by 17 publications

(14 citation statements)

References 132 publications

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“…SLC9A9 functions an ion transport and is a risk gene for ADHD ( de Silva et al, 2003 ). This is consistent with findings, that FAS is accompanied by an increased risk for ADHD ( Burd et al, 2003 ; Rojas-Mayorquin et al, 2016 ). This connection may offer a model how PAE and finally FAS are linked to the increased risk of ADHD.…”

Section: Discussionsupporting

confidence: 93%

“…Increasing evidence suggests that epigenetic mechanisms are potential mediators linking environmental conditions; gene transcription and the phenotypic outcome (see for review, Murgatroyd and Spengler, 2012 ; Murgatroyd et al, 2015 ; Lussier et al, 2017 ). Indeed, numerous lines of evidence now point to epigenetic alterations in the etiology of FAS, including evidence from cell culture, various animal models, as well as a few clinical investigations on FAS ( Rojas-Mayorquin et al, 2016 ; Lussier et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children

Frey

Eichler

Stonawski

et al. 2018

Front. Behav. Neurosci.

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Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children

Frey

Eichler

Stonawski

et al. 2018

Front. Behav. Neurosci.

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“…Maternal exposure to ethanol causes fetal alcohol syndrome (FAS), which is characterized by many neurological disorders, including cognitive and behavioral impairments. Acute administration of ethanol to postnatal pups produces remarkable neurodegenerative effects, and studies have shown that the neurotoxicity that is induced in the developing brain may persist for a long time, even into adulthood [ 1 – 4 ]. Several mechanisms have been investigated and proposed for ethanol-induced neuronal degeneration; the well-documented mechanism is the generation of elevated reactive oxygen species (ROS), which increase oxidative stress and consequently lead to the development of neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Acute dose of melatonin via Nrf2 dependently prevents acute ethanol-induced neurotoxicity in the developing rodent brain

Ali

Rehman

Shah

et al. 2018

J Neuroinflammation

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BackgroundMelatonin is a well-known potent endogenous antioxidant pharmacological agent with significant neuroprotective actions. Here in the current study, we explored the nuclear factor erythroid 2-related factor 2 (Nrf2) gene-dependent antioxidant mechanism underlying the neuroprotective effects of the acute melatonin against acute ethanol-induced elevated reactive oxygen species (ROS)-mediated neuroinflammation and neurodegeneration in the developing rodent brain.MethodsIn vivo rat pups were co-treated with a single dose of acute ethanol (5 g/kg, subcutaneous (S.C.)) and a single dose of acute melatonin (20 mg/kg, intraperitoneal (I.P.)). Four hours after a single S.C. and I.P. injections, all of the rat pups were sacrificed for further biochemical (Western blotting, ROS- assay, LPO-assay, and immunohistochemical) analyses. In order to corroborate the in vivo results, we used the in vitro murine-hippocampal HT22 and microglial BV2 cells, which were subjected to knockdown with small interfering RNA (siRNA) of Nrf2 genes and exposed with melatonin (100 μM) and ethanol (100 mM) and proceed for further biochemical analyses.ResultsOur biochemical, immunohistochemical, and immunofluorescence results demonstrate that acute melatonin significantly upregulated the master endogenous antioxidant Nrf2 and heme oxygenase-1, consequently reversing the acute ethanol-induced elevated ROS and oxidative stress in the developing rodent brain, and in the murine-hippocampal HT22 and microglial BV2 cells. In addition, acute melatonin subsequently reduced the activated MAPK-p-P38-JNK pathways and attenuated neuroinflammation by decreasing the expression of activated gliosis and downregulated the p-NF-K-B/p-IKKβ pathway and decreased the expression levels of other inflammatory markers in the developing rodent brain and BV2 cells. Of note, melatonin acted through the Nrf2-dependent mechanism to attenuate neuronal apoptosis in the postnatal rodent brain and HT22 cells. Immunohistofluorescence results also showed that melatonin prevented ethanol-induced neurodegeneration in the developing rodent brain. The in vitro results indicated that melatonin induced neuroprotection via Nrf2-dependent manner and reduced ethanol-induced neurotoxicity.ConclusionsThe pleiotropic and potent neuroprotective antioxidant characteristics of melatonin, together with our in vivo and in vitro findings, suppose that acute melatonin could be beneficial to prevent and combat the acute ethanol-induced neurotoxic effects, such as elevated ROS, neuroinflammation, and neurodegeneration in the developing rodent brain.

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“…While FASD is the clinical disorder caused by the maternal consumption of alcohol in humans, alcohol exposure or PAE are terms commonly used to describe embryonic development in the presence of alcohol in experimental models; mainly mouse, rat, Xenopus , zebrafish, and chick (Fainsod & Kot‐Leibovich, ; Fernandes, Buckley, & Eberhart, ; Flentke & Smith, ; Gerlai, ; Kiecker, ; Petrelli et al, ; Rojas‐Mayorquín, Padilla‐Velarde, & Ortuño‐Sahagún, ; Shabtai et al, ; Sulik & Johnston, ; Sulik, Johnston, & Webb, ). These animal models have been shown to recapitulate most of the developmental malformations characteristic of individuals with FASD.…”

Section: Experimental Vertebrate Models To Study Fasdmentioning

confidence: 99%

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

Petrelli

Bendelac

Hicks

et al. 2019

Genesis

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Summary Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder, and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge (22q11.2 Deletion Syndrome), CHARGE, Smith‐Magenis, Matthew‐Wood, and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head, and craniofacial development will reveal underlying etiologies of these disorders.

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Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis

Cited by 17 publications

References 132 publications

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children

Acute dose of melatonin via Nrf2 dependently prevents acute ethanol-induced neurotoxicity in the developing rodent brain

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

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