Behavioral effects of prenatal folate deficiency in mice

Ferguson, Sherry A.; Berry, Kimberly J.; Hansen, Deborah K.; Wall, Kelly S.; White, Gene A.; Antony, Asok

doi:10.1002/bdra.20111

Cited by 53 publications

(38 citation statements)

References 24 publications

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“…Suboptimal folate deficiency in dams during pregnancy can produce behavioral disorders in pups even after their folate status is fully restored. These disorders can manifest in the form of anxiety-related behavior [32].…”

Section: Animal Models Of the Effects Of Folate Deficiency On Developmentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD. Autism spectrum disorder: an emerging disorder with unclear etiology Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children in the USA [1]. Although it is defined through observation of the presence of abnormal behavior and absence of typical developmental milestones, ASD is associated with a wide range of medical abnormalities such as sleep, immune and gastrointestinal disorders and epilepsy. In addition to medical comorbidities, many children with ASD have disruptions in body physiology such as abnormalities in folate, cobalamin, tetrahydrobiopterin (BH 4 ), neurotransmitter, carnitine, redox and mitochondrial metabolism [2]. The connection between underlying physiological abnormalities and behavior is an area of active research. In this review, we will provide evidence that abnormalities of one-carbon folate metabolism are particularly important in ASD.Although the etiology of ASD is not known, genetics has been the focus of ASD research for many decades [3]. A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5]. Studies that have examined the contribution of the environmental and genetic components highlight that ASD arises as a consequence of complicated interactions between genetic predisposition and environmental factors [6,7]. As we will outline in this review, abnormalities in folate metabolism provide an excellent model of how environment factors can interact with genetic predisposition to cause ASD.At this time, the standard of care for ASD treatment is applied behavioral analysis and other equivalent behavioral interventions along with educational, developmental, occupational and speech therapy. Optimal application of behavioral therapy requires full-time one-on-one therapist for many years; however, even when this optimal therapy is applied, suboptimal outcomes are common. In addition, controlled studies examining the efficacy of variou...

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Section: Animal Models Of the Effects Of Folate Deficiency On Developmentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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“…Confirmation of such networks would further open the field for a deeper voyage of discovery that could help to explain the expression of diverse genes in the fetal brain during gestational folate deficiency, especially those genes (such as TH and NF-M) that can be predicted to lead to the imprinting of neural circuits in utero or to induce neurohormonal-neurotransmitter imbalance that predisposes to altered behavior in postnatal life (52,72,73). See supplemental Discussion, "Homocysteinylation of hnRNP-E1/PCBP1 as an alternative determinant in enabling IRES-dependent translation".…”

Section: Evidence Incriminating Hnrnp-e1 As a Bona Fide Sensor Ofmentioning

confidence: 99%

Incrimination of Heterogeneous Nuclear Ribonucleoprotein E1 (hnRNP-E1) as a Candidate Sensor of Physiological Folate Deficiency

Tang

Khan

Zhang

et al. 2011

Journal of Biological Chemistry

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Background: How do cells sense folate deficiency and then somehow restore folate homeostasis? Results: Accumulated intracellular homocysteine covalently binds heterogeneous nuclear ribonucleoprotein-E1 (hnRNP-E1) to open its high affinity mRNA-binding site and accommodate folate receptor (FR) mRNA; this triggers up-regulation of FR. Conclusion: hnRNP-E1 fulfills criteria as a cellular sensor of physiological folate deficiency. Significance: (Homocysteinylated) hnRNP-E1 also orchestrates a nutrition-sensitive posttranscriptional RNA operon during folate deficiency.

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“…Folate supports proper neural tube closure, neurogenesis, cell growth, and myelination of the fetal brain [16,17]. Animal data indicate that deficiency in gestational folate impacts cell mitosis and apoptosis [18] and is associated with anxiety like behavior in the offspring [19]. Some human studies suggest an increased risk for behavioral problems in offspring of folate-deficient women [20,21].…”

Section: Introductionmentioning

confidence: 99%

Deficient maternal zinc intake—but not folate—is associated with lower fetal heart rate variability

Spann

Smerling

Gustafsson

et al. 2015

Early Human Development

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Objective Few studies of maternal prenatal diet and child development examine micronutrient status in relation to fetal assessment. Methods Twenty-four-hour dietary recall of zinc and folate and 20min of fetal heart rate were collected from 3rd trimester pregnant adolescents. Results Deficient zinc was associated with less fetal heart rate variability. Deficient folate had no associations with HRV. Neither deficient zinc nor deficient folate was related to fetal heart rate. Conclusions These findings, from naturalistic observation, are consistent with emerging data on prenatal zinc supplementation using a randomized control design. Practical Implication Taken together, the findings suggest that maternal prenatal zinc intake is an important and novel factor for understanding child ANS development.

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Behavioral effects of prenatal folate deficiency in mice

Abstract: Prenatal folate deficiency that is repleted at birth can manifest later with increased anxiety 9-12 weeks after birth.

Cited by 53 publications

References 24 publications

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Incrimination of Heterogeneous Nuclear Ribonucleoprotein E1 (hnRNP-E1) as a Candidate Sensor of Physiological Folate Deficiency

Deficient maternal zinc intake—but not folate—is associated with lower fetal heart rate variability

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