Multiple Congenital Abnormalities Resulting from Transitory Deficiency of Pteroylglutamic Acid during Gestation in the Rat

Mm, Nelson; Hv, Wright; Cw, Asling; Hm, Evans

doi:10.1093/jn/56.3.349

Cited by 124 publications

(23 citation statements)

References 13 publications

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“…Using rodent or avian models, we targeted the embryo during the primitive-streak stage. Previous studies have exposed the embryo to Li or HCy, but only after a tubular cardiac structure was already present at E8.0, or later (Nelson et al, 1955;Rosenquist et al, 1996;Smithberg and Dixit, 1982). This communication compares our HCy exposure studies during gastrulation with the cardiac defects induced by Li and analyzes the common FA rescue of the defects.…”

Section: Discussionmentioning

confidence: 88%

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Han

Serrano

Lastra-Vicente

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARY Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt–β-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt–β-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis.

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Section: Discussionmentioning

confidence: 88%

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Han

Serrano

Lastra-Vicente

et al. 2009

Disease Models &Amp; Mechanisms

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“…This finding is in agreement with the previously mentioned results of the study of Tolarova. 4 In addition, Nelson et al 18 were able to induce CL in Ͼ90% of the rat offspring subjected to a transitory folic acid deficiency attributable to an antimetabolite during the critical period of this congenital abnormality.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent Effect of Folic Acid on the Prevention of Orofacial Clefts

1999

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ABSTRACT. Objective. In 1982, Tolarova 4 found a reduction in the recurrence rate of isolated cleft lip (CL) with or without cleft palate (CP; CL ؎ CP) after periconceptional supplementation with a multivitamin including a very high dose (10 mg) of folic acid. The Hungarian randomized, double-blind, controlled trial of periconceptional supplementation with a multivitamin including a physiologic dose (.8 mg) of folic acid did not show any preventive effect on the first occurrence of isolated CL ؎ CP and CP. However, the general evaluation of congenital abnormalities in the Hungarian Case-Control Surveillance of Congenital Abnormalities indicated, among others, a reduction of isolated CL ؎ CP and CP after the use of high doses of folic acid in the critical period for the development of these congenital abnormalities in the 12-year dataset between 1980 and 1991. We hypothesized that the prevention of orofacial clefts by folic acid has a dose-dependent effect, and this hypothesis was tested in 2 recent Hungarian datasets.Design. In a prospective cohort study, the occurrence of isolated CL ؎ CP and CP was studied in the newborn infants born to mothers with or without periconceptional folic acid-containing (.8 mg) multivitamin supplementation. Supplemented women with confirmed pregnancy were recruited from the participants of the periconceptional service. Unsupplemented women were invited to take part in the study after the first visit between the 8th and 12th week of gestation in the antenatal care. Supplemented and unsupplemented women were matched based on age, socioeconomic status, and residence. In contrast, the occurrence of high-dose (in general daily 6 mg) folic acid supplementation was evaluated in the case-control pairs of CL ؎ CP and CP, particularly during the critical period of these 2 types of orofacial clefts in the 17 years dataset of the Case-Control Surveillance of Congenital Abnormalities, between 1980 and 1996. Cases were selected from the population-based Hungarian Congenital Abnormality Registry, whereas population controls without congenital abnormality were ascertained from the national birth registry. Two population controls were matched to every case according to sex, week of birth, and district of parental residence. The drug uses, including pregnancy supplements as folic acid, were evaluated based on retrospective self-reported maternal questionnaire and prospective medically documented data of antenatal care logbook.Results. In the prospective cohort study, of 3019 informative offspring (termination of pregnancies in the second and third trimesters because of fetal defect, stillborn fetuses, and liveborn infants) in the supplemented group, 3 had CL ؎ CP and 1 was affected with CP, whereas of 3432 informative offspring in the unsupplemented group, 2 had CL ؎ CP and 1 had CP. The lack of preventive effect was in agreement with the result of the previous Hungarian randomized double-blind controlled trial; thus, these 2 datasets were combined. The preventive effect of a folic acid containing m...

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“…Experimental cardiovascular anomalies associated with serious malformations of other organs or systems have been induced in laboratory animals by a variety of teratogenic agents: trypan blue [Fox and Goss, 1958], thalidomide [Vickers, 1968], deficiency in pteroglutamic acid [Nelson et al, 1955] or in vitamin A [Wilson and Warkany, 1949], hypoxic stress [Clemmer and Telford, 1966], In our previous studies, gly cerol formal (GF), a product of glycerin for maldehyde condensation used in phar macological experiments as a drug solvent, when administered to pregnant rats, was found to induce preferentially cardiac and aortic arch malformations in the offspring; some fetuses found dead in utero were affected by widespread edema. Sporadic skeletal anomalies were limited to wavy ribs [Aliverti et al, 1977;Giavini et al, 1977;Giavini and Prati, 1980], The above finding stimulated an investi gation about the pathological evolution of the aortic arch system in rat embryos after maternal treatment with GF in order to obtain some indications as to the mecha nisms involved in the genesis of these mal formations.…”

Section: Introductionmentioning

confidence: 99%

Morphogenesis of Aortic Arch Malformations in Rat Embryos after Maternal Treatment with Glycerol Formal during Pregnancy

Giavini¹,

Vismara²

1981

Cells Tissues Organs

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The morphogenesis of the aortic arch system was studied in rat embryos whose mothers had been treated with glycerol formal (GF) during pregnancy. The fetuses were removed from the uterus on days 13–17 of gestation and India ink was injected into their vascular system while they were still alive. The teratogenic effect of GF manifests itself by developmental retardation of the aortic arch system, vessel dilatation and persistence or anomalous regression of embryonic vessels. These conditions result in several aortic arch malformations: right aortic arch, double aortic arch and persistence of the 3rd aortic arch.

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Multiple Congenital Abnormalities Resulting from Transitory Deficiency of Pteroylglutamic Acid during Gestation in the Rat

Cited by 124 publications

References 13 publications

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Dose-dependent Effect of Folic Acid on the Prevention of Orofacial Clefts

Morphogenesis of Aortic Arch Malformations in Rat Embryos after Maternal Treatment with Glycerol Formal during Pregnancy

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