One-time lithium dose in early gestation causes placental and cardiac dysfunction

Serrano, Maria; Linask, Kérsti K.; Acharya, Ganesh; Chen, Jizhen; Han, Mingda; Huhta, James C.

doi:10.1016/j.ajog.2006.10.756

Cited by 4 publications

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“…Maternal drinking of alcohol is a direct cause of FAS. Women drink during pregnancy for many reasons, including having little information about the risks of drinking while pregnant and not knowing that early alcohol ingestion, even a one‐time exposure as early as gastrulation in the second week of pregnancy (Serrano et al, , ), can induce cardiac and neural birth defects. This is much earlier before pregnancy is usually realized at 5 to 6 weeks after conception (Jonsson et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…We chose to use a single, acute exposure to be more precise in regards to the timing of our exposure and its effects. Our acute early alcohol (ethanol, EtOH) exposure resulted in 86% of embryos displaying cardiac abnormalities in the mouse model (Serrano et al, , ).…”

Section: Introductionmentioning

confidence: 99%

“…There are several hypotheses for how alcohol disrupts development, and many mechanisms have been implicated, including effects on lipid metabolism, zinc, lipid rafts, L1 cell adhesion molecule, alcohol dehydrogenase, and catalase (Lindi et al, 2001;Goodlett et al, 2005). We previously provided evidence that lithium (Li 1 ), homocysteine (HCy), and alcohol exposure all induce similar cardiac and placental defects that can be prevented by FA supplementation (Serrano et al, 2007(Serrano et al, , 2010Han et al, 2009), and because we recently demonstrated that Li1 and HCy exposure altered lipid metabolism in abnormally developing hearts and placentas (Han et al, 2016), our present hypothesis is that embryonic alcohol exposure alters lipid metabolism and lipid related gene expression, as well as genes associated with the FA cycle ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…Based on alcohol exposure studies using the pregnant mouse model or chick embryos, the risk would be high for cardiac birth defects being induced by alcohol even with only one exposure occurring early in pregnancy during gastrulation (Serrano et al, , ; Karunamuni et al, ). The published animal results extrapolated to human pregnancy indicate that exposures between 16 to 19 days after conception, that is, during gastrulation, is a sensitive period for the induction of heart defects.…”

Section: Introductionmentioning

confidence: 99%

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Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

Linask

Han

2016

Birth Defects Research

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BackgroundEmbryonic acute exposure to ethanol (EtOH), lithium, and homocysteine (HCy) induces cardiac defects at the time of exposure; folic acid (FA) supplementation protects normal cardiogenesis (Han et al., 2009, 2012; Serrano et al., 2010). Our hypothesis is that EtOH exposure and FA protection relate to lipid and FA metabolism during mouse cardiogenesis and placentation.MethodsOn the morning of conception, pregnant C57BL/6J mice were placed on either of two FA‐containing diets: a 3.3 mg health maintenance diet or a high FA diet of 10.5 mg/kg. Mice were injected a binge level of EtOH, HCy, or saline on embryonic day (E) 6.75, targeting gastrulation. On E15.5, cardiac and umbilical blood flow were examined by ultrasound. Embryonic cardiac tissues were processed for gene expression of lipid and FA metabolism; the placenta and heart tissues for neutral lipid droplets, or for medium chain acyl‐dehydrogenase (MCAD) protein.ResultsEtOH exposure altered lipid‐related gene expression on E7.5 in comparison to control or FA‐supplemented groups and remained altered on E15.5 similarly to changes with HCy, signifying FA deficiency. In comparison to control tissues, the lipid‐related acyl CoA dehydrogenase medium length chain gene and its protein MCAD were altered with EtOH exposure, as were neutral lipid droplet localization in the heart and placenta.ConclusionEtOH altered gene expression associated with lipid and folate metabolism, as well as neutral lipids, in the E15.5 abnormally functioning heart and placenta. In comparison to controls, the high FA diet protected the embryo and placenta from these effects allowing normal development. Birth Defects Research (Part A) 106:749–760, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

Linask

Han

2016

Birth Defects Research

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“…Two important pathways critical to placental development, implantation, and cardiac development during the same period of early development are canonical Wnt/ β -catenin signaling and pathways associated with folate metabolism [17–21]. If these pathways are altered, developmental anomalies ensue.…”

Section: Environmental Influencesmentioning

confidence: 99%

The Heart-Placenta Axis in the First Month of Pregnancy: Induction and Prevention of Cardiovascular Birth Defects

Linask

2013

Journal of Pregnancy

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Extrapolating from animal studies to human pregnancy, our studies showed that folate (FA) deficiency as well as one-time exposure to environmental factors in the first two to three weeks of human gestation can result in severe congenital heart defects (CHDs). Considering that approximately 49% of pregnancies are unplanned, this period of pregnancy can be considered high-risk for cardiac, as well as for neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. Using avian and mouse vertebrate models, we demonstrated that FA supplementation prevents CHD induced by alcohol, lithium, or elevation of the metabolite homocysteine, a marker for FA deficiency. All three factors affected the important Wnt signaling pathway by suppressing Wnt-mediated gene expression in the heart fields, resulting in a delay of cardiomyocyte migration, cardiomyogenesis, and CHD. Optimal protection of cardiogenesis was observed to occur with FA supplementation provided upon morning after conception and at higher doses than the presently available in prenatal vitamin supplementation. Our studies demonstrate pathways and cell processes that are involved with protection of one-carbon metabolism during heart development.

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Environmental origins of congenital heart disease: The heart–placenta connection

Huhta¹,

Linask²

2013

Seminars in Fetal and Neonatal Medicine

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One-time lithium dose in early gestation causes placental and cardiac dysfunction

Cited by 4 publications

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Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention

The Heart-Placenta Axis in the First Month of Pregnancy: Induction and Prevention of Cardiovascular Birth Defects

Environmental origins of congenital heart disease: The heart–placenta connection

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