Maternal folic acid–deficient diet causes congenital malformations in the mouse eye

Maestro-de-las-Casas, Carmen; Pérez-Miguelsanz, Juliana; López-Gordillo, Yamila; Maldonado, Estela; Partearroyo, Teresa; Varela‐Moreiras, Gregorio; Martı́nez-Álvarez, Concepción

doi:10.1002/bdra.23176

Cited by 20 publications

(18 citation statements)

References 52 publications

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“…Despite such analytic differences, similar results were observed between studies for folate intake. Given that animal studies suggest that folate deficiency is associated with eye malformations, findings from our previous and now current study further support the experimental findings.…”

Section: Commentsupporting

confidence: 86%

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia

Weber

Yang

Carmichael

et al. 2018

Paediatric Perinatal Epid

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Background We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining. Methods Data were from the National Birth Defects Prevention Study, a multicentre, case‐control study from 10 centres in the United States. There were 134 cases of “isolated” and 87 “nonisolated” (with other major birth defects) of anophthalmia/microphthalmia and 11 052 nonmalformed controls with delivery dates October 1997‐December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals. Results Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception. Conclusions Results appear to support previously hypothesised risk factors, socio‐economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre‐pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

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Section: Commentsupporting

confidence: 86%

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia

Weber

Yang

Carmichael

et al. 2018

Paediatric Perinatal Epid

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“…Mice were randomly divided into 2 experimental groups ( n = 65 each) that were fed different types of diets ad libitum for 8 wk. The normal folate (NF) group received a maintenance diet containing standard folate levels (A04/A04C/R04; Scientific Animal Food & Engineering, Panlab, Corneliá de Llobregat, Spain), whereas the folate‐deficient (FD) group received a folate‐depleted diet (folic acid ≤0.1‐0.2 mg/kg) as previously described (26, 27). At least 6 different mouse cohorts including both experimental groups were studied independently.…”

Section: Methodsmentioning

confidence: 99%

“…Altogether, human epidemiology and mouse genetic data reinforce the hypothesis that folic acid deficiency and Hcy metabolism play an important role in hearing disorders, although the mechanisms by which cochlear function is affected remain poorly understood. In this study, we used a rodent model for folic acid deficiency (26, 27) to show that reduced intake of this essential vitamin causes cochlear impairment of Hcy metabolism, oxidative stress, severe cellular damage, and apoptotic cell death, leading to accelerated hearing loss.…”

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confidence: 99%

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

et al. 2014

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Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, α-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress.

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“…More recent studies identified ROS scavenging properties of FA (Ibrahim, Tousson, El-Masry, Arafa, & Akela, 2012; Joshi, Adhikari, Patro, Chattopadhyay, & Mukherjee, 2001). FA deficiency, consequently, produces a wide range of birth defects including severe ocular defects, such as microphthalmia, delayed lamination, and optic cup abnormalities (Maestro-de-las-Casas et al, 2013). Embryonic ethanol exposure affects FA metabolism, including reduced maternal-to-fetal folate transfer and reduced expression of folate metabolizing enzymes (Hutson, Stade, Lehotay, Collier, & Kapur, 2012).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement

Muralidharan

Sarmah

2015

Alcohol

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Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2–24 hours post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16–24 hpf) produced retinal defects like those seen with ethanol exposure between 2–24 hpf. Significantly, during an ethanol-sensitive time window (16–24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects.

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Maternal folic acid–deficient diet causes congenital malformations in the mouse eye

Abstract: This study suggests that an adequate folic acid/folate status plays a key role in the formation of ocular tissues and structures, whereas a vitamin deficiency is negatively associated with a normal eye development even after a short-term exposure.

Cited by 20 publications

References 52 publications

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia

Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement

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