Maternal Folic Acid Deficiency Is Associated to Developing Nasal and Palate Malformations in Mice
<p>Head and nasopalatine region measurements. (<b>a</b>) Lateral view of a control head E17-fetus. The yellow rectangle crossing the eye indicates the block of sections selected for measurements. (<b>b</b>) Coronal section showing the landmarks for measurements: The nasal meatus (arrows), the eyes (E) and the developing molars (arrows heads) (En: encephalon; P: palate; T: tongue; asterisk: nasal septum; double asterisk: nasopharynx). (<b>c</b>) Description of head measurements on the same black and white image: width (red line), height from palate to top of the head (yellow line) and area of the half head (discontinuous black line). (<b>d</b>) Magnification of the nasopalatine region (T: tongue; P: palate; M: developing molar; double asterisk: nasopharynx; asterisk: nasal septum; En: encephalon). (<b>e</b>) Description of nasopalatine region measurements on the same black and white image: thick of the palate (red line); area of the half of the palate (green line); area of the bone tissue inside the palate area (orange line), area of the nasopharynx (pink line), area (yellow line) and height (blue line) of the nasal septum. (<b>f</b>) Magnification of the right half palate: bone tissue (arrowhead) and the osteogenic condensation (asterisk). (<b>g</b>) Magnification of the rectangle marked in (<b>f</b>): bone tissue (arrowhead) and the osteogenic condensation (asterisk). Scale bars: (<b>a</b>–<b>c</b>) 1 mm; (<b>d</b>–<b>e</b>) 500 µm; (<b>f</b>) 100 µm; (<b>g</b>) 50 µm.</p> "> Figure 2
<p>Mean number of fetuses per litter according to weeks on maternal folic acid deficient (FAD) diet. ** <span class="html-italic">p</span> ≤ 0.01 (Spearman’s rho test).</p> "> Figure 3
<p>Head and palatine malformations. Control fetus head: lateral view (<b>a</b>), frontal view (<b>b</b>) and coronal section (<b>c</b>). Arrowhead: ear. Arrow: eye. Asterisk: mandible. Severely malformed fetus: lateral view (<b>d</b>), frontal view (<b>e</b>,<b>f</b>) coronal section. The eye, ear and mandible were not developed, the palate is not recognized. Malformed fetus head: lateral view (<b>g</b>), frontal view (<b>h</b>) and coronal section (<b>i</b>). This case showed asymmetrical head and high arched palate (HAP), lack of mandible and tongue. Arrowhead: ear. Arrow: eye. Magnification of nasopalatine region of control fetus (<b>j</b>): the palate (P) showed a form of truncated pyramid, the nasopharynx was like lips and they were two nasal meatus on each side of the nasal septum. Arrow: nasopharynx. Arrowheads: nasal meatus. Asterisk: nasal septum. Magnification of a malformed fetus (<b>k</b>) with HAP palate, aglossia and head asymmetry because the meatus dysmorphology. M: developing molar. T: tongue; Scale bar: (<b>a</b>–<b>i</b>) 1 mm; (<b>j</b>–<b>k</b>) 500 µm.</p> "> Figure 4
<p>Nasopalatin region. (<b>a</b>) Coronal section of a control fetus: the nasopharyngeal duct (N) was placed between palate (P).and the nasal septum (NS), which was below the encephalon (En). Arrowhead marked the area of interest. (<b>b</b>) Magnification the control respiratory epithelium with the columnar and ciliated cells. (<b>c</b>) Malformed fetus with the tongue (T) placed between palatal shelves (PS). (<b>d</b>) Magnification of the rectangle showing the transition epithelium (TE) among respiratory (RE) to medial edge epithelium (MEE). Arrows: cilia. (<b>e</b>) Measurement of nasopharynx area (yellow line) in cleft palate. The lower limit was an imaginary line (discontinuous black line) drawn on the transitional epithelium in clef palate fetuses. (<b>f</b>) Anomalous nasopharyngeal cilia. (<b>g</b>) Arrows pointed lack of cilia in some cells. (<b>h</b>) The cells were not columnar, and cilia seemed to be atrophied. (<b>i</b>) Aberrant shape of the nasal septum (NS) and nasopharyngeal duct (N). The palate (P) was normal. En: Encephalon. (<b>j</b>) Magnification of altered nasal septum showing how the area was measured (yellow line) the height of the septum (blue line). Scale bars: (<b>a</b>,<b>c</b>,<b>i</b>) 500 µm; (<b>b</b>,<b>d</b>,<b>f</b>–<b>h</b>) 10 µm; (<b>e</b>,<b>j</b>) 100 µm.</p> "> Figure 5
<p>Correlations between head measurements with weeks on maternal FAD diet. (<b>a</b>) Head width; (<b>b</b>) head height; (<b>c</b>) right half head area; (<b>d</b>) left half head area and (<b>e</b>) total head area. ** <span class="html-italic">p</span> ≤ 0.01; Spearman’s Rho.</p> "> Figure 6
<p>Correlations between palate measurements with weeks on maternal FAD diet. (<b>a</b>) Palate thickness; (<b>b</b>) right half palate area; (<b>c</b>) left half palate area; (<b>d</b>) total palate area and (<b>e</b>) palate bone area. * <span class="html-italic">p</span> ≤ 0.05; ** <span class="html-italic">p</span> ≤ 0.01.</p> "> Figure 7
<p>Correlations between palate measurements and total palate area. (<b>a</b>) Palate thickness and (<b>b</b>) palate bone area. ** <span class="html-italic">p ≤</span> 0.01; Spearman’s Rho.</p> "> Figure 8
<p>Correlations between palate measurements and total head area. (<b>a</b>) Total palate area and (<b>b</b>) palate bone area. ** <span class="html-italic">p ≤</span> 0.01; Spearman’s Rho.</p> "> Figure 9
<p>Correlations between nasal measurements with weeks on maternal FAD diet. (<b>a</b>) Nasopharynx duct area, (<b>b</b>) nasal septum area and (<b>c</b>) nasal septum height. * <span class="html-italic">p ≤</span> 0.05; Spearman’s Rho.</p> "> Figure 10
<p>Correlations between nasal measurements and total head area. (<b>a</b>) Nasopharynx duct area and (<b>b</b>) nasal septum area. ** <span class="html-italic">p ≤</span> 0.01; Spearman’s Rho.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals and Diet
2.2. Morphological Study
2.3. Head and Nasopalatine Region Measurements
2.4. Statistical Analysis
3. Results
3.1. General Outcomes
3.2. Morphological Analysis
3.3. Head, Palate, and Nasal Measurements
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Sperber, G.H. Craniofacial Development; BC Decker: Hamilton, ON, Canada, 2000. [Google Scholar]
- Ornoy, A. Craniofacial Malformations and Their Association with Brain Development: The Importance of a Multidisciplinary Approach for Treatment. Odontology 2020, 108, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Mossey, P.; Castilla, E. Global Registry and Database on Craniofacial Anomalies. In Report of a WHO Registry Meeting on Craniofacial Anomalies; World Health Organization: Geneva, Switzerland, 2003. [Google Scholar]
- Mossey, P.A.; Little, J.; Munger, R.G.; Dixon, M.J.; Shaw, W.C. Cleft Lip and Palate. Lancet 2009, 374, 1773–1785. [Google Scholar] [CrossRef]
- Maldonado, E.; López-Gordillo, Y.; Partearroyo, T.; Varela-Moreiras, G.; Martínez-Álvarez, C.; Pérez-Miguelsanz, J. Tongue Abnormalities Are Associated to a Maternal Folic Acid Deficient Diet in Mice. Nutrients 2017, 10, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maldonado, E.; López, Y.; Herrera, M.; Martínez-Sanz, E.; Martínez-Álvarez, C.; Pérez-Miguelsanz, J. Craniofacial Structure Alterations of Foetuses from Folic Acid Deficient Pregnant Mice. Ann. Anat. 2018, 218, 59–68. [Google Scholar] [CrossRef]
- Wilcox, A.J.; Lie, R.T.; Solvoll, K.; Taylor, J.; McConnaughey, D.R.; Åbyholm, F.; Vindenes, H.; Vollset, S.E.; Drevon, C.A. Folic Acid Supplements and Risk of Facial Clefts: National Population Based Case-Control Study. BMJ 2007, 334, 464. [Google Scholar] [CrossRef] [Green Version]
- Wehby, G.L.; Murray, J.C. Folic Acid and Orofacial Clefts: A Review of the Evidence. Oral Dis. 2010, 16, 11–19. [Google Scholar] [CrossRef]
- López-Gordillo, Y.; Maldonado, E.; Nogales, L.; Del Río, A.; Barrio, M.C.; Murillo, J.; Martínez-Sanz, E.; Paradas-Lara, I.; Alonso, M.I.; Partearroyo, T.; et al. Maternal Folic Acid Supplementation Reduces the Severity of Cleft Palate in Tgf-β 3 Null Mutant Mice. Pediatr. Res. 2019, 85, 566–573. [Google Scholar] [CrossRef]
- Millacura, N.; Pardo, R.; Cifuentes, L.; Suazo, J. Effects of Folic Acid Fortification on Orofacial Clefts Prevalence: A Meta-Analysis. Public Health Nutr. 2017, 20, 2260–2268. [Google Scholar] [CrossRef]
- National Organization for Rare Disorders (NORD) Database; NIH/NIDCD: Danbury, CT, USA; Available online: https://rarediseases.org/for-patients-and-families/information-resources/rare-disease-information/ (accessed on 1 June 2020).
- Young, A.; Spinner, A. Hemifacial Microsomia. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2020. [Google Scholar]
- Howe, A.M.; Hawkins, J.K.; Webster, W.S. The Growth of the Nasal Septum in the 6–9 Week Period of Foetal Development—Warfarin Embryopathy Offers a New Insight into Prenatal Facial Development. Aust. Dent. J. 2004, 49, 171–176. [Google Scholar] [CrossRef]
- Foster, A.; Holton, N. Variation in the Developmental and Morphological Interaction between the Nasal Septum and Facial Skeleton. Anat. Rec. 2016, 299, 730–740. [Google Scholar] [CrossRef] [Green Version]
- Katsube, M.; Yamada, S.; Yamaguchi, Y.; Takakuwa, T.; Yamamoto, A.; Imai, H.; Saito, A.; Shimizu, A.; Suzuki, S. Critical Growth Processes for the Midfacial Morphogenesis in the Early Prenatal Period. Cleft Palate Craniofac. J. 2019, 56, 1026–1037. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maldonado, E.; Murillo, J.; Barrio, C.; del Río, A.; Pérez-Miguelsanz, J.; López-Gordillo, Y.; Partearroyo, T.; Paradas, I.; Maestro, C.; Martínez-Sanz, E.; et al. Occurrence of Cleft-Palate and Alteration of Tgf-β(3) Expression and the Mechanisms Leading to Palatal Fusion in Mice Following Dietary Folic-Acid Deficiency. Cells Tissues Organs (Print) 2011, 194, 406–420. [Google Scholar] [CrossRef] [PubMed]
- Maestro-de-las-Casas, C.; Pérez-Miguelsanz, J.; López-Gordillo, Y.; Maldonado, E.; Partearroyo, T.; Varela-Moreiras, G.; Martínez-Álvarez, C. Maternal Folic Acid-Deficient Diet Causes Congenital Malformations in the Mouse Eye. Birth Defects Res. Part A Clin. Mol. Teratol. 2013, 97, 587–596. [Google Scholar] [CrossRef] [PubMed]
- Landis, J.R.; Koch, G.G. The Measurement of Observer Agreement for Categorical Data. Biometrics 1977, 33, 159–174. [Google Scholar] [CrossRef] [Green Version]
- Ray, J.G.; Laskin, C.A. Folic Acid and Homocyst(e)Ine Metabolic Defects and the Risk of Placental Abruption, Pre-Eclampsia and Spontaneous Pregnancy Loss: A Systematic Review. Placenta 1999, 20, 519–529. [Google Scholar] [CrossRef]
- Sikora, J.; Magnucki, J.; Zietek, J.; Kobielska, L.; Partyka, R.; Kokocinska, D.; Białas, A. Homocysteine, Folic Acid and Vitamin B12 Concentration in Patients with Recurrent Miscarriages. Neuro Endocrinol. Lett. 2007, 28, 507–512. [Google Scholar]
- De la Calle, M.; Usandizaga, R.; Sancha, M.; Magdaleno, F.; Herranz, A.; Cabrillo, E. Homocysteine, Folic Acid and B-Group Vitamins in Obstetrics and Gynaecology. Eur. J. Obstet. Gynecol. Reprod. Biol. 2003, 107, 125–134. [Google Scholar] [CrossRef]
- Pickell, L.; Li, D.; Brown, K.; Mikael, L.G.; Wang, X.-L.; Wu, Q.; Luo, L.; Jerome-Majewska, L.; Rozen, R. Methylenetetrahydrofolate Reductase Deficiency and Low Dietary Folate Increase Embryonic Delay and Placental Abnormalities in Mice. Birth Defects Res. Part A Clin. Mol. Teratol. 2009, 85, 531–541. [Google Scholar] [CrossRef]
- Heid, M.K.; Bills, N.D.; Hinrichs, S.H.; Clifford, A.J. Folate Deficiency Alone Does Not Produce Neural Tube Defects in Mice. J. Nutr. 1992, 122, 888–894. [Google Scholar] [CrossRef] [Green Version]
- Burgoon, J.M.; Selhub, J.; Nadeau, M.; Sadler, T.W. Investigation of the Effects of Folate Deficiency on Embryonic Development through the Establishment of a Folate Deficient Mouse Model. Teratology 2002, 65, 219–227. [Google Scholar] [CrossRef]
- Kalhan, S.C.; Marczewski, S.E. Methionine, Homocysteine, One Carbon Metabolism and Fetal Growth. Rev. Endocr. Metab. Disord. 2012, 13, 109–119. [Google Scholar] [CrossRef] [PubMed]
- Jamilian, A.; Sarkarat, F.; Jafari, M.; Neshandar, M.; Amini, E.; Khosravi, S.; Ghassemi, A. Family History and Risk Factors for Cleft Lip and Palate Patients and Their Associated Anomalies. Stomatologija 2017, 19, 6. [Google Scholar]
- Wehby, G.L.; Félix, T.M.; Goco, N.; Richieri-Costa, A.; Chakraborty, H.; Souza, J.; Pereira, R.; Padovani, C.; Moretti-Ferreira, D.; Murray, J.C. High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth. Int. J. Environ. Res. Public Health 2013, 10, 590–605. [Google Scholar] [CrossRef] [PubMed]
- Tabler, J.M.; Barrell, W.B.; Szabo-Rogers, H.L.; Healy, C.; Yeung, Y.; Perdiguero, E.G.; Schulz, C.; Yannakoudakis, B.Z.; Mesbahi, A.; Wlodarczyk, B.; et al. Fuz Mutant Mice Reveal Shared Mechanisms between Ciliopathies and FGF-Related Syndromes. Dev. Cell 2013, 25, 623–635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gorlin, R.J.; Cohen, M.M.; Hennekam, R.C.M. Syndromes of the Head and Neck. Oxford Monographs on Medical Genetics, 4th ed.; Oxford University Press: Oxford, UK, 2001. [Google Scholar]
- Hartman, C.; Holton, N.; Miller, S.; Yokley, T.; Marshall, S.; Srinivasan, S.; Southard, T. Nasal Septal Deviation and Facial Skeletal Asymmetries. Anat. Rec. 2016, 299, 295–306. [Google Scholar] [CrossRef] [Green Version]
- Goergen, M.J.; Holton, N.E.; Grünheid, T. Morphological Interaction between the Nasal Septum and Nasofacial Skeleton during Human Ontogeny. J. Anat. 2017, 230, 689–700. [Google Scholar] [CrossRef]
- Xiao, S.; Hansen, D.K.; Horsley, E.T.M.; Tang, Y.-S.; Khan, R.A.; Stabler, S.P.; Jayaram, H.N.; Antony, A.C. Maternal Folate Deficiency Results in Selective Upregulation of Folate Receptors and Heterogeneous Nuclear Ribonucleoprotein-E1 Associated with Multiple Subtle Aberrations in Fetal Tissues. Birth Defects Res. Part A Clin. Mol. Teratol. 2005, 73, 6–28. [Google Scholar] [CrossRef]
- Gray, J.D.; Nakouzi, G.; Slowinska-Castaldo, B.; Dazard, J.-E.; Sunil Rao, J.; Nadeau, J.H.; Elizabeth Ross, M. Functional Interactions between the LRP6 WNT Co-Receptor and Folate Supplementation. Hum. Mol. Genet. 2010, 19, 4560–4572. [Google Scholar] [CrossRef] [Green Version]
- Copp, A.J.; Stanier, P.; Greene, N.D.E. Neural Tube Defects: Recent Advances, Unsolved Questions, and Controversies. Lancet Neurol. 2013, 12, 799–810. [Google Scholar] [CrossRef] [Green Version]
- Canellos, G.P.; Mead, J.A.; Greenberg, N.H.; Schrecker, A.W. The Effect of Treatment with Cytotoxic Agents on Mouse Spleen Dihydrofolate Reductase Activity. Cancer Res. 1967, 27, 784–788. [Google Scholar]
- Ross, M.E. Gene-Environment Interactions, Folate Metabolism and the Embryonic Nervous System. Wiley Interdiscip. Rev. Syst. Biol. Med. 2010, 2, 471–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Antony, A.C.; Hansen, D.K. Hypothesis: Folate-Responsive Neural Tube Defects and Neurocristopathies. Teratology 2000, 62, 42–50. [Google Scholar] [CrossRef]
- Dorsky, R.I.; Moon, R.T.; Raible, D.W. Environmental Signals and Cell Fate Specification in Premigratory Neural Crest. BioEssays 2000, 22, 708–716. [Google Scholar] [CrossRef]
- Santoso, M.I.E.; Rohman, M.S. Decreased TGF-Beta1 and IGF-1 Protein Expression in Rat Embryo Skull Bone in Folic Acid-Restricted Diet. J. Nutr. Biochem. 2006, 17, 51–56. [Google Scholar] [CrossRef] [PubMed]
- Simpson, F.; Kerr, M.C.; Wicking, C. Trafficking, Development and Hedgehog. Mech. Dev. 2009, 126, 279–288. [Google Scholar] [CrossRef]
- Badano, J.L.; Mitsuma, N.; Beales, P.L.; Katsanis, N. The Ciliopathies: An Emerging Class of Human Genetic Disorders. Annu. Rev. Genom. Hum. Genet. 2006, 7, 125–148. [Google Scholar] [CrossRef] [Green Version]
- Fry, A.M.; Leaper, M.J.; Bayliss, R. The Primary Cilium. Organogenesis 2014, 10, 62–68. [Google Scholar] [CrossRef] [Green Version]
- Cela, P.; Hampl, M.; Shylo, N.A.; Christopher, K.J.; Kavkova, M.; Landova, M.; Zikmund, T.; Weatherbee, S.D.; Kaiser, J.; Buchtova, M. Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development. J. Dent. Res. 2018, 97, 108–117. [Google Scholar] [CrossRef] [Green Version]
- Crider, K.S.; Yang, T.P.; Berry, R.J.; Bailey, L.B. Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role2. Adv. Nutr. 2012, 3, 21–38. [Google Scholar] [CrossRef] [Green Version]
Weeks on Maternal FAD Diet | Mothers (n) | Number of Fetuses (n) | Nasal Malformations Only n (% Total) | Nasopalatine Malformations n (% Total) | Total Malformed n (% Group) |
---|---|---|---|---|---|
Control | 3 | 24 | 0 (0.0) | 0 (0.0) | 0 (0.0) |
2 | 6 | 56 | 0 (0.0) | 0 (0.0) | 0 (0.0) |
4 | 7 | 51 | 13 (5.0) | 0 (0.0) | 13 (5.0) |
6 | 4 | 19 | 0 (0.0) | 2 (0.8) | 2 (0.8) |
8 | 5 | 30 | 5 (1.9) | 5 (1.9) | 10 (3.8) |
10 | 9 | 58 | 4 (1.5) | 13 (5.0) | 17 (6.5) |
12 | 5 | 23 | 7 (2.7) | 1 (0.4) | 8 (3.1) |
14 | 3 | 12 | 1 (0.4) | 2 (0.8) | 3 (1.1) |
16 | 3 | 11 | 1 (0.4) | 2 (0.8) | 3 (1.1) |
Total | 45 | 284 | 31 (11.9) | 25 (9.6) | 56 (21.5) |
Asymmetry | Palatal Region Malformations | Nasal Region Malformations | |||||
---|---|---|---|---|---|---|---|
Weeks on Maternal FAD Diet | n (% Total; % Malformed) | HAP | CP | Nasal Septum | Nasopharynx Duct Shape | Cilia | Nasopharynx Epithelium |
n (% Total; % Malformed) | n (% Total; % Malformed) | n (% Total; % Malformed) | n (% Total; % Malformed) | n (% Total; % Malformed) | n (% Total; % Malformed) | ||
Control | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) |
2 | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) |
4 | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 9 (3.5; 16.1) | 12 (4.6; 21.4) | 5 (1.9; 8.9) |
6 | 0 (0.0; 0.0) | 1 (0.4; 1.8) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 1 (0.4; 1.8) | 0 (0.0; 0.0) | 0 (0.0; 0.0) |
8 | 5 (1.9; 8.9) | 1 (0.4; 1.8) | 3 (1.2; 5.4) | 6 (2.31; 10.71) | 7 (2.7; 12.5) | 4 (1.5; 7.1) | 1 (0.4; 1.8) |
10 | 5 (1.9; 8.9) | 5 (1.9; 8.9) | 5 (1.9; 8.9) | 10 (3.08; 14.29) | 14 (5.4; 25.0) | 5 (1.9; 8.9) | 4 (1.5; 7.1) |
12 | 2 (0.7; 3.6) | 0 (0.0; 0.0) | 1 (0.4; 1.8) | 2 (0.8; 3.6) | 5 (1.9; 8.9) | 5 (1.9; 8.9) | 3 (1.2; 5.4) |
14 | 0 (0.0; 0.0) | 1 (0.4; 1.8) | 0 (0.0; 0.0) | 0 (0.0; 0.0) | 1 (0.4; 1.8) | 1 (0.4; 1.8) | 1 (0.4; 1.8) |
16 | 0 (0.0; 0.0) | 1 (0.4; 1.8) | 1 (0.4; 1.8) | 1 (0.4; 1.8) | 2 (0.8; 3.6) | 2 (0.8; 3.6) | 1 (0.4; 1.8) |
Total | 12 (4.6; 21.4) | 9 (3.5; 16.1) | 10 (3.8; 17.9) | 19 (7.3; 33.9) | 39 (15.0; 69.6) | 29 (11.2; 51.8) | 15 (5.8; 26.8) |
Weeks on Maternal FAD Diet | |||||
---|---|---|---|---|---|
0 | 2–6 | 8–16 | Total | ||
Mothers without malformed fetuses | n (% group) | 3 a (100.0) | 11 a (64.7) | 4 b (16.0) | 18 (40.0) |
Mothers with malformed fetuses | n (% group) | 0 (0.0) | 6 a (35.3) | 21 b (84.0) | 27 (60.0) |
Total | n (% group) | 3 (100.0) | 17 (100.0) | 25 (100.0) | 45 (100) |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Maldonado, E.; Martínez-Sanz, E.; Partearroyo, T.; Varela-Moreiras, G.; Pérez-Miguelsanz, J. Maternal Folic Acid Deficiency Is Associated to Developing Nasal and Palate Malformations in Mice. Nutrients 2021, 13, 251. https://doi.org/10.3390/nu13010251
Maldonado E, Martínez-Sanz E, Partearroyo T, Varela-Moreiras G, Pérez-Miguelsanz J. Maternal Folic Acid Deficiency Is Associated to Developing Nasal and Palate Malformations in Mice. Nutrients. 2021; 13(1):251. https://doi.org/10.3390/nu13010251
Chicago/Turabian StyleMaldonado, Estela, Elena Martínez-Sanz, Teresa Partearroyo, Gregorio Varela-Moreiras, and Juliana Pérez-Miguelsanz. 2021. "Maternal Folic Acid Deficiency Is Associated to Developing Nasal and Palate Malformations in Mice" Nutrients 13, no. 1: 251. https://doi.org/10.3390/nu13010251