Tongue Abnormalities Are Associated to a Maternal Folic Acid Deficient Diet in Mice

Abstract

Abstract:It is widely accepted that maternal folic acid (FA) deficiency during pregnancy is a risk factor for abnormal development. The tongue, with multiple genes working together in a coordinated cascade in time and place, has emerged as a target organ for testing the effect of FA during development. A FA-deficient (FAD) diet was administered to eight-week-old C57/BL/6J mouse females for 2-16 weeks. Pregnant dams were sacrificed at gestational day 17 (E17). The tongues and heads of 15 control and 210 experimental fetuses were studied. In the tongues, the maximum width, base width, height and area were compared with width, height and area of the head. All measurements decreased from 10% to 38% with increasing number of weeks on maternal FAD diet. Decreased head and tongue areas showed a harmonic reduction (Spearman nonparametric correlation, Rho = 0.802) with respect to weeks on a maternal FAD diet. Tongue congenital abnormalities showed a 10.9% prevalence, divided in aglossia (3.3%) and microglossia (7.6%), always accompanied by agnathia (5.6%) or micrognathia (5.2%). This is the first time that tongue alterations have been related experimentally to maternal FAD diet in mice. We propose that the tongue should be included in the list of FA-sensitive birth defect organs due to its relevance in several key food and nutrition processes.

Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice

“…Regarding our tongue-tumor model, the relation between maternal FA depletion and tongue tumor in the offspring has not been clarified. However, maternal FA depletion causes congenital abnormalities of the tongue (aglossia and microglossia) at 10% prevalence in the offspring, 15 which implies that adequate maternal FA intake is essential for normal tongue development and homeostasis. Thus, tongue papilloma formation could be accelerated here by maternal FA depletion during early pregnancy probably through a different, Cyld-independent mechanism.…”

“…Furthermore, recent studies focused on the effects of maternal FA intake on the DNA methylation status in offspring have demonstrated that folate/FA in the maternal diet can potentially alter the DNA methylation status in the offspring in a highly organ-specific manner. [11][12][13][14][15][16] However, the physiological mechanism by which maternal FA intake regulates the offspring phenotype remains to be elucidated.…”

“…Maternal FA regulates the expression levels of numerous genes in the offspring through methylation. An interesting gene that is epigenetically altered in an organ-specific manner by maternal FA insufficiency is Cyld [11][12][13][14][15][16] ; the gene encodes the deubiquitinating enzyme cylindromatosis, which is absent or downregulated in nonalcoholic steatohepatitis 17 and several types of cancer, such as melanoma, 18 myeloma, 19 and cancers of the skin, 20 colon, 21 liver, 21,22 and breast. 23 Especially in the skin, Cyld functions physiologically as a regulator of epidermal differentiation, 24 and its deficiency in the skin accelerates sensitivity to chemically induced skin-tumor development in mice.…”

Maternal Folic Acid Deficiency Is Associated to Developing Nasal and Palate Malformations in Mice

“…Environmental factors such as vitamin B complex deficiencies may cause developmental disorders. It has been previously shown by our group that a folate deficiency (vitamin B 9 ), or its synthetic form, folic acid (FA), in maternal diet may trigger multiple craniofacial malformations as oral clefts [ 3 , 4 ] or tongue and mandible abnormalities [ 5 , 6 ]. Moreover, it seems that FA supplementation is beneficial in reducing abnormalities such as oral clefts [ 7 , 8 , 9 ].…”

A case of isolated aglossia

“…Aglossia is rarely isolated and is usually accompanied by other anomalies such as adactyly, mental retardation, short stature and craniofacial deformities as micrognathia, cleft palate or lip, facial asymmetry and partial anodontia [1,2]. Aglossia whether isolated or in association with other symptoms may be due to Folic acid deficiency [3], maternal febrile illness, infection, hypothyroidism or vascular disruption during tongue development [4].…”