, 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31

, 19., 20., 21., 22., 23., 24., 25., 26., 27., 28., 29., 30., 31., 32. and 33.. The role of nutrition in the etiology of non-syndromic orofacial clefts has been appreciated since the beginning of 20th century, when find more Strauss

suggested a possible link between diet without fresh meat for jaguars, and delivering cubs with a cleft palate [34]. We are living in a society that is over-fed and undernourished, with deficiencies apparent from a so-called “well-balanced” diet. This topic is the subject of an excellent recent review by Glenville [35]. Vitamin E deficiency-associated teratogenicity has been suggested by Cheng and Thomas in 1952 [36]. A significant reduction of the incidence of maternal diabetes-related fetal malformations including orofacial clefts

has been reported in rodents supplemented with vitamin E [37]. In a study aimed to evaluate the association between vitamin E and clefting, the ratio of α-tocopherol to total serum cholesterol were analyzed in 26 mothers of children with isolated OSI-744 cleft lip and 36 control mothers [20]. The ratio, as well as α-tocopherol level in erythrocytes, was significantly lower in Polish mothers of cleft-affected children. Interestingly further studies on vitamin E in mothers of children with CL/P showed: 1) The distribution of results to the clusters was significantly dependent on type of the cleft: isolated cleft lip or cleft lip with cleft palate (p=0.03), which may suggest etiological distinction between them [38]; 2) The multiple linear regression model with body mass index (BMI), BMI2, age, concentration of plasma retinol, and fish consumption as independent variabs predicted a 40% of variance in C-X-C chemokine receptor type 7 (CXCR-7) the plasma α-tocopherol concentration [39]. These findings indicating a variance of α-tocopherol concentration should be considered in future studies. It has not yet been proven whether the teratogenic effects of an α-tocopherol deficiency are due directly to a deficiency of the vitamin, or whether they indirectly occur through modulators associated with α-tocopherol homeostasis. Moreover, future studies are recommended to test whether isolated cleft lip and cleft lip and palate have distinct

etiologies, which has also been suggested by other investigators [40]. Maternal intake of vitamin A from supplements >10,000 IU has been shown to cause CL/P in addition to other malformations [15, 41]. Vitamin A intoxication results in a multitude of alternations in mammalian embryos and several genes involved in palate development (i.e. muscle segment homeobox homolog 1, MSX1 and transforming growth factor β3, TGFβ3) interact or can be modified in expression by vitamin A and its analogs [41]. It is noteworthy that among unsupplemented Polish women high plasma retinol levels, exceeding the upper laboratory norm, were detected in mothers of children with orofacial cleft at two times that of control mothers, 11.5% (11/96) vs. 5.8% (3/52), respectively [19].

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