jimmylegs wrote:Gene expression of IL-2 and IL-2 receptors (both α and β) and binding of NF-kB to DNA were decreased by zinc deficiency in HUT-78.
...Cases had significantly low serum zinc and selenium levels (62.48±15.9 vs 102.6±23.7 and 55.16±11.3 vs 77.4±5.5, respectively, p<0.001). Serum Cu and whole-blood Pb levels were significantly high when compared to controls. ...an interaction among environmental, genetic, and nutritional factors such as trace elements and vitamins would explain these anomalies. If folic acid supplementation is given, additional Zn supplementation should be considered for the further decrease in the recurrence and occurrence of NTDs.
"...There were 76 cases with three or more defects, whereas less than one case was expected. Of these 76 cases, seven had recognized causes (five chromosomal anomalies, two single-gene disorders); another 19 had recognized clinical phenotypes or syndromes of unknown etiology. In the remaining 50 cases ... Their most common limb defects were reduction deformities (34%) and polydactyly (20%). This study confirms the clinically recognized nonrandom occurrence of the VACTERL association. ... A common denominator of the VACTERL association is suggested to be a defective mesodermal development during embryogenesis, due to a variety of causes and leading to overlapping manifestations."
" ...of the gene Sonic hedgehog(Shh) in limb buds and lateral plate mesoderm during development causes preaxial polydactylyand sternal defects respectively..."
"From work with experimental animals, it is well documented that deficiencies of certain nutrients, including folate, vitamin B12, Zn, Fe and Cu, during pregnancy can result in abnormal CNS development, and deficiencies of these nutrients are commonly noted in alcoholics [18–23]. With respect to the above nutrients, the hypothesis that maternal Zn status is an important predictor of the risk for FASD has received particular attention. Over 25 years ago, Flynn et al reported that maternal plasma Zn and fetal cord plasma Zn were lower in pregnant women who consumed alcohol versus non-alcohol drinking women . Importantly, these investigators reported that there were negative correlations between maternal plasma Zn concentrations and the severity and frequency of birth defects in the infants, suggesting an etiologic role for Zn deficiency in human FASD."
"It is important to note that mechanistically, one would predict multiple synergistic interactions between an alcohol insult and a condition of marginal Zn deficiency. As an example of the above, it is well documented that Zn contributes to the oxidant defense system through multiple means, including through its ability to: (1) regulate Cu-Zn superoxide dismutase (CuZn SOD) activity; (2) regulate metallothionein levels; (3) protect sulfhydryl groups from oxidation; (4) modulate intracellular thiol groups; and (5) inhibit the binding of redox active metals, such as Fe and Cu, to intracellular sites where they can generate free radical reactions (e.g., Fenton-type reactions). Given the above, it is evident that one functional consequence of Zn deficiency is an increased susceptibility to exogenous oxidative stressors, such as smoking, endotoxin challenge, and, particularly germane to this paper, alcohol [27,39,41] The consequences of excessive tissue oxidative stress in the embryo can include lipid, protein and DNA oxidative damage, and an increase in apoptosis, all of which can trigger abnormal development. It is important to note that all of the above are common findings in animal models for FASD ."
"Another potential point of interaction between Zn deficiency and an alcohol challenge involves sonic hedgehog (Shh) signaling. Shh signaling is critical for polarizing activity, and Shh null fetuses are characterized by a postaxial forelimb ectrodactyly in mouse models . Shh is a Zn-dependent developmental trigger, and reduced Shh expression has been implicated in ethanol-induced postaxial forelimb ectrodactyly in the mouse . Schreiner and co-workers  have suggested that a state of embryonic Zn deficiency secondary to an alcohol-induced acute-phase response (see below; [46–48]) in the mother results in reduced Shh signaling with subsequent dysmorphology . This is an interesting hypothesis that merits further investigation. Importantly, if it is shown to be correct, there are numerous other Zn-dependent developmental proteins, many in the hedgehog signaling pathway (e.g., Gli Zn finger transcription regulators), that might also be affected through the mechanism described above."
"Several polydactyly syndromes are thought to result from mutations in GLI3... It has been postulated that preaxial polydactyly in humans could result from ectopic expression of Shh in the anterior limb bud. Mutations in GLI3, a downstream target of SHH, can be seen in Grieg syndrome (craniofacial anomalies with postaxial polydactyly of hands"
"Single doses of 2,3,4,6,8,10, and 15 mg/kg of cadmium chloride were administered (SC) to groups of MF1 mice on one of day to 12 of gestation. Fetuses collected on day 18 were observed for limb malformations, and alizarin red-S stained skeletons were examined for their skeletal bases. ... Ectrodactyly, postaxial polydactyly, syndactyly, brachydactyly, adactyly, phocomelia, meromelia, and malrotation of the limbs were detected in a significant number of fetuses."
"Cadmium and zinc are chemically similar.. they therefore compete with one another for a variety of ligands... because cadmium is considered to have only adverse effects in biological systems... and zinc is an essential nutrient, the significance of their competitive interactions for health merits investigation.
...Cadmium enters man from several sources.. these include air, cigarette smoke, drinking water, and food... the availability of dietary zinc for absorption is also influenced by the diet composition. The digestibility of food is a crucial factor. Hence zinc in meat, sea food, or milk products ... is considerably more available than zinc in grains, legumes and other vegetables, which contain phytate or other ligands that can complex with zinc to form insoluble chelates in the alkaline environment of the small intestine.
...A recent autopsy study ... revealed a positive corelation between renal cortical cadmium:zinc ratio and the severity of atherosclerosis."
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