Vitamin A-deficiency impairs the normal mannosylation, conformation and iodination of thyroglobulin: a new etiological approach to endemic goitre.
This study was undertaken in order to validate the hypothesis that vitamin A-deficiency alters the structure of thyroglobulin (Tg). For that purpose, four groups of 20 Sprague-Dawley rats were submitted during two months to varying dietary conditions, namely a control diet (C+), a vitamin A-deficient diet (A-), an iodine-deficient diet (I-) and a diet characterized by the association of both deficiencies (A-I-). Both the conventional parameters of thyroid function, the intracellular steps of Tg glycosylation and iodination were analyzed. In the A- and A-I- groups, blood levels of retinol fell to one tenth of the control mean and circulating concentrations of total and free T4 and T3 increased significantly. This biochemical hyperthyroidism contrasted with the maintenance of normal TSH plasma values, suggesting a generalized peripheral refractoriness to thyroid hormones. In both A- and A-I- groups, thyroid cytosol 3H-RPM (retinyl-phosphate-mannose) and 3H-mannose incorporation into the core of the 12S-Tg and 19S-Tg species were reduced by 40-50%. In contrast, cytosolic concentrations of 3H-DPM (dolichyl-phosphate-mannose) rose, suggesting that the N-glycosylation pathways are affected in opposite direction. The sedimentation coefficient in sucrose gradient of the purified dimeric 125I-19S-Tg after guanidine 6M and dithiothreitol denaturation showed that most of the A- Tg molecules were transformed into monomeric 12S species, implying alterations of both noncovalent and covalent bonds. Finally, the radiochromatogram of 125I-iodothyronines recovered after Tg pronase digestion revealed a significant increase in the mono- (MIT) and diiodothyronine (DIT) fractions in contrast with a significant decrease in the T3 and T4 hormonal compounds. These findings are consistent with the view that vitamin A-depletion impairs the endogenous RPM synthesis and, therefore, the normal Tg 0-mannosylation. The growing peptide is characterized by steric hindrance, leading to abnormal closure of disulphide bonds, reduced MIT-DIT coupling reactions and depressed generation of physiologically active thyroid hormones. pure iodine deficit (I-) induces no effects on the above-mentioned glycosylation reactions, but iodine shortage superimposed on preexisting vitamin A-deficit (A-I-) aggravates the Tg dysmaturation.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D004224:Diterpenes; D006043:Goiter, Endemic / Q000209:etiology* / Q000378:metabolism; D007455:Iodine / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000378:metabolism; D011103:Polyisoprenyl Phosphate Monosaccharides / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism; D013954:Thyroglobulin / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000150:complications / Q000378:metabolism*
D004224:Diterpenes; D011103:Polyisoprenyl Phosphate Monosaccharides; D013963:Thyroid Hormones; C013101:mannosylretinylphosphate; D013954:Thyroglobulin; D007455:Iodine; D008358:Mannose