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Thyroid hormone (TH) deficiency leads to extensive apoptosis during cerebellar development, but the mechanism still remains unclear. Different signals also converge on mitochondria during apoptosis to induce the release of apoptogenic proteins that activate proteolytic cascade through specific enzymes called caspases. Here we studied the effect of hypothyroidism on alterations in mitochondrial structure and translocation of apoptogenic molecules during rat cerebellar development. Structural analysis of mitochondria was studied by electron microscopy. The translocation of apoptogenic molecules was analyzed by Western blotting. TH deficiency led to vacuolization, enlargement and decrease in the number of cristae. The majority of the proapoptotic molecule, Bax, was localized in mitochondria under hypothyroid conditions whereas a limited presence of Bax was detected in the euthyroid state. Translocation of cytochrome c, apoptosis-inducing factor (AIF) and second mitochondrial-derived activator of caspases (SMAC) from mitochondria to cytosol was detected primarily in early developmental stages in the hypothyroid condition. These experimental results demonstrate that TH maintains mitochondrial architecture and inhibits the release of apoptogenic molecules to prevent excess apoptosis during cerebellar development.
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SUMMARY
Gonadotrophin content in the pituitary gland and blood serum as well as ovarian 32P uptake were studied in response to methallibure treatment in H. fossilis. There was a marked reduction in the gonadotrophic activity of the pituitary gland and blood serum within 3 weeks of methallibure treatment (100 μg/g). A simultaneous significant reduction was also recorded in the ovarian activity of these fish. The fall in ovarian activity caused by methallibure could not be prevented by the administration of LH, FSH or LH + FSH. After cessation of methallibure treatment, LH + FSH (50 μg each) administration restored ovarian activity. It is evident from these results that methallibure alters the secretion of gonadotrophin, and also prevents its action on the ovary.
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SUMMARY
The interrenal tissue of the air-breathing fish, Heteropneustes fossilis, became hypertrophied during the breeding period. The interrenal cell cytoplasm became acidophilic and vacuolated, cytoplasmic granulation disappeared and the cell nuclei increased in size. The diameter of the nuclei varied from 2·07 to 3·12 μm in the non-breeding period while in the breeding season there was almost uniform enlargement (4·54 ± 0·36 μm). Variation in nuclear size was most pronounced during maturation of the gonads, i.e. in April. However, the size of larger nuclei (average diameter 6·53 ± 0·98 μm) was not significantly different from that of thesmaller nuclei (average diameter 4·61 ± 0·61 μm) during this period (P > 0·05).
The volume density of the cell components of the interrenal tissue nearly doubled in the breeding period but the relative proportions remained more or less the same. Glycogen granules, which appeared to be uniformly distributed in the interrenal cells in the non-breeding period, became aggregated and clumped in many parts of the cell during the breeding period. There was a clear increase in the chromaffin reaction in the chromaffin cells during the breeding period but the iodate reaction, indicating noradrenaline content, decreased considerably.
In the ovarian cycle there was a close relationship between gonadosomatic index, ova diameter and water temperature. There was a more than tenfold increase in the gonadosomatic index in the breeding period (1·30 in the non-breeding and 15·27 in the breeding periods). In males, the rise in the gonadosomatic index in the breeding period corresponded to that of the ovary in degree (0·22 in the non-breeding and 3·20 in the breeding periods).
In the non-breeding period the thyroid follicles were composed of squamous epithelium (epithelial height 1·2–2·2 μm) with a follicular diameter of 48–76 μm and the colloid completely filling the lumina of the follicles; features indicative of hypofunction of the gland. In the breeding period, the follicles were composed of cuboidal epithelium (epithelial height nearly three times that in the preceding period, 4·1–6·3 μm) follicular diameter was reduced (36–48 μm) and the colloid incompletely filled the lumina, thus suggesting normal or slight hyperfunction of the gland.
Search for other papers by D. V. SINGH in
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SUMMARY
One hundred and twenty albino female rats (Sprague-Dawley-Rolfsmeyer) were divided into five equal groups. Rates of thyroxine secretion (TSR) and food consumption were determined during the control period, and 10 and 25 days after initiation of dietary treatment. Animals in each group served as their own controls for the following modifications of their diet: (1) protein-free diet, (2) 5% protein (casein) diet, (3) 10% protein diet, (4) 15% protein diet, and (5) 20% protein diet. Purina lab chow (23·4% protein) and the 20% casein diet served as control diets. The TSR, the body weight and amount of food consumed were depressed significantly in the group fed on a protein-free diet for 10 and 25 days. The group fed 5% protein diet had a non-significant decrease in TSR as compared with the controls. Similarly, TSR was not reduced by 10, 15 or 20% protein diets. Food consumption decreased significantly in the groups fed a 5, 10 and 15% protein diet, but not in the group on 20% casein. Body weight decreased significantly in the groups on a protein-free diet and on a 5% protein diet.
It would appear from these results that protein content of the diet does not become a limiting factor for TSR until it is lower than 5%. It is suggested that the calorie intake plays a more important role in regard to TSR than a low protein content of the food.
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Search for other papers by MAN MOHAN SINGH in
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SUMMARY
Sodium and potassium levels were determined in the rat endometrium and uterine washings during normal and 'delayed' implantation. Both endometrium and uterine washings of normal rats differed from those of 'delayed' animals in their electrolyte concentrations. A dose of oestradiol dipropionate (1 μg/rat) capable of inducing implantation in 'delayed' rats (ovariectomized and maintained on progesterone) did not evoke any significant changes in electrolyte concentration of either the endometrium or uterine washings. These findings are discussed in the light of a hypothesis regarding delayed implantation in rats.
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Thyroid hormone (TH) deficiency results in delayed proliferation and migration of cerebellar granule cells. Although extensive cell loss during the development of the cerebellum under hypothyroid conditions is known, its nature and its mechanism are poorly understood. Bcl-2 family gene expression is known to determine the fate of cells to undergo apoptosis. We evaluated the effect of hypothyroidism on Bcl-2 family gene expression in the developing rat cerebellum. Electrophoresis and Western blotting were used to analyze DNA fragmentation and expression of DNA fragmentation factor (DFF-45), Bcl-2, Bcl-xL and Bax genes respectively. In the hypothyroid condition, extensive DNA fragmentation and enhanced cleavage of DFF-45 were seen throughout development (postnatal day 0 to day 24) and adulthood whereas they were absent in the euthyroid state. The anti-apoptotic genes Bcl-2 and Bcl-xL were down-regulated and the pro-apoptotic gene Bax was expressed at higher levels compared with the euthyroid state. These results suggest that normal levels of TH prevent cerebellar apoptosis to a large extent, whereas hypothyroidism not only increases the extent but also the duration of apoptosis by down-regulating the anti-apoptotic genes and maintaining a high level of the pro-apoptotic gene Bax.
Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
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Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
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Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
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Myometrial inflammation is thought to have a pivotal role in the onset of term and some forms of preterm labour. This is based on the comparison of samples taken from women undergoing term elective CS prior to the onset of labour with those taken from women in established labour. Consequently, it is not clear whether myometrial inflammation is a cause or a consequence of labour. Our objective is to test the hypothesis that myometrial inflammation is a consequence of the onset of labour. To test this hypothesis, we have obtained myometrial samples from women at various stages of pregnancy and spontaneous labour and studied the activation of the AP-1 (c-Jun) and NFκB (p65) systems, cytokine mRNA expression and protein levels and inflammatory cell infiltration and activation. We found that the activation of p65 declined from preterm to term not in labour samples and thereafter increased in early and established labour. Cytokine mRNA expression and protein levels increased in established labour only. Using flow cytometry of myometrial tissue, we found that the number of neutrophils did increase with the onset of labour, but on tissue section, these were seen to be intravascular and not infiltrating into the myometrium. These data suggest that myometrial inflammation is a consequence rather than a cause of term labour.
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ABSTRACT
Dietary factors are known to modulate concentrations of sex hormone-binding globulin (SHBG). In the present study we have investigated the possibility that insulin like growth factor-type I (IGF-I) may be an additional regulator of SHBG using cultured human hepatoma cells which secrete SHBG. The inhibitory effect of insulin on SHBG secretion by these cells was confirmed but, in addition, IGF-I was shown to inhibit SHBG secretion by about 40% at a concentration of 100 nmol/l. A similar degree of inhibition was achieved using insulin at a concentration of 10 umol/l. Insulin, but not IGF-I, was also found to inhibit the secretion of a low molecular weight IGF-binding protein (IBP-I), which is also secreted by hepatoma cells. It is concluded that IGF-I is an additional regulator of SHBG secretion by these cells and that it may be involved in regulating SHBG secretion in vivo in response to dietary factors.
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Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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SLC30A8 encodes the zinc transporter ZnT8. SLC30A8 haploinsufficiency protects against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D. We show here that, while adult chow fed Slc30a8 haploinsufficient and knockout (KO) mice have normal glucose tolerance, they are protected against diet-induced obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this protection against DIO may represent one mechanism whereby SLC30A8 haploinsufficiency protects against T2D in humans and that, while SLC30A8 is predominantly expressed in pancreatic islet beta cells, this may involve a role for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we show in humans, using electronic health record-derived phenotype analyses, that the ‘C’ allele of the non-synonymous rs13266634 SNP, which confers a gain of ZnT8 function, is associated not only with increased T2D risk and blood glucose, but also with increased risk for hemolytic anemia and decreased mean corpuscular hemoglobin (MCH). In Slc30a8 KO mice, MCH was unchanged but reticulocytes, platelets and lymphocytes were elevated. Both young and adult Slc30a8 KO mice exhibit a delayed rise in insulin after glucose injection, but only the former exhibit increased basal insulin clearance and impaired glucose tolerance. Young Slc30a8 KO mice also exhibit elevated pancreatic G6pc2 gene expression, potentially mediated by decreased islet zinc levels. These data indicate that the absence of ZnT8 results in a transient impairment in some aspects of metabolism during development. These observations in humans and mice suggest the potential for negative effects associated with T2D prevention using ZnT8 inhibitors.
