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ABSTRACT: Maternal hypothyroidism affects postnatal lung structure. High prevalence of hypothyroxinemia (low T4, normal T3) in iodine-deficient pregnant women and associated risk for neuropsychological development along with high infant/neonatal mortality ascribed to respiratory distress prompted us to study the effects of maternal hypothyroxinemia on postnatal lung development. Female Sprague Dawley rats were given a low-iodine diet (LID) with 1% KClO(4) in drinking water for 10 days, to minimize thyroid hormone differences. Half of these rats were continued on iodine-deficient diet; ID (LID with 0.005% KClO(4)) for 3 mo, whereas the rest were switched to an iodine-sufficient diet; IS [LID + potassium iodide (10 μg iodine/20 g of diet + normal drinking water)]. Pups born to ID mothers were compared with age-matched pups from IS mothers at postnatal days 8 (P8) and 16 (P16) (n = 6-8/group). ID pups had normal circulating T3 but significantly low T4 levels (P < 0.05) and concomitantly approximately sixfold higher thyroid hormone receptor-β mRNA in alveolar epithelium. Lung histology revealed larger and irregularly shaped alveoli in ID pups relative to controls. Lung function was assessed at P16 using a double-chambered plethysmograph and observed reduced tidal volume, peak inspiratory and expiratory flow, and dynamic lung compliance in ID pups compared with IS pups. Significant lowering of surfactant protein (SP)-B and SP-C mRNA and protein found in ID pups at P16. ID pups had 16-fold lower matrix metalloproteinase-9 mRNA levels in their alveolar epithelium. In addition, mRNA levels of thyroid transcription factor-1 and SP-D were significantly higher (3-fold) compared with IS pups. At P16, significantly lower levels of SP-B and SP-C found in ID pups may be responsible for immature lung development and reduced lung compliance. Our data suggest that maternal hypothyroxinemia may result in the development of immature lungs that, through respiratory distress, could contribute to the observed high infant mortality in ID neonates.
AJP Lung Cellular and Molecular Physiology 03/2012; 302(10):L1037-43. · 3.66 Impact Factor
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ABSTRACT: Neurological deficits due to maternal and neonatal hypothyroxinemia under mild-moderate iodine deficiency are a major preventable health problem worldwide. The present study assesses the impact of hypothyroxinemia on postnatal neocortical development and also compares it to the known effects of severe hypothyroidism. Our results strongly suggest that even within elevated circulating triiodothyronine (T3) levels, hypothyroxinemia significantly impairs thyroid hormone responsiveness in developing rat neocortex. The significant compensatory alteration in deiodinase levels with unaltered monocarboxylate transporter 8 (MCT8) and thyroid hormone receptors (TRs), although found to be similar in hypothyroxinemic and hypothyroid condition, is more pronounced under later condition. The resultant downregulation of nuclear myelin binding protein (MBP) and mitochondrial transcripts Cytochrome oxidase III (Cox III) as well as significantly enhanced mitochondrial localization of Bax and reduced Bcl-2 and Bcl-xL accompanied by enhanced release of Cytochrome c and Smac with activation of caspase-3 indicates pronounced apoptosis leading to compromised cellular survival. The similarities of this responsiveness albeit with difference in degree under hypothyroidism and hypothyroxinemic state with adequate availability of T3 are suggestive of an independent role of thyroxine in neocortex development. Taken together, this study brings forth the neurophysiological aspects of hypothyroxinemia and underscores the importance of adequate iodine nutrition along with mandatory thyroxin monitoring during pregnancy and after birth.
Experimental Neurology 03/2011; 228(1):91-8. · 4.70 Impact Factor
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ABSTRACT: Hypothyroidism during early mammalian brain development is associated with decreased expression of various mitochondrial encoded genes along with evidence for mitochondrial dysfunction. However, in-spite of the similarities between neurological disorders caused by perinatal hypothyroidism and those caused by various genetic mitochondrial defects we still do not know as to how thyroid hormone (TH) regulates mitochondrial transcription during development and whether this regulation by TH is nuclear mediated or through mitochondrial TH receptors? We here in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1alpha, NRF-1alpha and Tfam. Also, we for the first time demonstrate a mitochondrial localization of thyroid hormone receptor (mTR) isoform in developing brain capable of binding a TH response element (DR2) present in D-loop region of mitochondrial DNA. These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.
Biochemical and Biophysical Research Communications 07/2010; 397(3):548-52. · 2.48 Impact Factor
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Subhash Yadav,
Sushil Kumar Gupta,
Madan M Godbole,
Manoj Jain,
Uttam Singh,
Praveen V Pavithran,
Raman Boddula,
Anand Mishra,
Ashutosh Shrivastava,
Ashwani Tandon,
Manish Ora,
Amit Chowhan,
Manoj Shukla,
Narendra Yadav, Satish Babu,
Manoj Dubey,
Pradeep K Awasthi
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ABSTRACT: The aim of the present study was to determine the impact of universal salt iodization (USI) on the prevalence of iodine deficiency in the population of an area previously known to have severe iodine deficiency in India.
In a cross-sectional survey, a total of 2860 subjects residing in fifty-three villages of four sub-districts of Gonda District were examined for goitre and urinary iodine concentration. Free thyroxine and thyroid-stimulating hormone levels were also measured. Salt samples from households were collected for estimation of iodine content.
A reduction in goitre prevalence was observed from 69 % reported in 1982 to 27.7 % assessed in 2007. However, 34 % of villages still had very high endemicity of goitre (goitre prevalence >30 %). Twenty-three per cent of households consumed a negligible amount (<5 ppm) and 56 % of households consumed an insufficient amount (5-15 ppm) of iodine from salt.
Although there was an overall improvement in iodine nutrition as revealed by decreased goitre prevalence and increased median urinary iodine levels, there were several pockets of severe deficiency that require a more targeted approach. Poor coverage, the use of unpackaged crystal salt with inadequate iodine and the washing of salt before use by 90 % of rural households are the major causes of persisting iodine-deficiency disorders. This demonstrates lapses in USI implementation, lack of monitoring and the need to identify hot spots. We advocate strengthening the USI programme with a mass education component, the supply of adequately iodized salt and the implementation of complementary strategies for vulnerable groups, particularly neonates and lactating mothers.
Public Health Nutrition 06/2009; 13(3):424-9. · 2.17 Impact Factor
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ABSTRACT: N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in a variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here, we show that 4-HPR and not all-trans retinoic acid and 9-cis retinoic acid effectively induce apoptosis in glioma cells. 4-HPR-induced apoptosis is associated with hydroperoxide production and loss of mitochondrial membrane potential (Delta Psi(m)). Ultrastructural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca(2+) as well as mitochondrial Ca(2+). Chelation of extracellular Ca(2+) by EGTA did not prevent Ca(2+) elevation, thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis; however, blocking the release of Ca(2+) from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca(2+) from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol and nucleus, respectively, along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors, thus suggesting involvement of a caspase-dependent and caspase-independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial-mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.
Carcinogenesis 11/2006; 27(10):2047-58. · 5.70 Impact Factor
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Carcinogenesis 01/2006; 27:2047-2058. · 5.70 Impact Factor
