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High prevalence of hypothyroxinaemia in iodine-deficient (ID) mothers has serious implications for mental health of the progeny. Independent supplementation of iodine and n-3 fatty acids (FA) markedly improves growth and cognitive performance of school children. Discerning effects of n-3 FA and iodine on the developing cerebellum have not been ascertained. The present study investigates effects of these two micronutrients separately as well as together in an ID rat model. We studied the effects of these micronutrients on progeny of ID dams by instituting the following supplementation diets: (1) low-iodine diet (LID), (2) LID+potassium iodide (KI), (3) LID+n-3 FA and (4) LID+KI+n-3 FA. Pups were investigated for morphological and biochemical parameters at the peak of cerebellar histogenesis on postnatal day (P) 16 and for neurobehavioural as well as motor coordination parameters at P40. Results indicate that n-3 FA alone, without improvement in circulating thyroid hormone (TH), significantly improves functional, morphological and biochemical indices of the developing cerebellum. Further, results show that co-supplementation with iodine and n-3 FA rescues not only the loss of neurotrophic support, but also salvages motor coordination, memory and learning. This additive effect results in significantly improving neurotrophic support and seems to be mediated by parallel significant increase in TH receptor (TR)α and normalisation of TRβ, retinoic orphan receptor α and p75 neurotrophin receptor, as well as noteworthy prevention of apoptotic cell death and strengthening of anti-oxidative defence. The overall results indicate important mitigating role that n-3 FA may play in enhancing TH nuclear receptor-mediated signalling in the developing cerebellum. [ABSTRACT FROM PUBLISHER]

DNA is one of the most biologically important targets of exogenous and endogenous toxicants as well as carcinogens. Damage to DNA can be of different types (e.g., DNA adducts, DNA protein cross-links, single-strand breaks, oxidized bases, abasic sites, and double-strand breaks (DSBs)). DSBs are considered the most lethal form of DNA damage for eukaryotic cells, and if left unrepaired or misrepaired, can cause cell death, chromosome instability, and cancer. DSBs can arise in the cells through different sources and can be distinguished as endogenous or exogenous DSBs. Exogenous sources can be chemotherapeutic drugs, irradiation, and environmental chemicals. The endogenous causes of DNA DSBs in the cells are mainly reactive oxygen species and faulty repair of oxidative clustered DNA lesions. Qualitative and quantitative analysis of DNA DSBs is of utmost importance to understand physiologically relevant cellular processes as well as to investigate the genotoxic or clastogenic effects of toxicants. Pulsed-field gel electrophoresis (PFGE) is a widely used method for direct quantification of DNA DSBs. In this method, the cells exposed to DSB-inducing agents are embedded in the agarose blocks and lysed. These agarose blocks containing DNA are then run under multiple electric fields which are at 120° angle, to aid in the movement of large DNA strands. It gives a direct and specific measure of DSBs unlike the foci-based assays. This chapter provides a brief overview of the various commonly used approaches to analyze DNA DSBs and describes the theory, advantages and method of PFGE, for use in cells exposed to DNA DSB inducing agents.

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.