Developmental Hypothyroxinemia Caused by Mild Iodine Deficiency Leads to HFS-Induced LTD in Rat Hippocampal CA1 Region: Involvement of AMPA Receptor

Hypothyroidism induced by severe iodine deficiency (ID) during developmental period seriously damages the central nervous system function. In addition to developmental hypothyroidism induced by severe ID, developmental hypothyroxinemia induced by mild ID is potentially damaging for neurodevelopment and learning and memory in children. Wistar rats were treated with iodine-deficient diet or methimazole (MMZ) during pregnancy and lactation to induce developmental hypothyroxinemia or hypothyroidism in the present study. Pups were weaned on postnatal day (PN) 21 and used for electrophysiological recordings on PN80. It is generally accepted that long-term depression (LTD) is induced at low-frequency stimulation (LFS) in hippocampal CA1 region. Surprisingly, we observed developmental hypothyroxinemia as well as developmental hypothyroidism led to high-frequency stimulation (HFS)-induced LTD in hippocampal CA1 region. The abnormal HFS-induced LTD suggests not only developmental hypothyroidism but also developmental hypothyroxinemia impairs learning and memory. To explore the mechanisms responsible for the HFS-induced LTD, the phosphorylation status of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) was investigated. The results showed that developmental hypothyroxinemia as well as developmental hypothyroidism decreased the phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1) at serine 831 and serine 845 in hippocampal CA1 region. Neither developmental hypothyroxinemia nor developmental hypothyroidism altered the phosphorylation of AMPAR subunit glutamate receptor 2 (GluR2) at serine 880. Increased levels of protein phosphatase-1 (PP1) were also observed in hippocampal CA1 regions of pups subjected to developmental hypothyroxinemia or hypothyroidism. Taken together, our results suggest that the increased levels of PP1 caused by developmental hypothyroxinemia or hypothyroidism may account for the dephosphorylation of GluR1 at serine 831 and serine 845, which may contribute to HFS-induced LTD in hippocampal CA1 region.     

Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs

Maternal hypothyroxinemia during early pregnancy poses an increased risk for poor neuropsychological development of the fetus. We tested the hypothesis that maternal hypothyroidism before the onset of fetal thyroid function also affects postnatal development of heart and lungs. This question was addressed in transgenic mice that express herpes simplex virus thymidine kinase in their thyroidal follicle cells. Treatment with ganciclovir rendered these mice severely hypothyroid because viral thymidine kinase converts ganciclovir into a cytotoxic nucleoside analog. Since ganciclovir crosses the placenta, it also destroyed the thyroid of transgenic embryos while leaving the thyroids of nontransgenic littermates unaffected. Hypothyroidism of both mother and fetus did not affect prenatal heart and lung development. However, the postnatal switch from beta- to alpha-myosin heavy chain (beta- and alpha-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers. Similarly, postnatal animals of the latter two groups retained elevated surfactant protein (SP) A, B, and C mRNA levels in their alveolar epithelium. In hypothyroid pups from hypothyroid mothers, these changes were accompanied by decreased alveolar septation. Our study shows that these effects of maternal hypothyroidism become manifest after birth and are aggravated by the concomitant existence of neonatal hypothyroidism.     

Maternal iodine supplementation improves motor coordination in offspring by modulating the mGluR1 signaling pathway in mild iodine deficiency-induced hypothyroxinemia rats

Iodine is an essential component for thyroid hormone synthesis. Epidemiological investigations have demonstrated that maternal mild iodine deficiency (ID)-induced hypothyroxinemia can affect intellectual and behavioral function in offspring. There is no definitive evidence demonstrating the effects of maternal iodine supplementation on neurobehavioral function in regional areas with mild ID. Thus, we aimed to clarify the effects of maternal mild ID and iodine supplementation on motor coordination in offspring and illuminate the underlying molecular mechanisms. Animal models of maternal mild ID and iodine supplementation were generated by providing Wistar rats an iodine-deficient diet and deionized water supplemented with potassium iodide during pregnancy and lactation. We found that mild ID-induced hypothyroxinemia led to a shorter latent time before falling down from the rotarod, a longer time to traverse the balance beam and poorer wire grip of the forelimbs, which imply motor coordination dysfunction. However, these impairments in the offspring were improved by iodine supplementation during pregnancy and lactation. We further observed that the ultrastructure and dendritic tree morphology of cerebellar Purkinje cells were altered in mild ID-induced hypothyroxinemia but that these changes could be reversed by iodine supplementation. Maternal mild ID and iodine supplementation also affected expression of the mGluR1 signaling pathway in offspring. Together, iodine supplementation during pregnancy and lactation can improve motor coordination in offspring by modulating the mGluR1 signaling pathway in mild ID-induced hypothyroxinemia rats.     

Developmental Hypothyroxinemia and Hypothyroidism Reduce Proliferation of Cerebellar Granule Neuron Precursors in Rat Offspring by Downregulation of the Sonic Hedgehog Signaling Pathway

Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during development result in dysfunction of the central nervous system, affecting psychomotor and motor function, although the underlying mechanisms causing these alterations are still unclear. Therefore, our aim is to study the effects of developmental hypothyroxinemia, caused by mild ID, and developmental hypothyroidism, caused by severe ID or methimazole (MMZ), on the proliferation of cerebellar granule neuron precursors (CGNPs), an excellent experimental model of cerebellar development and function. The sonic hedgehog (Shh) signaling pathway is essential for CGNP proliferation, and as such, its activation is also investigated here. A maternal hypothyroxinemia model was established in Wistar rats by administrating a mild ID diet, and two maternal hypothyroidism models were developed either by administrating a severe ID diet or MMZ water. Our results showed that hypothyroxinemia and hypothyroidism reduced proliferation of CGNPs on postnatal day (PN) 7, PN14, and PN21. Accordingly, the mean intensity of proliferating cell nuclear antigen and Ki67 nuclear antigen immunofluorescence was reduced in the mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of the Shh signaling pathway on PN7, PN14, and PN21. Our study supports the hypothesis that developmental hypothyroxinemia induced by mild ID, and hypothyroidism induced by severe ID or MMZ, reduce the proliferation of CGNPs, which may be ascribed to the downregulation of the Shh signaling pathway.     

Developmental Iodine Deficiency and Hypothyroidism Impair Neural Development, Upregulate Caveolin-1, and Downregulate Synaptotagmin-1 in the Rat Cerebellum

Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during gestation and postnatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study, we implicate cerebellar caveolin-1 and synaptotagmin-1, the two important molecules involved in neuronal development, in developmental iodine deficiency, and in developmental hypothyroidism. Two developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 or 15?ppm)-added drinking water from gestational day?6 till postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptotagmin-1 in cerebella were assessed on PN28 and PN42. The results show that the numbers of Purkinje cells were reduced in the iodine-deficient and PTU-treated rats. The upregulation of caveolin-1 and the downregulation of synaptotagmin-1 were observed in both iodine-deficient and PTU-treated rats. These findings may implicate decreases in the number of Purkinje cells and the alterations in the levels of caveolin-1 and synaptotagmin-1 in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism.     

Thyroid dependent maturation of β-adrenergic receptors in the rat lung

β-Adrenergic receptors were identified in membranes of fetal and postnatal rat lung with (?)-[³H]dihydroalprenolol, [³H]DHA. β-Receptor number (Bmax) increased 11-fold from day 18 of gestation to adult levels by day 28 of postnatal life. The increase of β-adrenergic receptors occurring between postnatal days 15 and 28 was dependent on thyroxine (T4) in propylthiouracil treated pups. β-Adrenergic receptors on day 28 were identical in euthyroid (PTU + T4) as compared to normal control pups (489±31 and 491±30 femtomoles·mg^?1) however receptors were markedly reduced in 28 day hypothyroid pups (PTU alone), Bmax = 294±21.5, m±S.E. p<0.01. Treatment of the hypothyroid pups with T4 for three days on postnatal day 25 increased β-adrenergic receptors approximately two-fold by day 28. This thyroid hormone dependent increase in lung β-adrenergic receptors occurs between postnatal days 15 and 28 coincident with the known increase in thyroid gland activity in the rat pup.     

Goitres in rats fed polychlorinated biphenyls.

Rats fed a polychlorinated biphenyl (PCB) mixture in a high- or low-iodine diet (HID or LID respectively) for 15 days had thyroid enlargement, low serum thyroxine (T4), and high serum thyrotropin concentrations. Although binding of thyroid hormones to serum proteins was reduced in PCB-fed animals, the free T4 index (reflecting free T4 in serum) was less in these rats. Both serum triiodothyronine (T3) and the free T3 index were elevated in rats fed PCB in HID. LID-maintained rats elevated serum T3 concentrations but the free T3 index was similar to that in HID-fed rats, owing to enhanced binding of thyroid hormone to serum proteins. Addition of PCB to LID reduced serum T3 levels but did not alter the free T3 index because binding was less. In rats fed HID containing PCB, thyroid 131I uptake was increased.     

Postnatal essential fatty acid deficiency in mice affects lipoproteins, hepatic lipids, fatty acids and mRNA expression

We have previously reported that essential fatty acid deficiency (EFAD) during suckling in mice resulted in an adult lean phenotype and a resistance to diet-induced obesity. We now hypothesized that postnatal EFAD would cause long-term effects on lipid metabolism. C57BL/6 mice were fed an EFAD or a control diet from the 16th day of gestation and throughout lactation. The pups were weaned to standard diet (STD) and at 15 weeks of age given either high fat diet (HFD) or STD. Lipoprotein profiles, hepatic lipids, fatty acids and mRNA expression were analyzed in 3-week-old and 25-week-old offspring. At weaning, the EFAD pups had higher cholesterol levels in both plasma and liver and 6-fold higher concentrations of hepatic cholesterol esters than control pups. Adult EFAD offspring had higher levels of hepatic cholesterol and linoleic acid, but lower levels of dihomo-γ-linolenic acid and Pparg mRNA expression in the liver. In addition, HFD fed EFAD offspring had lower plasma total cholesterol, lower hepatic triglycerides and lower liver weight compared to controls fed HFD. In conclusion, early postnatal EFAD resulted in short-term alterations with increased hepatic cholesterol accumulation and long-term protection against diet-induced liver steatosis and hypercholesterolemia.     

Postnatal glucocorticoids induce alpha-ENaC formation and regulate glucocorticoid receptors in the preterm rabbit lung

At birth, lung fluid clearance is coupled to Na+ transport through epithelial Na+ channels (ENaC) in the distal lung epithelium. We evaluated the effect of postnatal glucocorticoids (GC) on lung alpha-ENaC expression in preterm 29-day gestational age (GA) fetal rabbits. Postnatal treatment of 29-day GA fetuses with 0.5 mg/kg of dexamethasone (Dex) iv resulted in a 2- and 22-fold increase in lung alpha-ENaC mRNA expression compared with saline-treated fetuses after 8 and 16 h, respectively. Lung alpha-ENaC protein levels in Dex-treated fetuses were also elevated compared with saline-treated counterparts. The extravascular lung water (EVLW)/dry lung tissue weight ratios of 29-day GA fetuses treated with either saline or Dex decreased over 24 h compared with that observed at birth; however, at 24 h, the EVLW/dry lung tissue weight ratios of saline- and Dex-treated fetuses were similar. Dex-induced alpha-ENaC mRNA and protein levels were attenuated by glucocorticoid receptor (GCR) antagonist RU-486 in fetal distal lung epithelial cells isolated from 29-day GA fetuses, indicating that GC-dependent augmentation of lung alpha-ENaC requires the presence of functional GCR. Lung GCR mRNA expression and protein levels were elevated in 29-day GA fetuses compared with fetuses at earlier GA. Exposure of 29-day GA fetuses to Dex for 16 h caused a 2.1-fold increase in lung GCR mRNA expression, but GCR protein levels were decreased in Dex-treated fetuses after 24 h. We conclude that postnatal treatment of preterm 29-day GA fetal rabbits with GC results in an elevation of lung alpha-ENaC accompanied by an autoregulation of pulmonary GCR.     

Effects of prenatal ethanol exposure on the lungs of postnatal lambs

Prenatal ethanol exposure increases collagen deposition and alters surfactant protein (SP) expression and immune status in lungs of near-term fetal sheep. Our objectives were to determine 1) whether these prenatal effects of repeated gestational ethanol exposure persist after birth and 2) whether surfactant phospholipid composition is altered following prenatal ethanol exposure. Pregnant ewes were chronically catheterized at 90 days of gestational age (DGA) and given a 1-h daily infusion of ethanol (0.75 g/kg, n = 9) or saline (n = 7) from 95 to 135 DGA; ethanol administration ceased after 135 DGA. Lambs were born naturally at full term (146 ± 0.5 DGA). Lung tissue was examined at 9 wk postnatal age for alterations in structure, SP expression, and inflammation; bronchoalveolar lavage fluid was examined for alterations in surfactant phospholipid composition. At 134 DGA, surfactant phospholipid concentration in amniotic fluid was significantly reduced (P < 0.05) by ethanol exposure, and the composition was altered. In postnatal lambs, there were no significant differences between treatment groups in birth weight, postnatal growth, blood gas parameters, and lung weight, volume, tissue fraction, mean linear intercept, collagen content, proinflammatory cytokine gene expression, and bronchoalveolar lavage fluid surfactant phospholipid composition. Although SP-A, SP-B, and SP-C mRNA levels were not significantly different between treatment groups, SP-D mRNA levels were significantly greater (P < 0.05) in ethanol-treated animals; as SP-D has immunomodulatory roles, innate immunity may be altered. The adverse effects of daily ethanol exposure during late gestation on the fetal lung do not persist to 2 mo after birth, indicating that the developing lung is capable of repair.     

Chronic maternal dietary iodine deficiency but not thiocyanate feeding affects maternal reproduction and postnatal performance of the rat

Iodine deficiency disorders affect reproductive performance in the afflicted populations. Environmental iodine deficiency (ID) and goitrogens are important in their aetiology. We observed earlier that chronic maternal dietary ID but not goitrogen feeding altered the blood-brain barrier nutrient transport in adult rats. Whether similar differences exist in their effects on reproduction of dams and postnatal performance of the offspring has been assessed. Inbred, female, weaning WNIN rats were rendered hypothyroid by feeding for 8-12 weeks, a low iodine test diet or a control diet with added potassium thiocyanate (KSCN) (@ 25 mg/rat/day). Following mating with control males, they continued on their respective diets till their pups were weaned. Indices of reproductive performance such as percentage of conception, mortality of dams during pregnancy and parturition, litter size, and survival of pups till weaning were affected markedly by ID but not thiocyanate feeding. Neither ID nor thiocyanate feeding from conception or parturition affected their reproductive performance. Nevertheless, postnatal weight gain of pups was less in all the three ID groups but not thiocyanate fed dams. Rehabilitation of chronically ID pregnant dams from conception or parturition did not improve their pregnancy weight gain, litter size or birth weight of pups but decreased abortion and mortality of mothers during pregnancy and parturition. Rehabilitation improved the pups' postnatal weight gain but the effect was only moderate. Based on the results of the present study it may be suggested that maternal ID but not thiocyanate feeding affects reproductive performance and postnatal performance of their offspring.     

Effects of iodine repletion on thyroid morphology in iodine and/or selenium deficient rat term fetuses, pups and mothers.

It has been suggested that selenium deficiency aggravates the iodine-induced thyroid inflammation and necrosis in iodine-deficient Wistar rats and possibly in man. Studies were carried out to determine whether large amounts of iodine given to iodine-deficient pregnant Sprague-Dawley rats with or without selenium deficiency would induce inflammation and necrosis in their term fetal thyroids. Iodine deficiency was induced in the dams by a low iodine diet or perchlorate in the drinking water and iodine excess was achieved by iodinated drinking water during pregnancy or daily subcutaneous injections of iodine from days 20 to 22 of pregnancy, 1 day after perchlorate was discontinued. Studies were also carried out in 30-day-old pups whose nursing mothers were iodine-deficient (perchlorate) with or without selenium deficiency from conception onward. The administration of iodine restored the morphologic changes in the thyroid induced by iodine deficiency, irrespective of selenium status, toward normal without inflammatory changes or necrosis. Possible explanations for these unexpected findings are discussed.     

Involvement of the GHSR in the developmental programming and metabolic disturbances induced by maternal undernutrition

The mismatch between maternal undernutrition and adequate nutrition after birth increases the risk of developing metabolic diseases. We aimed to investigate whether the hyperghrelinemia during maternal undernourishment rewires the hypothalamic development of the offspring and contributes to the conversion to an obese phenotype when fed a high-fat diet (HFD). Pregnant C57BL/6 J, wild type (WT) and ghrelin receptor (GHSR)^−/− mice were assigned to either a normal nourished (NN) group, or an undernutrition (UN) (30% food restricted) group. All pups were fostered by NN Swiss mice. After weaning, pups were fed a normal diet, followed by a HFD from week 9. Plasma ghrelin levels peaked at postnatal day 15 (P15) in both C57BL/6 J UN and NN pups. Hypothalamic Ghsr mRNA expression was upregulated at P15 in UN pups compared to NN pups and inhibited agouti-related peptide (AgRP) projections. Adequate lactation increased body weight of UN WT but not of GHSR^−/− pups compared to NN littermates. After weaning with a HFD, body weight and food intake was higher in WT UN pups but lower in GHSR^−/− UN pups than in NN controls. The GHSR prevented a decrease in ambulatory activity and oxygen consumption in UN offspring during ad libitum feeding. Maternal undernutrition triggers developmental changes in the hypothalamus in utero which were further affected by adequate feeding after birth during the postnatal period by affecting GHSR signaling. The GHSR contributes to the hyperphagia and the increase in body weight when maternal undernutrition is followed by an obesity prone life environment.     

Obesity Induced by Neonatal Overfeeding Worsens Airway Hyperresponsiveness and Inflammation

Background

Obesity is a risk factor for the development of certain respiratory diseases, and neonatal overfeeding results in an early onset of obesity in adulthood. However, the influence of neonatal overfeeding on respiratory diseases has rarely been studied. Therefore, this paper is aimed at investigating the effect of neonatal overfeeding on airway responsiveness and inflammation.

Methodology/Principal Findings

The neonatal overfeeding was induced by reducing litter size to three pups per litter (small litter, SL) in contrast to the normal litter size with ten pups per litter (NL) on postnatal day 3 (P3) in male ICR mice. On P21, mice were weaned to standard chow diet. Airway responsiveness to methacholine was measured either on P21 or P150. Total and classified inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted, lung inflammatory cells were evaluated through staining with hematoxylin & eosin and F4/80 immunohistochemistry; lung fibrosis was evaluated through staining with Masson and α-SAM immunohistochemistry. Leptin levels in serum were measured by RIA; TNF-α levels in serum and BALF were quantified by ELISA; mRNA levels of TNF-α, CTGF and TGF-β1 in lung tissues were measured using real-time PCR. Mice from SL exhibited accelerated body weight gain, impaired glucose tolerance and hyperleptinemia. Enhanced airway responsiveness to methacholine was observed in SL mice on P150, but not on P21. Pulmonary inflammation was evident in SL mice on P150, as reflected by inflammatory cells especially macrophages around bronchi and interstitium. BALF and serum TNF-α levels and lung TNF-α mRNA expression were significantly increased in SL mice on P150. More collagen accumulated surrounding the bronchi on P150; lung mRNA levels of TGF-β1 and CTGF were also increased on P150.

Conclusion

In addition to inducing a variety of metabolic defects, neonatal overfeeding enhanced lung inflammation, which may lead to airway remodeling and airway hyperresponsiveness in adulthood.     

Thyroid hormone stimulation of NADPH P450 reductase expression in liver and extrahepatic tissues. Regulation by multiple mechanisms.

The role of thyroid hormone in regulating the expression of the flavoprotein NADPH cytochrome P450 reductase was studied in adult rats. Depletion of circulating thyroid hormone by hypophysectomy, or more selectively, by treatment with the anti-thyroid drug methimazole led to a 75-85% depletion of hepatic microsomal P450 reductase activity and protein in both male and female rats. Thyroxine substantially restored P450 reductase activity at a dose that rendered the thyroid-depleted rats euthyroid. Microsomal P450 reductase activity in several extrahepatic tissues was also dependent on thyroid hormone, but to a lesser extent than in liver (30-50% decrease in kidney, adrenal, lung, and heart but not in testis from hypothyroid rats). Hepatic P450 reductase mRNA levels were also decreased in the hypothyroid state, indicating that the loss of P450 reductase activity is not a consequence of the associated decreased availability of the FMN and FAD cofactors of P450 reductase. Parallel analysis of S14 mRNA, which has been studied extensively as a model thyroid-regulated liver gene product, indicated that P450 reductase and S14 mRNA respond similarly to these changes in thyroid state. In contrast, while the expression of S14 and several other thyroid hormone-dependent hepatic mRNAs is stimulated by feeding a high carbohydrate, fat-free diet, hepatic P450 reductase expression was not increased by this lipogenic diet. Injection of hypothyroid rats with T3 at a supraphysiologic, receptor-saturating dose stimulated a major induction of hepatic P450 reductase mRNA that was detectable 4 h after the T3 injection, and peaked at approximately 650% of euthyroid levels by 12 h. However, this same treatment stimulated a biphasic increase in P450 reductase protein and activity that required 3 days to reach normal euthyroid levels. T3 treatment of euthyroid rats also stimulated a major induction of P450 reductase mRNA that was maximal (12-fold increase) by 12 h, but in this case no major increase in P450 reductase protein or activity was detectable over a 3-day period. Together, these studies establish that thyroid hormone regulates P450 reductase expression by pretranslational mechanisms. They also suggest that other regulatory mechanisms, which may involve changes in P450 reductase protein stability and/or changes in the translational efficiency of its mRNA, are likely to occur.     

Uncoupling protein-3 gene expression in skeletal muscle during development is regulated by nutritional factors that alter circulating non-esterified fatty acids.

Uncoupling protein-3 gene expression in skeletal muscle is up-regulated during postnatal development of mice. A high-carbohydrate diet at weaning induces a decrease in uncoupling protein-3 mRNA levels that does not occur when mice were weaned onto a high-fat diet. Uncoupling protein-3 mRNA levels do not increase in response to fasting in young pups. Only after day 15 of life, when fasting increases serum non-esterified fatty acids, uncoupling protein-3 mRNA is up-regulated by starvation. Over-nutrition or under-nutrition during lactation increases or decreases, respectively, uncoupling protein-3 mRNA expression in skeletal muscle. Regulation of uncoupling protein-3 gene expression in skeletal muscle during development is mediated by ontogenic and nutritional factors determining changes in circulating non-esterified fatty acids.     

Effect of iodine supplement on iodine status and 5′-deiodinase activity in the brain of neonatal rats with iodine deficiency

The weanling Wistar rats of iodine deficiency were divided into three groups for supplementation of different levels of iodine (iodine-excessive [IE], iodine-adequate [IA], and iodine-deficient [ID]), with a control group (C). The iodine content in the thyroid was determined by epithermal neutron activation analysis. The activities of 5′-deiodinase and 5-deiodinase in the brains were assayed by determining the conversion ratios of T4 to T3 and rT3, respectively. The thyroid hormones levels in serum were also tested. The results indicated that the ID group had a goiter containing a small amount of iodine, but the IE group had a slightly swollen thyroid with rich iodine; the concentration of iodine per unit mass of thyroid was lower in group IE than in groups IA and C. The highest 5′-deiodinase and lowest 5-deiodinase activities in group ID and the lowest 5′-deiodinase activity in group IE were found. The iodine deficiency or excess resulted in a compensated hypothyroid state. The results suggest that the iodine status and the deiodinases activities would become normal for the rats of iodine deficiency if adequate iodine is supplemented soon after birth. Meanwhile, it is also critical to avoid excessive intake of iodine to reduce the risk for overcorrecting.     

Food restriction induced thyroid changes and their reversal after refeeding in female rats and their pups

In the present study, two groups of pregnant female rats were submitted to food restriction (24 h fast versus 24 h diet intake) from the 14th day of pregnancy until either the 14th day (group B) or the 4th day after parturition (group C). All pups and their mothers were sacrificed on day 14 after delivery. The body weight of the 14-day-old pups (group B) was 46% less than the controls (group A). Free thyroxine and free triiodothyronine levels in the plasma were reduced by 44 and 16% in pups and by 20 and 36% in their mothers, respectively. These reductions were correlated with a decrease in thyroid iodine content of the pups (-50%) and their mothers (-24%). Radioiodine uptake (131I) by the thyroid gland of pups was significantly increased by 27%. Plasma TSH levels were decreased by 38% in pups and by 44% in dams. Morphological changes in thyroid glands were observed in energy restricted dams and in their pups. Some of follicles in pups were empty. Moroever in dams, we noted the presence of peripheral resorbed vacuoles, sign of thyroid hyperactivity. After a refeeding (group C) period of ten days, total recovery occurred in plasma thyroid hormone levels (FT4 and FT3) and in thyroid iodine contents of pups in spite of a partial recovery of body weights and plasma TSH levels. In dams, a partial recovery occurred in plasma thyroid hormone levels in spite of total recovery in thyroid iodine contents, while plasma TSH levels exceeded control values. A significant amelioration in thyroid histological aspects was observed in pups and their dams.