A radiation-induced gene signature distinguishes post-Chernobyl from sporadic papillary thyroid cancers

We investigated selected gene targets to differentiate radiation-induced papillary thyroid cancers (PTCs) from other etiologies. Total RNA was isolated from 11 post-Chernobyl PTCs and 41 sporadic PTCs characterized by a more aggressive tumor type and lacking a radiation exposure history. RNA from 10 tumor samples from both groups was pooled and hybridized separately on a whole genome microarray for screening. Then 92 selected gene targets were examined quantitatively on each tumor sample using an RTQ-PCR-based low-density array (LDA). Screening for more than fivefold differences in gene expression between the groups by microarray detected 646 up-regulated and 677 down-regulated genes. Categorization of these genes revealed a significant (P < 0.0006) over-representation of the number of up-regulated genes coding for oxidoreductases, G-proteins and growth factors, while the number of genes coding for immunoglobulin appeared to be significantly down-regulated. With the LDA, seven genes (SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC and PAGE1) made a complete differentiation between the groups possible. Gene expression patterns known to be associated with a more aggressive tumor type in older patients appeared to be more pronounced in post-Chernobyl PTC, thus underlining the known aggressiveness of radiation-induced PTC. Seven genes were found that completely distinguished post-Chernobyl (PTC) from sporadic PTC.     

Functional morphology of the rat thyroid during the first months of the pubertal period

Morphofunctional parameters of the rat thyroid gland, at the light optic and electron microscopic levels, during first months of the pubertal period are not stable. Quantitative values of these parameters fluctuate with a period of 32-36 days. Some morphofunctional parameters, such as diameter of the thyrocyte nucleus and content of albumine-binding iodine in blood, depend on the animal's body mass, other parameters do not depend on it.     

Bulbospinal serotonergic activity during changes in thyroid status.

A three-part study explored the basis for an interaction between changes in thyroid status and bulbospinal serotonin (5HT) metabolism. In experiment 1, three well-characterized models of primary hypothyroidism were all accompanied by significant increases in 5HT metabolism. In experiment 2, circulating thyroid hormone levels were experimentally varied from very low methimazole (Meth) treatment to very high (T3 implants: 2.5, 5.0, or 7.5 mg triiodothyronine). As in experiment 1, Meth led to elevated 5HT. Hyperthyroidism was accompanied by significant reductions in 5HT, while urinary norepinephrine excretion paralleled 5HT. In experiment 3, rats were subjected to Meth either 2 weeks before or after induction of diabetes with streptozotocin (Stz). Meth prevented Stz-associated reductions in 5HT and attenuated development of hyperphagia. Meth could not reverse established Stz-associated reduction in 5HT or hyperphagia, although both were slightly attenuated. Thus, although the first two experiments argue for a simple inverse relationship between circulating thyroid hormone levels and 5HT in the brain, experiment 3 demonstrated that Stz-associated decrements in 5HT could not be reversed by subsequent lowering of circulating thyroid hormone. Nor did accompanying measurements indicate that glycemic status or circulating levels of leptin were important predictors of 5HT. Thus the interaction between thyroid hormones and 5HT is both more subtle and more complex than previously thought.     

Enzyme clusters during the metamorphic period of Ambystoma mexicanum: role of thyroid hormone

Enzyme activities and DNA content have been measure in axolotl liver during the metamorphic period (4-8 months after spawning). Three different types of enzyme activity profiles were observed. In the type I profile (carbamoyl-phosphate synthase, arginase, ornithine transcarbamoylase, and glutamate dehydrogenase) enzyme activity is high in the youngest animals studied, and shows a minimum at 5 months followed by a maximum at 8 months of age. Thereafter activities do not change or slightly decrease. In the type II profile (tyrosine aminotransferase, glucose-6-phosphatase) enzyme activity shows a peak at 5 months of age and is low thereafter. Hexokinase, the enzyme with a type III profile, shows high activity throughout the metamorphic period. DNA content remains high throughout the metamorphic period but decreases 50% between 9 and 12 months of age, probably due to an increase in the size of the hepatocytes. No glucokinase activity was detected. High activities of cluster II enzymes represent early metamorphic events, while the rising part of cluster I is associated with late metamorphic events. The apparent molecular specific activity increases during natural development between 5 and 9 months of age, or precociously, upon thyroid hormone treatment. This change in apparent molecular specific activity is correlated to the advent of ureotelism.     

Microarray comparative genomic hybridization reveals genome-wide patterns of DNA gains and losses in post-Chernobyl thyroid cancer

Genetic gains and losses resulting from DNA strand breakage by ionizing radiation have been demonstrated in vitro and suspected in radiation-associated thyroid cancer. We hypothesized that copy number deviations might be more prevalent, and/or occur in genomic patterns, in tumors associated with presumptive DNA strand breakage from radiation exposure than in their spontaneous counterparts. We used cDNA microarray-based comparative genome hybridization to obtain genome-wide, high-resolution copy number profiles at 14,573 genomic loci in 23 post-Chernobyl and 20 spontaneous thyroid cancers. The prevalence of DNA gains in tumors from cases in exposed individuals was two- to fourfold higher than for cases in unexposed individuals and up to 10-fold higher for the subset of recurrent gains. DNA losses for all cases were low and more prevalent in spontaneous cases. We identified unique patterns of copy variation (mostly gains) that depended on a history of radiation exposure. Exposed cases, especially the young, harbored more recurrent gains that covered more of the genome. The largest regions, spanning 1.2 to 4.9 Mbp, were located at 1p36.32-.33, 2p23.2-.3, 3p21.1-.31, 6p22.1-.2, 7q36.1, 8q24.3, 9q34.11, 9q34.3, 11p15.5, 11q13.2-12.3, 14q32.33, 16p13.3, 16p11.2, 16q21-q12.2, 17q25.1, 19p13.31-qter, 22q11.21 and 22q13.2. Copy number changes, particularly gains, in post-Chernobyl thyroid cancer are influenced by radiation exposure and age at exposure, in addition to the neoplastic process.     

Effect of thyroid status on microsomal enzymes during liver regeneration in the rat

The effects of thyroid status upon cyt. P 450 concentration and ethoxycoumarin deethylase, benzopyrene hydroxylase and UDP-glucuronosyltransferase activities in the liver microsome fraction were far more important in partially hepatectomized rats than in control animals. The partial hepatectomy simultaneously lowered the MFO enzymes activities in the hepatic microsome fraction and made them more sensitive to thyroid hormones effects.     

The thyroid status and lipid metabolism of the suslik Citellus parryi during hibernation

Thyroid hormone concentrations in blood were elevated all through the hibernating season while thyroid gland showed morphological signs of high activity. The specificities of lipid metabolism, increased fatty acid unsaturation and reduced cholesterol/phospholipids molar ratio in plasma membranes were attributed to high thyroid activity.     

The significance of the latent period in thyroid hormone induced tissue regression during amphibian metamorphosis

Tail fin disks removed from tadpoles of Rana pipiens that were immersed in thyroxine or triiodothyronine for 3 days (referred to as donors) were fused to premetamorphic tail fin blocks that had never been exposed to this hormone (referred to as recipients) so that triplets were formed, consisting of one recipient tail block sandwiched between two donor tail fin blocks. Such recipient tail blocks responded with characteristic resorptive activity within 24 or 48 hr, instead of the minimum 72-hr latent period normally intervening in donor blocks, until shrinkage was initiated in response to triiodothyronine (T₃) or tetraiodothyronine (T₄). The presence of T₃ or T₄ hormone was not required continuously throughout the latent period. Hormone could be withdrawn after 30 hr contact in vivo and after 24 hr contact in vitro without interfering with the rate of tissue regression of tadpole tail fins, suggesting that the “latent period” probably does not coincide with the “critical period” during which subtle biochemical changes presumably occur that precede regression of the tadpole tail during metamorphosis. It is suggested that during the latent period active intermediates may be synthesized that are subsequently transferred from donor tail fins to recipients, thus reducing the latent period of the latter.     

Effect of nitrates in drinking water on the prevalence of thyroid cancer and other thyroid diseases: a literature review and post-Chernobyl research experience in Belarus

Nitrate content in the groundwater of Belarus has increased dramatically due to intensive use of nitrogen fertilizers in agriculture. Research performed during the post-Chernobyl period showed that the increased incidence of thyroid cancer is affected both by the level of nitrates in the groundwater and the radiation dose to which the thyroid was exposed.     

The role of thyroid status in the cardiac protection during heat adaptation in rats

Thyroid status is important for realization of protective cardiac effects on heat adaptation as evaluated by the changes induced by the heat stress (40-42 degree C during 3 hrs) in parameters of the heart main contractile function and in contraction of lipid peroxidation products. Adaptation to heat against the background of administration of small doses of thyroid in potentiated these effects, whereas heat training against the background of thyrostatic agent Mercasolil prevented them.     

The changes of thyroglobulin in the lysosomal particles of thyroid during the postnatal period in rats.

The distribution of radioactivity and protein-SH groups was studied in neonatal rats injected with 125-I- in the 15,000 g pellets of thyroid glands to obtain information about the colloid which undergoes phagocytosis by lysosomes. The 15,000 g pellet was solubilized in Triton X--100. The soluble portion was enhanced on the 16th day of age, whereas the portion of the insoluble fraction remained almost unchanged. The content of protein-SH groups in the insoluble fraction decreased with age and was increased in the soluble fraction. The concentration of immunoreactive thyroid stimulating hormone (TSH) in the pituitary and in the blood of rats during ontogenesis was higher on the first day after delivery, then decreased within the first seven days and again markedly increased during the third postnatal week. It was concluded that higher amounts of Triton soluble thyroglobulin occurring during the postnatal period in rats reflects the availability of more substrate, i.e. thyroglobulin for pinocytosis and partially depends upon the TSH level. These findings also support the suggestion on maturation of the pituitary-thyroid system during the postnatal period in rats.     

Effects of anti-thyrotropin-releasing hormone anti-serum treatment during the neonatal period on the development of rat thyroid function

Effects of anti-thyrotropin-releasing hormone (TRH) anti-serum treatment during the neonatal period on the development of rat thyroid function were studied. On postnatal days 2 and 4, rats were administered anti-TRH anti-serum ip, and they were serially decapitated at the 4th, 8th and 12th week after birth. TRH, thyrotropin (TSH), thyroxine (T4) and 3,3',5-triiodothyronine (T3) were measured by radioimmunoassay. Immunoreactive TRH (ir-TRH) in the hypothalamus did not change significantly after anti-TRH anti-serum treatment, and plasma ir-TRH tended to decrease. The plasma ir-TRH and TSH responses to cold were significantly inhibited. The plasma TSH response to TRH was also significantly inhibited. The plasma basal TSH levels were significantly lower than in controls. The plasma T4 and T3 levels were found to be lower than those in the controls. Findings suggested that treatment with anti-TRH anti-serum during the neonatal period disturbed the development of rat thyroid function, inhibiting TRH release and altering thyrotroph sensitivity to TRH.     

Effects of single-dose external gamma irradiation on rat thyroid status as observed during the year

We studied the rat thyroid status depending on the dose of external radiation and the time passed after the exposure. The experiments were carried out on female albino Wistar rats. The doses absorbed amounted to 0.25; 0.5; 1.0; 2.0 and 5.0 Gy. The animals were decapitated after 3, 6, 24 hours and 7, 30, 180 and 365 days following the radiation. The blood serum was assayed for the contents of thyroxin (T4) and triiodothyronine (T3) using a radioimmunological technique. The liver tissue was assayed spectrophotometrically for the activity of thyroid-induced NADP malate dehydrogenase (NADP-MDH). No changes were found in the blood thyroid hormone contents within short periods after the radiation effect. After 6 hours the T4 levels was 1.2-1.3-fold decreased in the blood of rats receiving the radiation doses of 1.0; 2.0; and 5.0 Gy. After a day the T4 concentration was diminished by 1.21-193-fold in all the experimental animals independently of the radiation dose and that of T3--in 2.0 Gy--and 5.0 Gy--irradiated group. After 7 days following the radiation the T4 and T3 contents remained to be decreased by 1.37-1.75 fold and those of NADP-MDH--by 1.3-1.8-fold in all the animal groups. In a month, the low dose-treated animals (0.25, 0.5, 1.0 Gy) showed the level of thyroid hormones reduced to the control values, whereas the 2.0 and 5.0 Gy--treated rats demonstrated this reduction only by 6 months. The decreased concentration of blood thyroid hormones was due not to the activation of their peripheral metabolism, but, probably, to inhibition of their biosynthesis in thyroid cells under conditions of radiation-induced activation of oxidative stress.     

Long-term effect on the immune status of defined diets during the early postnatal period in the rat

Germ-free and conventional infant rats delivered by hysterectomy were reared artificially, using one of two diets--diet LNa (with a high saturated fatty acid content) and diet K 50 (with a high unsaturated fatty acid content). Animals reared for a short time (up to 5 days) after birth on the LNa diet had a low antibody (PFC = plaque-forming lymphocyte) response and low resistance to Yoshida's sarcoma. Rats reared on the K 50 diet had the same response as the suckled controls. The first 5 days after birth were found to be the decisive period for long-term consequences of nutrition.