Ágnes Inczefi-Gonda

Effect of Vitamin D3 Treatment in the Neonatal or Adolescent Age (Hormonal Imprinting) on the Thymic Glucocorticoid Receptor of the Adult Male Rat

Single neonatal treatment with 25 μg vitamin D3 significantly decreased the thymic glucocorticoid receptor density (Bmax) of 6-week-old male rats. In females, a similar treatment did not cause any changes. Single vitamin D3 treatment (50 μg) during adolescence (i.e. 6-week-old animals) significantly increased the glucocorticoid receptor density in adult (10-week-old) males. No significant changes in receptor affinity (Kd) could be observed. Considering that in earlier experiments similar neonatal treatments influenced bone mineral mass and sexual behavior, the hormonal imprinting effect of vitamin D3 and its harmful effect on the development of other members of the steroid receptor superfamily, seems to be unquestionable.

Transgenerational effect of a single neonatal benzpyrene treatment on the glucocorticoid receptor of the rat thymus

Hormonal imprinting is provoked perinatally by the appropriate hormone on its receptor, causing a life-long adjustment of the connection between the two participants. Faulty imprinting is caused by the presence of molecules similar to the hormone in this critical period, which results in a persistent alteration of the receptor. In the present experiment the transgenerational imprinting effect of a steroid-like environmental pollutant, benzpyrene, on the receptor binding capacity of filial thymic dexamethasone and uterine estrogen receptors was studied. The receptor density (Bmax) of the thymic glucocorticoid receptors of the males was reduced up to the third (F2) generation. In females this reduction was observed only in the F1 generation of treated animals. There was no change in receptor affinity (Kd). Uterine estrogen receptors were not subjected to transgenerational imprinting. The experiments demonstrate (1) the possibility of the transgenerational transmission of imprinting effect, (2) the differences of steroid receptors in different organs, and (3) the differences of males and females reactions from this aspect. The results call attention to the dangers of perinatal aromatic hydrocarbon exposition to the progeny generations.

Induction of steroid binding sites (receptors) and presence of steroid hormones in the unicellular Tetrahymena pyriformis

The unicellular Tetrahymena does not normally possess a steroid hormone (dehydroepiandrosterone, DHEA) or a glucocorticoid (dexamethasone) receptor, but both kinds of receptor can be induced in it by pretreatment (imprinting) with the adequate hormone. The specific receptors which arise are demonstrable experimentally. Examination of Tetrahymena cells for endogenous steroids by the radioimmunoassay (RIA) technique detected an appreciable concentration of DHEA and DHEA sulphate, and lesser concentrations of testosterone and estradiol in this unicellular organism.

Lasting impact of a single benzpyrene treatment in pre-natal and growing age on the thymic glucocorticoid receptors of rats

1. Rats exposed to benzpyrene in utero at 19 days of pre-natal life showed a relative decrease in the number of thymic glucocorticoid receptors at 6 weeks of age. 2. Primary exposure to benzpyrene at 6 weeks of age had a similar effect on females 4 weeks later, but did not change the glucocorticoid receptor number of males. 3. In utero exposure accounted for an increase in the fetal cytochrome P450 level within 1 day, whereas exposure at 6 weeks of age did not change it within 4 weeks. 4. It appears that exposure to benzpyrene gives rise to a faulty imprinting of the thymic glucocorticoid receptor in both fetal and growing age, to judge from a lasting change in the receptor number.

Impact of single neonatal serotonin treatment (hormonal imprinting) on the brain serotonin content and sexual behavior of adult rats

Hormonal imprinting takes place perinatally at the first encounter between the developing receptor and its target hormone. As a consequence of imprinting the receptor accomplishes its maturation and reaches the binding capacity characteristic to the adult age. In the excess of target hormone or presence of molecules similar to the target hormone, which are able to bind to the unmatured receptors, faulty imprinting develops with life-long consequences. At present, serotonin was given to neonatal rats and their sexual activity, brain serotonin level and steroid receptors binding capacity was measured in adult age. Brain serotonin level was significantly reduced in males striatum and parallel with this, males sexual activity significantly increased. In other regions of the male brain (prefrontal cortex, hypothalamus, hippocampus) there was a statistically non-significant tendency for a decrease in serotonin level. No significant differences were detected in female brain values, and there was only slight change in females sexual activity. There was also no change in the binding capacity of thymic glucocorticoid and uterine estrogen receptors. The experiments call attention to the possibility of perinatal imprinting by a neurotransmitter causing changes in brain neurotransmitter level for life, which is manifested in altered sexual activity.

Effect of a single treatment (imprinting) with genistein or combined treatment with genistein+benzpyrene on the binding capacity of glucocorticoid and estrogen receptors of adult rats

Hormonal imprinting takes place perinatally at the first encounter between the hormone and its target receptor. This is needed for the normal finishment of the maturation of the receptor–signal transduction system. In excess of foreign molecules, which can also bind to the receptor, faulty imprinting develops with life-long consequences. Genistein, a soybean phytosteroid (isoflavone), has estrogen-like effects and can be bound by steroid receptors. In the present experiments, single neonatal treatment (imprinting) with 20 m g of genistein, or combined treatment with 20 m g of genistein+20 m g of benzpyrene was done and liver and thymus glucocorticoid receptors of adult male and female rats and uterine estrogen receptors were studied. There was no difference in the binding capacity of uterine estrogen receptors. Genistein treatment alone caused a significant reduction of liver glucocorticoid receptor density in males; however, there were no other significant alterations. After combined genistein+benzpyrene treatment, more than half of the thymus and liver glucocorticoid receptor values significantly changed. The results call attention to the imprinting-modifying effect of a second (environmental) imprinter.

H1-receptor blocker antihistamine, terfenadine durably influences the glucocorticoid receptor, and lymphocyte histamine content of weanling rats.

Hormonal imprinting takes place perinatally when a hormone and its maturing target receptor meet. As a consequence of imprinting the receptor accomplishes its maturation reaching the binding capacity characteristic to the adult age. In this critical period the presence of foreign molecules which are able to bind to the receptor can cause faulty imprinting with life-long consequences. In the recent years it was cleared that not only receptors are influenced by faulty imprinting, however, also the hormone production of the given cell. In addition imprinting was provoked at non-perinatal periods (adolescence and adult age) in cytogenic organs. In the present experiment the prolonged effect of a non-perinatal imprinting by an antihistamine to the histamine content of white blood cells and glucocorticoid receptors of liver and thymus was studied. Two weeks after 3-day terfenadine treatment at weaning, flow cytometry of peritoneal cells and blood lymphocytes for histamine, and receptor kinetic analysis of dexamethasone binding were done. Histamine content of blood lymphocytes and glucocorticoid receptor density of liver cells were significantly decreased. This means that a short treatment with a H(1)-receptor blocker antihistamine durably influences physiological indexes which were not known till now. This means that not only the acute effects, but the prolonged side-effects must be considered.

Insulin binding sites induced in the Tetrahymena by rat liver receptor antibody.

Abstract Tetrahvmena cells treated with purified rabbit anti bodies to rat hepatocellular membrane exhibited a consider able increase in binding capacity on reexposure to the antibody 24 h later. Insulin binding was similarly enhanced by preexposure to the antibody, and vice versa, preex posure to insulin enhanced the later binding of rat liver receptor antibodies. This suggests that (1) the Tetrahymena and the rat possess similar insulin receptors, and (2) the receptor antibody is also able to induce imprinting for itself as well as for insulin. Concanavalin-A, noted for binding overlap with insulin, failed to induce imprinting either for insulin or for antibodies to receptors, whereas the latter did induce imprinting for Concanavalin-A.

Benzpyrene exposure at 15 days of prenatal life reduces the binding capacity of thymic glucocorticoid receptors in adulthood

1. The offspring of female rats treated with a single dose of benzpyrene on day 15 of gestation showed in adulthood a significant relative decrease in the number of thymic glucocorticoid receptors, without an appreciable decrease in binding affinity. 2. There is experimental evidence that exposure to a hormone analogue in the early stage of organogenesis effects receptor development and the maternal organism fails to confer protection against that untoward influence.

Impact of neonatal treatment with cardioactive glycosides (digoxin, ouabain) on receptor binding capacity, blood level and cardiac function in the adult rat. Extension of the imprinting theory

A single neonatal treatment with a cardioactive glycoside (ouabain, digoxin) altered the response of the adult rat to digitaloid treatment. As demonstrated by RIA, re-exposure to digoxin at 2 months of age was followed within 30 min by a more than twofold increase in serum digoxin over the not pretreated control and, although a steady concentration decrease followed, the experimental rats still had a higher serum digoxin level than the controls at 4 h. In the not presensitized control group the serum digoxin peak appeared at 60 min at a considerably lower level than the 30-min maximum of the experimental rats. Neonatal pretreatment with ouabain depressed myocardial ouabain binding, but enhanced the Na+ K+ -ATPase activity. The above differences were conspicuous in the functional response, yet a greater atrial response to the positive inotropic action of K-strophanthoside and a greater ventricular response to beta adrenergic excitation were readily seen in the experimental group. It follows that not only hormones, but also other ligands acting at receptor level can be regarded as potential inducers of imprinting.