Search

The study examined transcriptional regulation of adrenal zona reticularis development in male Wistar rats exposed to low doses of endocrine disruptor dichlorodiphenyltrichloroethane (DDT) prenatally and postnatally. At pubertal age, zona reticularis demonstrated a retarded growth with a low proliferative activity of its cells. At this age, zona reticularis was characterized with overexpression of β-catenin by steroid-producing cells; a high percentage of cells with membrane and cytoplasmic localization of β-catenin, and reduced number of cells with nuclear β-catenin attesting to insufficient activation of Wnt signaling. Expression of transcriptional factor Oct4 by reticularis cells was down-regulated indicating their diminished proliferative potency. No significant alterations in Sonic Hedgehog expression were observed. Thus, DDT-provoked disorders of transcriptional regulation result in abnormal development of zona reticularis thereby disturbing sexual maturation in males.

Skin represents a natural barrier and a site of contact with antigens. Skin demonstrates higher intensity of immune reactions compared to other organs, which implies the additional cell interactions. Dendritic cells are traditionally considered as the main antigen­presenting cells of the skin, however, in recent years, some data on the ability of another population, mast cells, to perform antigen­presenting functions have appeared. The review presents novel data on the interaction of skin dendritic and mast cells, including formation of immune synapses, exchange of surface molecules, and transfer of secretory material. The authors have developed and presented a new concept for the initiation and modulation of immune responses provided by the functional dendritic cell–mast cell complex. Keywords: dendritic cells, mast cells, skin, immunological synapse, degranulatory synapse, immune response

The study is aimed at elucidation of ultrastructural mechanisms underlying impaired aldosterone synthesis by glomerulosa cells in Wistar rats exposed to low doses of endocrine disrupter DDT during prenatal and postnatal development. Analysis of rat zona glomerulosa histology and function during the pubertal and postpubertal periods showed that exposure to endocrine disrupter DDT disturbs its development and reduced the production of aldosterone. Electron microscopy showed that changes in the aldosterone synthesis are related to impaired reorganization of the mitochondrial apparatus, one of the leading factors in the regulation of steroidogenesis, in glomerulosa cells in DDT-exposed rats during puberty.

We studied histophysiology of the adrenal medulla in adult (70-day-old) male Wistar rats developmentally exposed to low doses of endocrine disruptor DDT. It was found that exposure to DDT during the prenatal and postnatal ontogeny decelerated the development of the adrenal medulla and reduced the synthesis of tyrosine hydroxylase, the rate-liming enzyme of catecholamine synthesis, in chromaffin cells, which led to a decrease in epinephrine secretion into the blood.

Exposure of developing organism to endocrine disrupting chemicals is an emerging scientific problem of wide concern. Dichlorodiphenyltrichloroethane (DDT) is considered to be one of the most wide-spread endocrine disruptors. Exposure of humans to low doses of DDT occurs around the globe. The present study was undertaken to elucidate the role of canonical Wnt-signaling in postnatal morphogenesis of the adrenal medulla in intact and developmentally exposed to DDT rats. The research was performed on male Wistar rats in pubertal (42nd day) and postpubertal (70th day) periods which were exposed to dDt during both prenatal and postnatal and only postnatal development. Adrenal histology showed enlargement of the adrenal medulla due to equal development of chromaffine cells and blood vessels from 42nd to 70th day in the intact rats and slower development of the adrenal medulla in the prenatally and postnatally exposed rats. Age-dependent changes in activation of canonical Wnt-signaling in the intact rats and altered Wnt-signaling along with impaired postnatal morphogenesis of the adrenal medulla in the DDT-exposed rats were found. The data obtained shows that prenatal exposure to DDT unlike postnatal exposure causes more profound decrease in activation of canonical Wnt-signaling in adrenal chromaffine cells and impairs development of adrenal medulla parenchyma.

This study is focused on the role of the canonical Wnt-signaling pathway in morphogenesis and regeneration of the adrenal cortex in rats exposed to the endocrine disruptor dichlorodiphenyltrichloroethane (DDT) during prenatal and postnatal development. Hypoplasia of the zona glomerulosa and, to a greater extent, of the zona reticularis was associated with suppression of canonical Wnt. This data indicates the role of the Wnt-signaling pathway in the development of the zona reticularis. Circulatory disorders in the adrenal cortex led to focal necrosis of the zona fasciculata and subsequent activation of cell proliferation and regeneration, mediated by the inhibition of the canonical Wnt in it. Thus, the disturbance of activation of the canonical Wnt-signaling pathway can be considered as a mechanism of the disrupting effect of DDT in postnatal development.

We studied secretory activity of adrenal zona fasciculata cells in pubertal rats exposed to low doses of endocrine disrupter DDT during prenatal and postnatal periods and only during postnatal period. In exposed animals, circulatory disturbances leading to degeneration and necrosis of cells as well as regeneration foci were revealed in the outer zona fasciculata. In rats exposed to DDT during the prenatal and postnatal periods, compensatory increase in secretory activity of cells due to increase in mitochondria content was noted in the inner zona fasciculata, which determined elevated serum concentration of corticosterone. In rats exposed to DDT only during the postnatal development, functional activity of zona fasciculata cells was suppressed, which attested to delayed upregulation of secretion.

The aim of the investigation was to study morphological and cytophysiological changes in the adult rat adrenal medulla after prenatal and postnatal exposure to endocrine-disrupting chemical dichlorodiphenyltrichloroethane (DDT). Materials and Methods The experiment was carried out on male Wistar rats (n=30). The rats were exposed to low doses of DDT during prenatal and postnatal development (n=10) and during postnatal development (n=10) only. The average daily intake of DDT by rats was 3.30±0.14 μg/kg. The control (n=10) and experimental animals were sacrificed at the age of 10 weeks (post-puberty), when rat adrenal glands reached their maximum development. Histological samples of the equatorial sections of the adrenal glands were prepared. The adrenal medulla was studied using light microscopy and computer morphometry. Immunohistochemistry was performed to evaluate tyrosine hydroxylase expression in chromaffin cells. Plasma epinephrine content was measured using enzyme-linked immunosorbent assay. Results Postnatal exposure of rats to low doses of the endocrine disruptor was found to interfere with adrenal medulla development and cytophysiology of chromaffin cells. Prenatal and postnatal exposure resulted in more profound delay in adrenal medulla development of adult rats as compared to the values of rats exposed postnatally, which was manifested by reduced area of the adrenal medulla and reduced total area of chromaffin cells in its section. Postnatal exposure is manifested by more significant functional disorders including decreased synthesis of tyrosine hydroxylase enzyme in the cytoplasm of chromaffin cells and elevated number of tyrosine-hydroxylase-negative cells in the medulla section, leading to a decrease in plasma epinephrine concentration. Conclusion Exposure to low doses of DDT in the early stages of development leads to morphological and cytophysiological changes in the adult rat adrenal medulla and, therefore, reduced functional activity of chromaffin cells, which allows considering the endocrine disruptor DDT a potential risk factor disrupting the function of the neuroendocrine system.

Affection of developing organism by endocrine disruptors is an actively studied topic of scientific research in medicine, caused by a progressive increase in the number of diseases and disorders in the development of the reproductive and endocrine systems. Dichlorodiphenyltrichloroethane (DDT) is the most wide-spread endocrine disruptor. Low-dose exposure to DDT disrupts production of sex steroids by poorly known mechanisms. The research was focused on assessment of morphology of adrenal zona reticularis and fine structure of reticularis endocrine cells and changes in their secretory machinery in rats exposed to low doses of DDT during prenatal and postnatal development. The experimental group consisted of the male offspring of dams, who daily consumed solution of o, p-DDT at a concentration of 20 µg/l, from mating until the end of the suckling period in offspring, which then consumed a similar solution of DDT. Daily consumption of DDT by the offspring was 2,90±0,12 µg/kg body weight. These doses corresponds to levels of exposure of humans to DDT with food products taking to account the differences in metabolism of DDT in rats and humans. The control and experimental rats were sacrificed on the 42nd day of postnatal development (pubertal period). Light microscopy of adrenal sections found hypoplasia of zona reticularis in rats after developmental exposure to endocrine disruptor. Electron microscopy revealed prevalence of cells with low lipid content in cytoplasm, less developed endoplasmatic reticulum and Golgi complex and signs of lowered functional activity of mitochondria indicated decreased steroidogenic activity of zona reticularis. These findings explain previously found impaired production of sex steroids in DDT-exposed rats. Electron microscopy also found that disruption of steroid secretion in reticularis cells by DDT led to compensatory enlargement of cells and increase in number of mitochondria per m2 of cytoplasm indicating development of structural support for long-term enhancement of steroidogenic activity.

Sex differences in the expression of iodide transporter SLC5A5 and thyroid peroxidase in thyroid follicular epithelium and thyroid serum profile were assessed in pubertal rats exposed to endocrine disruptor DDT starting from the first postnatal day. It was found that exposure to DDT reduced expression of SLC5A5 in peripheral regions of thyroid lobes in males and in central regions in females. The most pronounced sex differences were observed in thyroid peroxidase expression that remained sensitive to thyroid stimulating hormone regulation in males and lost sensitivity to pituitary stimulation in females after exposure to disruptor, which determines more pronounced hypothyroidism in females.

The structure of the thymus in newborn rats exposed in utero to endocrine disruptor DDT was studied. We found that exposure to low doses of DDT during pregnancy does not disturb thymus formation in the offspring, but leads to changes in its structure than manifested as slower lobulation, wider epithelium-free areas in the cortex, and lower number of thymic corpuscles in the medulla. The results attest to sensitivity of the reticuloepithelial stroma of the thymus to the effects of endocrine disruptor.

We studied the expression of transcriptional factors regulating postnatal morphogenesis of the adrenal zona fasciculata in rats after developmental exposure to endocrine disruptor DDT. It was found that tissue reparation after trophic disorders and cell death triggered by prenatal and postnatal exposure to DDT was accompanied by an increase in the number of Oct4- and Shh-expressing cells forming a pool located outside the regeneration zones and involved in the maintenance of tissue homeostasis in the zona fasciculata. DDT exposure also disrupted the expression of antiproliferative factor Hhex. The data showed that proliferation of fasciculata cells after termination of adrenal cortex growth was downregulated by inhibition of the expression of Oct4 and Shh and suppression of canonical Wnt signaling, i.e. due to a decrease in the reserve cell pool essential for physiological regeneration, which can reduce the reactive potential of the zona fasciculata.

We studied the formation of proliferative response of thymic lymphocytes to T-cell mitogen in rats exposed to endocrine disrupter DDT during prenatal and postnatal ontogeny. Developmental exposure to the endocrine disruptor was found to attenuate proliferative response during puberty and adulthood due to maintenance of higher proliferation rate of thymic lymphocytes in comparison with age-matched controls. Insufficient proliferative response to mitogens in rats developmentally exposed to the endocrine disrupter increases the risk of impairment of cell-mediated reactions of adaptive immunity.

We analyzed the expression of transcriptional factor Oct4 in rat adrenal cortical cells during postnatal development. It was found that Oct4 is expressed by typical cortical cells of the zona glomerulosa, zona fasciculata, and zona reticularis in pubertal and postpubertal periods. The maximum number of Oct4+ cells was found in the zona glomerulosa. An inverse correlation between the number of Oct4+ glomerulosa cells and serum level of aldosterone both in pubertal and postpubertal periods was revealed. After puberty, the number of Oct4+ glomerulosa cells directly correlated with the number of Ki-67+ cells. A hypothesis was put forward that Oct4 is involved in postnatal morphogenesis, regeneration, and functioning of the adrenal cortex.

The effects of endocrine disrupters of transcriptional control of morphogenesis are poorly studied. Changes in the expression of transcriptional factor PRH and proliferation of adrenal cortical cells were analyzed in pubertal and postpubertal rats exposed prenatally and postnatally to low doses of endocrine disrupter DDT. In rats exposed to DDT, the expression of PRH and proliferation of adrenal cortical cells differed from those in control rats. Association between these parameters was weakened in the zona glomerulosa and zona reticularis and was absent in the zona fasciculata. These findings suggest that exposure to DDT in pre- and postnatal periods impairs the regulation of proliferative processes by transcriptional factor PRH in all zones of rat adrenal cortex, which can be a mechanism of the disruptive action of DDT.

Transcription factor PRH/Hhex suppresses cell proliferation and contributes to regulation of prenatal and postnatal ontogeny. Neurons of the peripheral nervous system and chromaffin cells were previously considered as non-expressing PRH/Hhex in postnatal development. In our study, the expression of PRH/Hhex in chromaffin cells of rat adrenal glands and association between the decrease of proliferation and activation of PRH/Hhex expression were demonstrated.