International Journal of Molecular Sciences

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14 pages, 2450 KiB

Open AccessArticle

Impact of Prenatal and Postnatal Exposure to Endocrine Disrupter DDT on Adrenal Medulla Function

by Nataliya V. Yaglova, Sergey S. Obernikhin, Dibakhan A. Tsomartova, Valentin V. Yaglov, Svetlana V. Nazimova, Elina S. Tsomartova, Ekaterina P. Timokhina, Elizaveta V. Chereshneva, Marina Y. Ivanova and Tatiana A. Lomanovskaya

Int. J. Mol. Sci. 2022, 23(9), 4912; https://doi.org/10.3390/ijms23094912 - 28 Apr 2022

Cited by 4 | Viewed by 1986

Abstract

Epinephrine is the most abundant catecholamine hormone, produced by the nervous system and adrenal glands. Endocrine disruption of epinephrine synthesis, secretion and signaling is less studied than steroid and thyroid hormones. Dichlorodiphenyltrichloroethane (DDT) is recognized as one of the most prominent environmental contaminants [...] Read more.

Epinephrine is the most abundant catecholamine hormone, produced by the nervous system and adrenal glands. Endocrine disruption of epinephrine synthesis, secretion and signaling is less studied than steroid and thyroid hormones. Dichlorodiphenyltrichloroethane (DDT) is recognized as one of the most prominent environmental contaminants with a long half-life. It is a potent endocrine disrupter affecting sex steroid, mineralocorticoid, glucocorticoid and thyroid hormone production. Exposure to low doses of DDT is universal and begins in utero. Therefore, we studied adrenal medulla growth and function in male Wistar rats exposed to low doses of DDT during prenatal and postnatal development until puberty and adulthood, as well as rats exposed to DDT since the first day of postnatal development. All the exposed rats demonstrated lowered epinephrine blood levels, gradually reducing with age. DDT was found to inhibit the synthesis of tyrosine hydroxylase and affect the mitochondrial apparatus of epinephrine-producing cells during puberty and even after maturation. Low-dose exposure to DDT from birth resulted in more pronounced changes in adrenomedullary cells and a more profound decrease (up to 50%) in epinephrine secretion in adult rats. Prenatal onset of exposure demonstrated a mild effect on epinephrine-producing function (30% reduction), but was associated with lower rate of adrenal medulla growth during maturation and 25% smaller adrenal medullar size in adult rats. All subjects exposed to low doses of DDT failed to develop adaptive changes and restore proper epinephrine production. These results indicate a dysmorphogenetic effect of prenatal exposure and disruption of secretory function of adrenal chromaffin cells by postnatal exposure to DDT. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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19 pages, 2572 KiB

Open AccessArticle

The Link between Activities of Hepatic 11beta-Hydroxysteroid Dehydrogenase-1 and Monoamine Oxidase-A in the Brain Following Repeated Predator Stress: Focus on Heightened Anxiety

by Vadim Tseilikman, Maxim Lapshin, Igor Klebanov, George Chrousos, Maria Vasilieva, Anton Pashkov, Julia Fedotova, David Tseilikman, Vladislav Shatilov, Eugenia Manukhina, Olga Tseilikman, Alexey Sarapultsev and H. Fred Downey

Int. J. Mol. Sci. 2022, 23(9), 4881; https://doi.org/10.3390/ijms23094881 - 28 Apr 2022

Cited by 8 | Viewed by 2625

Abstract

We investigated the presence of a molecular pathway from hepatic 11-βHSD-1 to brain MAO-A in the dynamics of plasma corticosterone involvement in anxiety development. During 14 days following repeated exposure of rats to predator scent stress for 10 days, the following variables were [...] Read more.

We investigated the presence of a molecular pathway from hepatic 11-βHSD-1 to brain MAO-A in the dynamics of plasma corticosterone involvement in anxiety development. During 14 days following repeated exposure of rats to predator scent stress for 10 days, the following variables were measured: hepatic 11-βHSD-1 and brain MAO-A activities, brain norepinephrine, plasma corticosterone concentrations, and anxiety, as reflected by performance on an elevated plus maze. Anxiety briefly decreased and then increased after stress exposure. This behavioral response correlated inversely with plasma corticosterone and with brain MAO-A activity. A mathematical model described the dynamics of the biochemical variables and predicted the factor(s) responsible for the development and dynamics of anxiety. In the model, hepatic 11-βHSD-1 was considered a key factor in defining the dynamics of plasma corticosterone. In turn, plasma corticosterone and oxidation of brain ketodienes and conjugated trienes determined the dynamics of brain MAO-A activity, and MAO-A activity determined the dynamics of brain norepinephrine. Finally, plasma corticosterone was modeled as the determinant of anxiety. Solution of the model equations demonstrated that plasma corticosterone is mainly determined by the activity of hepatic 11-βHSD-1 and, most importantly, that corticosterone plays a critical role in the dynamics of anxiety following repeated stress. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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14 pages, 1320 KiB

Open AccessCommunication

Deficiency of Thyroid Hormone Reduces Voltage-Gated Na⁺ Currents as Well as Expression of Na⁺/K⁺-ATPase in the Mouse Hippocampus

by Sivaraj Mohana Sundaram, Romy Marx, Heiko M. Lesslich and Irmgard D. Dietzel

Int. J. Mol. Sci. 2022, 23(8), 4133; https://doi.org/10.3390/ijms23084133 - 8 Apr 2022

Cited by 2 | Viewed by 2487

Abstract

Mice lacking functional thyroid follicular cells, Pax8^−/− mice, die early postnatally, making them suitable models for extreme hypothyroidism. We have previously obtained evidence in postnatal rat neurons, that a down-regulation of Na⁺-current density could explain the reduced excitability of the [...] Read more.

Mice lacking functional thyroid follicular cells, Pax8^−/− mice, die early postnatally, making them suitable models for extreme hypothyroidism. We have previously obtained evidence in postnatal rat neurons, that a down-regulation of Na⁺-current density could explain the reduced excitability of the nervous system in hypothyroidism. If such a mechanism underlies the development of coma and death in severe hypothyroidism, Pax8^−/− mice should show deficits in the expression of Na⁺ currents and potentially also in the expression of Na⁺/K⁺-ATPases, which are necessary to maintain low intracellular Na⁺ levels. We thus compared Na⁺ current densities in postnatal mice using the patch-clamp technique in the whole-cell configuration as well as the expression of three alpha and two beta-subunits of the Na⁺/K⁺-ATPase in wild type versus Pax8^−/− mice. Whereas the Na⁺ current density in hippocampal neurons from wild type mice was upregulated within the first postnatal week, the Na⁺ current density remained at a very low level in hippocampal neurons from Pax8^−/− mice. Pax8^−/− mice also showed significantly decreased protein expression levels of the catalytic α1 and α3 subunits of the Na⁺/K⁺-ATPase as well as decreased levels of the β2 isoform, with no changes in the α2 and β1 subunits. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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17 pages, 3226 KiB

Open AccessArticle

The Influence of Interaction between Cadmium with 17β-Estradiol, 2-Methoxyestradiol and 16α-Hydroxyestrone on Viability and p-Glycoprotein in Ovarian Cancer Cell Line

by Ewa Sawicka, Jolanta Saczko, Julita Kulbacka, Martyna Szydełko, Beata Szymańska and Agnieszka Piwowar

Int. J. Mol. Sci. 2022, 23(5), 2628; https://doi.org/10.3390/ijms23052628 - 27 Feb 2022

Cited by 5 | Viewed by 2037

Abstract

Occupational and environmental exposure to xenoestrogens, a subgroup of endocrine disruptors (EDCs), can affect the endocrine system and increase the risk of cancer, primarily the hormone-dependent kind. This type of cancer includes ovarian cancer, which is the leading cause of death from gynecological [...] Read more.

Occupational and environmental exposure to xenoestrogens, a subgroup of endocrine disruptors (EDCs), can affect the endocrine system and increase the risk of cancer, primarily the hormone-dependent kind. This type of cancer includes ovarian cancer, which is the leading cause of death from gynecological tumors. The aim of this study was to assess the role of 17β-estradiol and its metabolites: 2-MeOE2, 16α-OHE1 in exposure to the metalloestrogen cadmium. The effect of interactions of cadmium with estrogens on the viability of cells in malignant ovarian cancer cells SKOV-3 was investigated, both in simultaneous action and in the pre-incubation model. There are no known interactions between estrogens and cadmium in ovarian cancer cells. Due to the frequent occurrence of multidrug resistance (MDR) in ovarian cancer, the effects of estrogens and cadmium on MDR in SKOV-3, measured as P-glycoprotein (P-gp), were assessed. An interaction study showed that E2 had an antagonistic effect on cadmium-induced cell damage, while 2-MeOE2 showed less of a protective effect in combination with CdCl₂ than E2. There were two types of interaction: toxic synergism and beneficial antagonism. E2 and cadmium increased P-gp expression in SKOV-3 cells, while 2-MeOE2 decreased P-gp expression to a potentially beneficial effect on MDR prevention. The obtained results constitute an interesting starting point for further research in the field of interactions between estrogens and xenoestrogens in ovarian cancer. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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13 pages, 8748 KiB

Open AccessArticle

Impairment of the Hypothalamus–Pituitary–Thyroid Axis Caused by Naturally Occurring GATA2 Mutations In Vitro

by Yuki Sakai, Kenji Ohba, Shigekazu Sasaki, Akio Matsushita, Hiroko Misawa Nakamura, Go Kuroda, Daisuke Tsuriya, Miho Yamashita and Takafumi Suda

Int. J. Mol. Sci. 2021, 22(18), 10015; https://doi.org/10.3390/ijms221810015 - 16 Sep 2021

Cited by 3 | Viewed by 2457

Abstract

The transcription factor GATA2 regulates gene expression in several cells and tissues, including hematopoietic tissues and the central nervous system. Recent studies revealed that loss-of-function mutations in GATA2 are associated with hematological disorders. Our earlier in vitro studies showed that GATA2 plays an [...] Read more.

The transcription factor GATA2 regulates gene expression in several cells and tissues, including hematopoietic tissues and the central nervous system. Recent studies revealed that loss-of-function mutations in GATA2 are associated with hematological disorders. Our earlier in vitro studies showed that GATA2 plays an essential role in the hypothalamus–pituitary–thyroid axis (HPT axis) by regulating the genes encoding prepro-thyrotropin-releasing hormone (preproTRH) and thyroid-stimulating hormone β (TSHβ). However, the effect of GATA2 mutants on the transcriptional activity of their promoters remains unelucidated. In this study, we created five human GATA2 mutations (R308P, T354M, R396Q, R398W, and S447R) that were reported to be associated with hematological disorders and analyzed their functional properties, including transactivation potential and DNA-binding capacity toward the preproTRH and the TSHβ promoters. Three mutations (T354M, R396Q, and R398W) within the C-terminal zinc-finger domain reduced the basal GATA2 transcriptional activity on both the preproTRH and the TSHβ promoters with a significant loss of DNA binding affinity. Interestingly, only the R398W mutation reduced the GATA2 protein expression. Subsequent analysis demonstrated that the R398W mutation possibly facilitated the GATA2 degradation process. R308P and S447R mutants exhibited decreased transcriptional activity under protein kinase C compared to the wild-type protein. In conclusion, we demonstrated that naturally occurring GATA2 mutations impair the HPT axis through differential functional mechanisms in vitro. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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Review

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16 pages, 14938 KiB

Open AccessReview

Kisspeptin Neurons and Estrogen–Estrogen Receptor α Signaling: Unraveling the Mystery of Steroid Feedback System Regulating Mammalian Reproduction

by Yoshihisa Uenoyama, Naoko Inoue, Sho Nakamura and Hiroko Tsukamura

Int. J. Mol. Sci. 2021, 22(17), 9229; https://doi.org/10.3390/ijms22179229 - 26 Aug 2021

Cited by 42 | Viewed by 8349

Abstract

Estrogen produced by ovarian follicles plays a key role in the central mechanisms controlling reproduction via regulation of gonadotropin-releasing hormone (GnRH) release by its negative and positive feedback actions in female mammals. It has been well accepted that estrogen receptor α (ERα) mediates [...] Read more.

Estrogen produced by ovarian follicles plays a key role in the central mechanisms controlling reproduction via regulation of gonadotropin-releasing hormone (GnRH) release by its negative and positive feedback actions in female mammals. It has been well accepted that estrogen receptor α (ERα) mediates both estrogen feedback actions, but precise targets had remained as a mystery for decades. Ever since the discovery of kisspeptin neurons as afferent ERα-expressing neurons to govern GnRH neurons, the mechanisms mediating estrogen feedback are gradually being unraveled. The present article overviews the role of kisspeptin neurons in the arcuate nucleus (ARC), which are considered to drive pulsatile GnRH/gonadotropin release and folliculogenesis, in mediating the estrogen negative feedback action, and the role of kisspeptin neurons located in the anteroventral periventricular nucleus-periventricular nucleus (AVPV-PeN), which are thought to drive GnRH/luteinizing hormone (LH) surge and consequent ovulation, in mediating the estrogen positive feedback action. This implication has been confirmed by the studies showing that estrogen-bound ERα down- and up-regulates kisspeptin gene (Kiss1) expression in the ARC and AVPV-PeN kisspeptin neurons, respectively. The article also provides the molecular and epigenetic mechanisms regulating Kiss1 expression in kisspeptin neurons by estrogen. Further, afferent ERα-expressing neurons that may regulate kisspeptin release are discussed. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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15 pages, 11611 KiB

Open AccessReview

The Role of Histone Deacetylase 3 Complex in Nuclear Hormone Receptor Action

by Sumiyasu Ishii

Int. J. Mol. Sci. 2021, 22(17), 9138; https://doi.org/10.3390/ijms22179138 - 24 Aug 2021

Cited by 15 | Viewed by 3208

Abstract

Nuclear hormone receptors (NRs) regulate transcription of the target genes in a ligand-dependent manner in either a positive or negative direction, depending on the case. Deacetylation of histone tails is associated with transcriptional repression. A nuclear receptor corepressor (N-CoR) and a silencing mediator [...] Read more.

Nuclear hormone receptors (NRs) regulate transcription of the target genes in a ligand-dependent manner in either a positive or negative direction, depending on the case. Deacetylation of histone tails is associated with transcriptional repression. A nuclear receptor corepressor (N-CoR) and a silencing mediator for retinoid and thyroid hormone receptors (SMRT) are the main corepressors responsible for gene suppression mediated by NRs. Among numerous histone deacetylases (HDACs), HDAC3 is the core component of the N-CoR/SMRT complex, and plays a central role in NR-dependent repression. Here, the roles of HDAC3 in ligand-independent repression, gene repression by orphan NRs, NRs antagonist action, ligand-induced repression, and the activation of a transcriptional coactivator are reviewed. In addition, some perspectives regarding the non-canonical mechanisms of HDAC3 action are discussed. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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11 pages, 507 KiB

Open AccessReview

An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone

by Kenji Ohba

Int. J. Mol. Sci. 2021, 22(12), 6611; https://doi.org/10.3390/ijms22126611 - 21 Jun 2021

Cited by 10 | Viewed by 3696

Abstract

Inappropriate secretion of thyroid-stimulating hormone (IST), also known as central hyperthyroidism, is a clinical condition characterized by elevated free thyroxine and triiodothyronine concentrations concurrent with detectable thyroid-stimulating hormone (TSH) concentrations. Similarly, the term syndrome of IST (SITSH) is widely used in Japan to [...] Read more.

Inappropriate secretion of thyroid-stimulating hormone (IST), also known as central hyperthyroidism, is a clinical condition characterized by elevated free thyroxine and triiodothyronine concentrations concurrent with detectable thyroid-stimulating hormone (TSH) concentrations. Similarly, the term syndrome of IST (SITSH) is widely used in Japan to refer to a closely related condition; however, unlike that for IST, an elevated serum free triiodothyronine concentration is not a requisite criterion for SITSH diagnosis. IST or SITSH is an important indicator of resistance to thyroid hormone β (RTHβ) caused by germline mutations in genes encoding thyroid hormone receptor β (TRβ) and TSH-secreting pituitary adenoma. Recent evidence has accumulated for several conditions associated with IST, including RTH without mutations in the TRβ gene (non-TR-RTH), the phenomenon of hysteresis involving the hypothalamus-pituitary-thyroid axis (HPT-axis), methodological interference, and Cushing’s syndrome after surgical resection. However, little information is available on the systematic pathophysiological aspects of IST in previous review articles. This report presents an overview of the recent advances in our understanding of the etiological aspects of IST that are relevant for diagnosis and treatment. Moreover, the report focuses on the potential mechanism of IST caused by hysteresis in the HPT-axis (lagging TSH recovery) in terms of epigenetic regulation. Full article

(This article belongs to the Special Issue Steroids and Lipophilic Hormones, and Their Actions 2.0)

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