scholarly journals Testosterone Decreases Placental Mitochondrial Content and Cellular Bioenergetics

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 176 ◽  
Author(s):  
Jay S. Mishra ◽  
Chellakkan S. Blesson ◽  
Sathish Kumar
Keyword(s):  
Mitochondrial Dysfunction ◽  
Copy Number ◽  
Structural Damage ◽  
Plasma Testosterone ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Testosterone Levels ◽  
Mitochondrial Copy Number ◽  
Maternal Testosterone

Placental mitochondrial dysfunction plays a central role in the pathogenesis of preeclampsia. Since preeclampsia is a hyperandrogenic state, we hypothesized that elevated maternal testosterone levels induce damage to placental mitochondria and decrease bioenergetic profiles. To test this hypothesis, pregnant Sprague–Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg/day) from gestation day (GD) 15 to 19. On GD20, the placentas were isolated to assess mitochondrial structure, copy number, ATP/ADP ratio, and biogenesis (Pgc-1α and Nrf1). In addition, in vitro cultures of human trophoblasts (HTR-8/SVneo) were treated with dihydrotestosterone (0.3, 1.0, and 3.0 nM), and bioenergetic profiles using seahorse analyzer were assessed. Testosterone exposure in pregnant rats led to a 2-fold increase in plasma testosterone levels with an associated decrease in placental and fetal weights compared with controls. Elevated maternal testosterone levels induced structural damage to the placental mitochondria and decreased mitochondrial copy number. The ATP/ADP ratio was reduced with a parallel decrease in the mRNA and protein expression of Pgc-1α and Nrf1 in the placenta of testosterone-treated rats compared with controls. In cultured trophoblasts, dihydrotestosterone decreased the mitochondrial copy number and reduced PGC-1α, NRF1 mRNA, and protein levels without altering the expression of mitochondrial fission/fusion genes. Dihydrotestosterone exposure induced significant mitochondrial energy deficits with a dose-dependent decrease in basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity. In summary, our study suggests that the placental mitochondrial dysfunction induced by elevated maternal testosterone might be a potential mechanism linking preeclampsia to feto-placental growth restriction.

scholarly journals STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

2012 ◽  
Vol 20 (1) ◽  
pp. 53-64 ◽  
Author(s):  
Joanna M Day ◽  
Paul A Foster ◽  
Helena J Tutill ◽  
Fabien Schmidlin ◽  
Christopher M Sharland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumour Growth ◽  
Plasma Testosterone ◽  
Prostate Hyperplasia ◽  
Testosterone Levels ◽  
Concept Model ◽  
Body Weights ◽  
Type 3

17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17β-HSD type 3 (17β-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17β-HSD3 inhibitor with an IC50 of ∼200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17β-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17β-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1×107 cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17β-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17β-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.

Abstract 420: Mrs2 is the Authentic Mammalian Mitochondrial Mg 2+ Channel

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Prema Velusamy ◽  
Shanmughapriya Santhanam
Keyword(s):  
Copy Number ◽  
Mitochondrial Permeability Transition ◽  
Critical Role ◽  
Permeability Transition ◽  
Inner Mitochondrial Membrane ◽  
Metabolic Switch ◽  
Knock Out ◽  
Mitochondrial Copy Number

Magnesium (Mg 2+ ) is an important cation critical for cellular functions and tissue integrity. Mitochondria have been demonstrated to be capable of both accumulate and release Mg 2+ . However, the exact molecular machinery associated with mitochondrial Mg 2+ (mMg 2+ ) influx has not yet been delineated. In the present study we characterized the mammalian mMg 2+ channel, Mrs2 and comprehensively studied its role in energy metabolism. Protein flux, membrane fractionation and STED microscopy studies revealed Mrs2 to localize on the inner mitochondrial membrane with its N and C-terminus in the matrix. Western blot and qPCR analysis confirmed the ubiquitous distribution of Mrs2 in all metabolically active tissues. We adopted lentiviral based strategy to stably knock down (KD) Mrs2 in vitro . Primarily, the use of FRET-based mMg 2+ sensor, MitoMario showed a decreased influx of Mg 2+ into mitochondria in Mrs2 KD cells. This was further confirmed by patch clamping the mitoplasts of the control and Mrs2 KD cells. Because Mg 2+ is an important co-factor in the machineries that replicate, we next assessed the mitochondrial copy number. The decreased influx of mMg 2+ impacted the mitochondrial copy number and electron transport chain (ETC) complex assembly. The defective ETC assembly was marked by increased generation of mitochondrial reactive oxygen species, increased proton leak, decreased ATP levels, and also prompted a metabolic switch from mitochondrial oxidative phosphorylation to glucose oxidation in Mrs2 KD cells. Additionally, Mrs2 KD cells had an increased sensitivity to mROS-induced mitochondrial permeability transition pore opening. To further study the role of Mrs2 in cardiac mitochondrial metabolism and cellular energetics, we have successfully adopted the CRISPR/Cas9 mediated gene targeting strategy to generate the cardiac-specific Mrs2 knock out mouse model. Our study is the first of its kind to characterize the mitochondrial Mg 2+ channel and its impact on mitochondrial copy number and cell viability. Our findings not only identify Mrs2 as an authentic mitochondrial Mg 2+ channel, but also validates the critical role of mMg 2+ in maintaining the bioenergetic state of the cell.

scholarly journals Dra/AfaE Adhesin of Uropathogenic Dr/Afa+Escherichia coli Mediates Mortality in Pregnant Rats

2005 ◽  
Vol 73 (11) ◽  
pp. 7597-7601 ◽  
Author(s):  
K. Wroblewska-Seniuk ◽  
R. Selvarangan ◽  
A. Hart ◽  
R. Pladzyk ◽  
P. Goluszko ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Maternal Mortality ◽  
Double Mutant ◽  
Lethal Effect ◽  
In Vivo Studies ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
E Coli

ABSTRACT Escherichia coli bearing adhesins of the Dr/Afa family frequently causes urogenital infections during pregnancy in humans and has been associated with mortality in pregnant rats. Two components of the adhesin, Dra/AfaE and Dra/AfaD, considered virulence factors, are responsible for bacterial binding and internalization. We hypothesize that gestational mortality caused by Dr/Afa+ E. coli is mediated by one of these two proteins, Dra/AfaE or Dra/AfaD. In this study, using afaE and/or afaD mutants, we investigated the role of the afaE and afaD genes in the mortality of pregnant rats from intrauterine infection. Sprague-Dawley rats, on the 17th day of pregnancy, were infected with the E. coli afaE + afaD and afaE afaD + mutants. The clinical E. coli strain (afaE + afaD +) and the afaE afaD double mutant were used as positive and negative controls, respectively. The mortality rate was evaluated 24 h after infection. The highest maternal mortality was observed in the group infected with the afaE + afaD + strain, followed by the group infected with the afaE + afaD strain. The mortality was dose dependent. The afaE afaD double mutant did not cause maternal mortality, even with the highest infection dose. The in vivo studies corresponded with the invasion assay, where the afaE + strains were the most invasive (afaE + afaD strain > afaE + afaD + strain), while the afaE mutant strains (afaE afaD + and afaE afaD strains) seemed to be noninvasive. This study shows for the first time that the afaE gene coding for the AfaE subunit of Dr/Afa adhesin is involved in the lethal outcome of gestational infection in rats. This lethal effect associated with AfaE correlates with the invasiveness of afaE + E. coli strains in vitro.

ENDOCRINE TESTICULAR FUNCTION IN VIVO AND IN VITRO IN INFERTILE MEN

1979 ◽  
Vol 90 (3) ◽  
pp. 544-551 ◽  
Author(s):  
E. Nieschlag ◽  
E. J. Wickings ◽  
J. Mauss
Keyword(s):  
Leydig Cell ◽  
Cell Function ◽  
Testicular Tissue ◽  
Plasma Testosterone ◽  
Cell Hyperplasia ◽  
Testosterone Levels ◽  
Infertile Men ◽  
Before And After

ABSTRACT In order to detect any possible Leydig cell dysfunction associated with male infertility, the endocrine capacity of the testes was investigated in vivo and in vitro in 21 infertile men. Plasma testosterone was determined before and after 3 days of hCG stimulation. Testicular tissue obtained by bilateral biopsies was subjected to (1) histological examination, (2) determination of basal testosterone concentration and (3) incubation with hCG. Patients were grouped according to histology. In vitro basal and stimulated testicular testosterone was similar in patients with normal histology, Sertoli-cell-only syndrome and spermatogenic arrest. Tissue from patients with Leydig cell hyperplasia showed 3-fold higher basal testosterone levels and a greater response to hCG. All patients had plasma testosterone levels and responses to hCG in the normal range. There was no significant correlation between the data obtained in vivo and in vitro, indicating that testosterone determinations in peripheral blood do not necessarily reflect the intratesticular situation. There was no evidence for gross abnormality in Leydig cell function accompanying disturbed spermatogenesis.

Abstract 20609: Abnormalities of Mitochondrial Number and Function in Pediatric Idiopathic Dilated Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kathryn C Chatfield ◽  
Marisa W Friederich ◽  
Shelley D Miyamoto ◽  
Carmen C Sucharov ◽  
Johan L Van Hove ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Mitochondrial Dysfunction ◽  
Copy Number ◽  
Citrate Synthase ◽  
Myocardial Dysfunction ◽  
Complex Iii ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Mitochondrial Copy Number ◽  
Z Scores ◽  
And Function

Introduction: Impaired mitochondrial energy production and substrate utilization have been implicated in the development of heart failure (HF) in adults. Little literature exists describing mitochondrial energetics in pediatric HF. We have previously shown that content of Cardiolipin (CL), a major mitochondrial membrane phospholipid, is depleted in both adult and pediatric idiopathic dilated cardiomyopathy (IDC), with preserved expression of mitochondrial-encodes genes. Similar CL changes occur in a rat model of HF with associated mitochondrial dysfunction that precedes myocardial dysfunction, which can be reversed by dietary interventions. Hypothesis: We hypothesize that mitochondrial dysfunction occurs in pediatric IDC. Methods: As a part of an on-going study a cross-sectional analysis of mitochondrial content and function was performed in left ventricle tissue from the University of Colorado Pediatric Heart Tissue Bank. Current contents: age 13-18: 11 IDC (64% male) and 13 NF (62% male). All NF are donor hearts with normal LVEF; all IDC specimens had LVEF <30%. Results: We show lower mitochondrial copy number in pediatric IDC compared with NF controls (IDC: 44 vs NF: 24, P<0.05), with paradoxical up-regulation of transcriptional co-activators, PGC1α and NRF1 (P<0.01). This is in contrast to what has been shown in adult HF where PGC1α and NRF1 expression are unchanged. Electron transport chain (ETC) complex enzymatic activities were quantified in a sub-group of pediatric IDC samples, expressed as Z-scores relative to normative values in 18 NFs. Significantly decreased activities of complexes I, IV, and citrate synthase were found (Z-scores -2.2, -3.3 and -1.7 respectively), with a significant increase in complex III activity (Z-score 0.7, all P<0.05). Conclusions: These results suggest impaired mitochondrial biogenesis occurs in pediatric HF by a unique mechanism from that seen in adults. Additionally, we show a very specific pattern of ETC dysfunction in pediatric IDC. Future studies will identify the how decreased mitochondrial copy number occurs in the context of PGC1α and NRF1 up-regulation and determine whether abnormalities in CL contribute to abnormalities in ETC activities.

Decreased in vitro responses to vasoconstrictors during gestation in normotensive and spontaneously hypertensive rats

1987 ◽  
Vol 65 (12) ◽  
pp. 2466-2471 ◽  
Author(s):  
G. Massicotte ◽  
J. St-Louis ◽  
A. Parent ◽  
E. L. Schiffrin
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Female Rats ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Response Curves ◽  
Pregnant Rats ◽  
Spontaneously Hypertensive ◽  
Vasoconstrictor Agents ◽  
Wistar Kyoto

We have investigated the in vitro vascular responses to vasoconstrictor agents in pregnant normotensive (Sprague–Dawley (SDR) and Wistar–Kyoto (WKR)) and spontaneously hypertensive rats (SHR) to measure the sensitivity and contractility of blood vessels of pregnant rats. In the perfused mesenteric vascular bed from rats on the 21st day of gestation, the concentration–response curves for the increase in perfusion pressure by arginine8-vasopressin and norepinephrine were displaced to the right by comparison to nonpregnant female rats when all strains of rats were considered together. The increase in EC50 to both agents in pregnant rats was from 1.3- to 2.7-fold in the mesenteric bed; SDR showed the highest increase in EC50, followed by SHR and WKR. No consistent effect was observed on the maximum response. Similar results were obtained in isolated portal veins for angiotensin II and norepinephrine, except that the increase in EC50 in pregnant rats was smaller in magnitude (from 1.0 to 1.7) and followed the same interstrain pattern. These data show that the decreased responsiveness to vasoconstrictor agents in pregnant rats observed in vitro is similar in normotensive and hypertensive rats and suggest that the factor(s) responsible for this effect is a phenomenon affecting vascular smooth muscle in both arteries and veins.

Norepinephrine sensitivity of mesenteric veins in pregnant rats

1990 ◽  
Vol 259 (4) ◽  
pp. R753-R759 ◽  
Author(s):  
M. Hohmann ◽  
T. M. Keve ◽  
G. Osol ◽  
M. K. McLaughlin
Keyword(s):  
Nerve Stimulation ◽  
Sympathetic Nerves ◽  
Transmural Pressure ◽  
Neuronal Uptake ◽  
Sprague Dawley ◽  
Adrenergic Stimulation ◽  
Pregnant Rats ◽  
Mesenteric Veins ◽  
Induced Changes

This study was designed to test the hypothesis that during the course of pregnancy there is a decrease in the venous response to adrenergic stimulation that is characterized by a decrease in venoconstriction to both exogenous norepinephrine (NE) and to transmural electric stimulation of endogenous sympathetic nerves. Capacitance-size mesenteric veins were removed from nonpregnant and early- (7/8 day) and late-pregnant (18/19 and 20/21 day) Sprague-Dawley rats and studied in vitro under pressurized conditions. Lumen diameter was measured continuously by a video-electronic method. There was a marked increase in the sensitivity of the veins to exogenous NE stimulation at the end of pregnancy, which was most dramatic at a transmural pressure of 6 compared with 2 mmHg. The increase in exogenous NE sensitivity was associated with a progressive decline in the response to transmural nerve stimulation during pregnancy. Cocaine, an inhibitor of neuronal uptake, resulted in a greater potentiation of the response to transmural nerve stimulation in the pregnant rats compared to controls, suggesting an increased reuptake mechanism during pregnancy. Additional studies in the pseudopregnant, lactating, and nonlactating rat suggested that the conceptus was necessary for the alterations in neural response but not for the increase in exogenous NE sensitivity. In conclusion there is a dramatic change in venous function during pregnancy in the rat that is characterized by a difference between endogenous and exogenous NE sensitivity. The fact that transmural pressure can profoundly affect exogenous NE sensitivity suggests that pregnancy-induced changes in venous volume could contribute to changes in venous reactivity.

Extended light period in the maternal circadian cycle impairs the reproductive system of the rat male offspring

2020 ◽  
pp. 1-8
Author(s):  
Fernanda Mithie Ogo ◽  
Glaucia Eloisa Munhoz Lion Siervo ◽  
Ana Maria Praxedes de Moraes ◽  
Katia Gama de Barros Machado ◽  
Suellen Ribeiro da Silva Scarton ◽  
...  
Keyword(s):  
Reproductive System ◽  
System Development ◽  
Sperm Count ◽  
Cell Number ◽  
Male Offspring ◽  
Constant Light ◽  
Plasma Testosterone ◽  
Circadian Cycle ◽  
Pregnant Rats ◽  
Testosterone Levels

Abstract Alterations in the circadian cycle are known to cause physiological disorders in the hypothalamic–pituitary–adrenal and the hypothalamic–pituitary–gonadal axes in adult individuals. Therefore, the present study aimed to evaluate whether exposure of pregnant rats to constant light can alter the reproductive system development of male offspring. The dams were divided into two groups: a light–dark group (LD), in which pregnant rats were exposed to an LD photoperiod (12 h/12 h) and a light–light (LL) group, in which pregnant rats were exposed to a photoperiod of constant light during the gestation period. After birth, offspring from both groups remained in the normal LD photoperiod (12 h/12 h) until adulthood. One male of each litter was selected and, at adulthood (postnatal day (PND) 90), the trunk blood was collected to measure plasma testosterone levels, testes and epididymis for sperm count, oxidative stress and histopathological analyses, and the spermatozoa from the vas deferens to perform the morphological and motility analyses. Results showed that a photoperiod of constant light caused a decrease in testosterone levels, epididymal weight and sperm count in the epididymis, seminiferous tubule diameter, Sertoli cell number, and normal spermatozoa number. Histopathological damage was also observed in the testes, and stereological alterations, in the LL group. In conclusion, exposure to constant light during the gestational period impairs the reproductive system of male offspring in adulthood.

scholarly journals A Mixture of Diethylhexyl, Diisononyl and Dibutyl Phthalate Decreased Anogenital Distance, Postnatal Testosterone Levels, and Changed Social Behavior in Wistar Rats

2021 ◽  
pp. S489-S498
Author(s):  
M MOROVÁ ◽  
T SENKO ◽  
L OLEXOVÁ ◽  
Z DZIRBÍKOVÁ ◽  
L KRŠKOVÁ
Keyword(s):  
Social Behavior ◽  
Dibutyl Phthalate ◽  
Behavioral Changes ◽  
Plasma Testosterone ◽  
Adult Males ◽  
Postnatal Exposure ◽  
Pregnant Rats ◽  
Anogenital Distance ◽  
Testosterone Levels ◽  
Early Developmental

Phthalates are chemicals interfering with the function of testosterone and are suspected to play a role in the emergence of neurodevelopmental diseases. This could be due to interference with brain development for which optimal testosterone levels are essential. We investigated the effect of prenatal and early postnatal exposure to a phthalate mixture on the anogenital distance (AGD), plasma testosterone levels and social behavior in rats. Pregnant rats were exposed to a mixture of diethylhexyl, diisononyl and dibutyl phthalate, each at a dose of 4.5 mg/kg/day, from gestational day 15 to postnatal day 4. A social interaction test was performed to assess sociability in the three ontogenetic stages (weaning, puberty, adulthood). AGD was measured in adulthood to assess changes in prenatal testosterone levels. Plasma testosterone levels were measured in adults by a radioimmunoassay. The total frequency and time of socio-cohesive interactions were decreased in phthalate exposed females in weaning, puberty and adulthood. Phthalate exposed males showed a decrease in the frequency of social interactions in weaning only. Shorter anogenital distance was observed in adult males exposed to phthalates. Decreased testosterone levels were observed in the exposed group in both sexes. Our results suggest that early developmental phthalate exposure may play an important role in the hormonal and behavioral changes associated with several neurodevelopmental diseases.

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