12 research outputs found
Prostaglandin receptors EP and FP are regulated by estradiol and progesterone in the uterus of ovariectomized rats
Prostaglandin treatment is associated with a withdrawal of progesterone and androgen at the receptor level in the uterine cervix
Treatment with prostaglandin(PG)-E2 is clinically efficient for cervical priming. The aim of this study was to evaluate the impact of PG-E2 on the expression of the progesterone (PR), androgen (AR) and glucocorticoid (GR) receptors in human uterine cervix in prolonged pregnancy
Testosterone Decreases Placental Mitochondrial Content and Cellular Bioenergetics
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
Prenatal Low-Protein Diet Affects Mitochondrial Structure and Function in the Skeletal Muscle of Adult Female Offspring
Gestational low-protein (LP) diet leads to glucose intolerance and insulin resistance in adult offspring. We had earlier demonstrated that LP programming affects glucose disposal in females. Mitochondrial health is crucial for normal glucose metabolism in skeletal muscle. In this study, we sought to analyze mitochondrial structure, function, and associated genes in skeletal muscles to explore the molecular mechanism of insulin resistance LP-programmed female offspring. On day four of pregnancy, rats were assigned to a control diet containing 20% protein or an isocaloric 6% protein-containing diet. Standard laboratory diet was given to the dams after delivery until the end of weaning and to pups after weaning. Gestational LP diet led to changes in mitochondrial ultrastructure in the gastrocnemius muscles, including a nine-fold increase in the presence of giant mitochondria along with unevenly formed cristae. Further, functional analysis showed that LP programming caused impaired mitochondrial functions. Although the mitochondrial copy number did not show significant changes, key genes involved in mitochondrial structure and function such as Fis1, Opa1, Mfn2, Nrf1, Nrf2, Pgc1b, Cox4b, Esrra, and Vdac were dysregulated. Our study shows that prenatal LP programming induced disruption in mitochondrial ultrastructure and function in the skeletal muscle of female offspring
Low Protein Programming Causes Increased Mitochondrial Fusion and Decreased Oxygen Consumption in the Hepatocytes of Female Rats
The liver is one of the major organs involved in the regulation of glucose and lipid homeostasis. The effectiveness of metabolic activity in hepatocytes is determined by the quality and quantity of its mitochondria. Mitochondrial function is complex, and they act via various dynamic networks, which rapidly adapt to changes in the cellular milieu. Our present study aims to investigate the effects of low protein programming on the structure and function of mitochondria in the hepatocytes of adult females. Pregnant rats were fed with a control or isocaloric low-protein diet from gestational day 4 until delivery. A normal laboratory chow was given to all dams after delivery and to pups after weaning. The rats were euthanized at 4 months of age and the livers were collected from female offspring for investigating the mitochondrial structure, mtDNA copy number, mRNA, and proteins expression of genes associated with mitochondrial function. Primary hepatocytes were isolated and used for the analysis of the mitochondrial bioenergetics profiles. The mitochondrial ultrastructure showed that the in utero low-protein diet exposure led to increased mitochondrial fusion. Accordingly, there was an increase in the mRNA and protein levels of the mitochondrial fusion gene Opa1 and mitochondrial biogenesis genes Pgc1a and Essra, but Fis1, a fission gene, was downregulated. Low protein programming also impaired the mitochondrial function of the hepatocytes with a decrease in basal respiration ATP-linked respiration and proton leak. In summary, the present study suggests that the hepatic mitochondrial dysfunction induced by an in utero low protein diet might be a potential mechanism linking glucose intolerance and insulin resistance in adult offspring
Preovulatory exposure to a protein-restricted diet disrupts amino acid kinetics and alters mitochondrial structure and function in the rat oocyte and is partially rescued by folic acid
Abstract Background Detrimental exposures during pregnancy have been implicated in programming offspring to develop permanent changes in physiology and metabolism, increasing the risk for developing diseases in adulthood such as hypertension, diabetes, heart disease and obesity. This study investigated the effects of protein restriction on the metabolism of amino acids within the oocyte, liver, and whole organism in a rat model as well as effects on mitochondrial ultrastructure and function in the cumulus oocyte complex. Methods Wistar outbred female rats 8–11 weeks of age (n = 24) were assigned to three isocaloric dietary groups, including control (C), low protein (LP) and low protein supplemented with folate (LPF). Animals were superovulated and 48 h later underwent central catheterization. Isotopic tracers of 1-13C-5C2H3-methionine, 2H2-cysteine, U-13C3-cysteine and U-13C3-serine were administered by a 4 h prime-constant rate infusion. After sacrifice, oocytes were denuded of cumulus cells and liver specimens were obtained. Results Oocytes demonstrated reduced serine flux in LP vs. LPF (p < 0.05), reduced cysteine flux in LP and LPF vs. C (p < 0.05), and a trend toward reduced transsulfuration in LP vs. C and LPF. Folic acid supplementation reversed observed effects on serine flux and transsulfuration. Preovulatory protein restriction increased whole-body methionine transmethylation, methionine transsulfuration and the flux of serine in LP and LPF vs. C (p = 0.003, p = 0.002, p = 0.005). The concentration of glutathione was increased in erythrocytes and liver in LP and LPF vs. C (p = 0.003 and p = 0.0003). Oocyte mitochondrial ultrastructure in LP and LPF had increased proportions of abnormal mitochondria vs. C (p < 0.01 and p < 0.05). Cumulus cell mitochondrial ultrastructure in LP and LPF groups had increased proportions of abnormal mitochondria vs. C (p < 0.001 and p < 0.05). Preovulatory protein restriction altered oocyte expression of Drp1, Opa-1, Mfn1/2, Parl and Ndufb6 (p < 0.05) and Hk2 (p < 0.01), which are genes involved in mitochondrial fission (division) and fusion, mitochondrial apoptotic mechanisms, respiratory electron transport and glucose metabolism. Conclusions Preovulatory protein restriction resulted in altered amino acid metabolism, abnormal cumulus oocyte complex mitochondrial ultrastructure and differential oocyte expression of genes related to mitochondrial biogenesis