Journals
2012 EN
Catherine A. Marler
Is endocrinology at a pivotal point for integrating the effects of the social environment on plasticity in physiology and behavior through changes in gene expression? Sex steroids have a canalizing effect during early sexual differentiation, emphasizing the organizational and longlasting effects of steroid hormones. What about hormonal effects on transcriptional regulation during adulthood? Using a systems integration of endocrinology, genes, and behavior that places the organism in the context of its social environment, O’Connell and Hofmann (1) in this issue focus primarily on the role of steroid hormone receptors in the adult male African cichlid fish, Astatotilapia burtoni. In this cichlid, male behavior and reproduction are fairly canalized into either being reproductive and dominant or reproductively suppressed (small gonads) and subordinate. These differences extend into behavior and communication: the dominants are brightly colored, court and mate with females, are territorial, and chase subordinate males. The subordinates are dull in coloration and school with females. What makes this an intriguing system to work with is that the subordinate status of an individual can very rapidly switch to a dominant status (2). Some highly coordinated changes have to occur for this transition in behavior, morphology and increased androgen and estrogen levels. O’Connell and Hofmann (1) manipulate androgen receptor (AR), estrogen receptor (ER), and progestin receptor in the dominants and subordinates. They then probe the preoptic area of the brain for candidate genes regulated in either social state, with a focus on ER manipulations. These manipulations are all conducted in a stable social group. Although aggression was positively influenced by ER manipulations in both social states, only the subordinates have decreases in 17 -estradiol, testosterone, and progesterone levels in response to ER antagonists. Behavioral changes and tissue responses were therefore not parallel between the two behavioral types. This dissociation between aggressive behavior and steroid hormones has been shown in other vertebrate systems as well (3, 4). Something about the ER and associated cellular mechanisms respond differently based on changes created by the social interactions. Interestingly, subordinates were more responsive to the manipulations. It is again not parallel when the focus is on courtship, although the mechanisms likely differ; only in dominants was courtship positively associated with AR manipulations, but again, dominants showed no change in hormone levels in response to the antagonists (subordinates do not display courtship behavior). Perhaps even more revealing is that ER antagonists decreased gonad size only in subordinates within days. It is again the subordinates that are showing rapid and dramatic changes in morphology to steroid receptor manipulations even if it is not expressed in the behavior; perhaps the ER system allows subordinates to physiologically prepare for the possibility of becoming a dominant, while maintaining dissociation with the behavior. In a relatively complex social system, independent control of behavior may be important because it is the most rapid mode of communication with others of the social group, and for a subordinate, it may create an increased risk of becoming injured. In a comparison using gene expression profiling through transcriptomeanalysis, theauthors found that the preoptic area expresses 56% more genes in dominants compared with subordinates. At the level of candidate genes, ER antagonists did not alter either isomorph of AR (AR or AR ) or ER (ER a or ER b) or ER in either dominants or subordinates. The focal point of change is
Journals
2012 EN
Ailing Liu · Isabelle Margaill · Shaodong Zhang
+13 more
Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5α-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates γ-aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemic damage by signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.
Journals
2012 EN
Ludovic Waeckel · Louis Potier · Catherine Chollet
+5 more
Tissue kallikrein (TK) is synthesized in arteries and distal renal tubule, the main target of aldosterone. Urinary kallikrein excretion increases in hyperaldosteronism. We tested the hypothesis that TK is involved in the cardiovascular and renal effects of high aldosterone. Kallikrein-deficient mice (TK−/−), and wild-type (WT) littermates, studied on two different genetic backgrounds, were treated with aldosterone and high-NaCl diet for 1 month. Control mice received vehicle and standard NaCl diet. Treatment induced 5- to 7-fold increase in plasma aldosterone, suppressed renin secretion, and increased urinary TK activity. In 129SvJ-C57BL/6J mice, blood pressure monitored by radiotelemetry was not different between control TK−/− and WT mice. In TK−/− mice, aldosterone induced larger increases in blood pressure than in WT mice (+47 vs. +27 mm Hg; genotype-treatment interaction, P < 0.05). Night-day difference was also exacerbated in treated TK−/− mice (P < 0.01). Moderate cardiac septal hypertrophy was observed in hypertensive animals without major change in heart function. Aldosterone-salt increased kidney weight similarly in both genotypes but induced a 2-fold increase in renal mRNA abundance of epithelial sodium channel subunits only in TK−/− mice. The hypertensive effect of TK deficiency was also documented in treated C57BL/6J mice. In this strain, aldosterone-induced hypertension was only observed in TK−/− mice (+16 mm Hg, P < 0.01). These findings show that TK deficiency exacerbates aldosterone-salt-induced hypertension. This effect may be due at least in part to enhanced sodium reabsorption in the distal nephron aggravating sodium retention. The study suggests that kallikrein plays an antihypertensive role in hyperaldosteronism.
Journals
2012 EN
Catherine Viguié · Séverine H. Collet · Véronique Gayrard
+5 more
The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg · d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 ± 0.02 and 0.18 ± 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T(4) concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T(4) plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment.
Journals
2012 EN
Spenser S. Smith · Catherine B. Kessler · Vikram Subraya Shenoy
+2 more
Reduced IGF-I is associated with low bone mass in humans and mice. C3H/He/J (C3H) mice have higher skeletal IGF-I and greater bone mass than C57BL/6J (B6). We hypothesized that strain-related genotypic differences in Igf1 affected skeletal function. The Igf1 coding region is nonpolymorphic, but its 3′ untranslated region (UTR) is polymorphic between C3H and B6. Luciferase-Igf1 3′ UTR reporter constructs showed that these polymorphic regions did not affect UTR function. IGF-I splice variants give rise to a common mature IGF-I peptide, but different E peptides. We identified two splice products, exon 4+6 (Ea) and exon 4+5+6 (Eb, mechano-growth factor) and found that their abundance was unchanged during osteoblastic differentiation. The Igf1 3′ UTR encoded by exon 6 contains alternative polyadenylation sites. Proximal site use produces a short 3′ UTR of approximately 195 bases, whereas distal site usage results in an approximately 6300-base UTR. Although Igf1 mRNA levels did not change during osteoblastic differentiation, distal polyadenylation site usage was increased in B6 cells but not in C3H. The resulting long Igf1 RNA isoform is less stable and has decreased translation efficiency, which may be one mechanism contributing to decreased IGF-I in B6 vs. C3H mice. Although the long UTR contains a conserved [GU]18 repeat, which is a positive regulator of UTR activity, it is also targeted by negative regulators, miR-29 and miR-365. These microRNAs are increased in B6 and C3H cells during osteoblastic differentiation. Differential expression of the long Igf1 3′ UTR isoform may be a possible mechanism for enhanced IGF-I regulation in B6 vs. C3H mice.
Journals
2012 EN
Charles L. Chaffin · Young S. Lee · Catherine A. VandeVoort
+2 more
Follicular somatic cells (mural granulosa cells and cumulus cells) and the oocyte communicate through paracrine interactions and through direct gap junctions between oocyte and cumulus cells. Considering that mural and cumulus cells arise through a common developmental pathway and that their differentiation is essential to reproductive success, understanding how these cells differ is a key aspect to understanding their critical functions. Changes in global gene expression before and after an ovulatory stimulus were compared between cumulus and mural granulosa cells to test the hypothesis that mural and cumulus cells are highly differentiated at the time of an ovulatory stimulus and further differentiate during the periovulatory interval. The transcriptomes of the two cell types were markedly different (>1500 genes) before an ovulatory hCG bolus but converged after ovulation to become completely overlapping. The predominant transition was for the cumulus cells to become more like mural cells after hCG. This indicates that the differentiated phenotype of the cumulus cell is not stable and irreversibly established but may rather be an ongoing physiological response to the oocyte.
Journals
2012 EN
Nino Tabatadze · Tereza Smejkalová · Catherine S. Woolley
Acute 17β-estradiol (E2) signaling in the brain is mediated by extranuclear estrogen receptors. Here we used biochemical methods to investigate the distribution, posttranslational modification, and E2 regulation of estrogen receptor-α (ERα) in synaptosomal fractions isolated by differential centrifugation from the adult female rat hippocampus. We find that ERα is concentrated presynaptically and is highly enriched with synaptic vesicles. Immunoisolation of vesicles using vesicle subtype-specific markers showed that ERα is associated with both glutamate and γ-aminobutyric acid-containing neurotransmitter vesicles as well as with some large dense core vesicles. Experiments using broad spectrum and residue-specific phosphatases indicated that a portion of ERα in synaptosomal fractions is phosphorylated at serine/threonine residues leading to a mobility shift in SDS-PAGE and creating a double band on Western blots. The phosphorylated form of ERα runs in the upper of the two bands and is particularly concentrated with synaptic vesicles. Finally, we used E2 with or without the acyl protein thioesterase 1 inhibitor, Palmostatin B, to show that 20 min of E2 treatment of hippocampal slices depletes ERα from the synaptosomal membrane by depalmitoylation. We found no evidence that E2 regulates phosphorylation of synaptosomal ERα on this time scale. These studies begin to fill the gap between detailed molecular characterization of extranuclear ERα in previous in vitro studies and acute E2 modulation of hippocampal synapses in the adult brain.
Journals
2012 EN
Naim Panjwani · Erin E. Mulvihill · Christine Longuet
+8 more
Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE(-/-) mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE(-/-) mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE(-/-), C57BL/6, and IL10(-/-) mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r(+/+) and Glp1r(-/-) mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE(-/-) mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation.
Journals
2012 EN
Catherine M. Gordon · Sarah A.B. Pitts
It is essential to develop contraceptive counseling skills given the potential complications associated with an unplanned pregnancy, especially for adolescents. Multiple factors must be considered when reviewing contraceptive options with an adolescent: maturity, finances, access to care and prescriptions, confidentiality, medical risks and benefits, and contraindications to use of certain hormonal agents. Many adolescents will be concerned about the possibility of weight gain or the development of acne associated with the use of certain contraceptive agents. They are usually unaware of the risks of thrombosis, stroke, or adverse bone health effects. Providers must be able to speak to these issues using an evidence-based approach.
Journals
2012 EN
Olfa Derbel · P. Zrounba · Catherine ChassagneClément
+5 more
Bone giant cell tumors (GCTs) are among the most common benign bone tumors and affect mostly young patients. They represent a rare etiology of head and neck cancer.