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Publications (4)12.17 Total impact

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    ABSTRACT: We previously reported elevated adipose leptin expression, plasma leptin concentrations and adrenocortical leptin receptor expression in the long term hypoxic (LTH) ovine fetus. This study addressed if leptin antagonist (LA) administration to LTH fetal sheep altered expression of key genes governing cortisol synthesis. Ewes were maintained at high altitude (3,820 m) from 40-130 days gestation (dG), returned to Loma Linda University and implanted with a maternal tracheal catheter. Reduced PO(2) was maintained by nitrogen infusion. On 132 dG, LTH (n=11) and age-matched, normoxic control (n=11) fetuses underwent vascular catheter implantation. At 138 dG, fetuses were continuously infused with either saline or the LA (1.5mg/kg/day) for four days and samples collected for blood gasses, ACTH and cortisol. Fetal adrenal cortex was collected for determination of StAR, ACTH and leptin receptor, CYP11A1, CYP11B1, CYP17, CYP21, STAT3, pSTAT3 and HSD3B expression. In the saline infused LTH fetuses, StAR, ACTH receptor, CYP11A1 and CYP17 expression was significantly lower compared to control (p<0.05) while levels of CYP11B1, CYP21 and HSD3B mRNA were similar between groups. LA infusion restored expression of StAR, pSTAT3, CYP11A1 and CYP17 but not ACTH receptor to normal ontogenic levels in the LTH group while having no effect on control fetuses. Neither fetal plasma ACTH nor cortisol concentrations were altered by LA infusion. We speculate that while leptin plays a role in governing expression of key enzymes and StAR in response to LTH, other factors play a role in modulating cortisol synthesis in these fetuses.
    AJP Regulatory Integrative and Comparative Physiology 01/2013; · 3.28 Impact Factor
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    ABSTRACT: Progesterone plays a critical role in regulating cervical structure necessary for pregnancy maintenance. Preterm labor and early cervical ripening are often associated with localized infection. We hypothesized that proinflammatory cytokines enhance progesterone metabolism in human cervical fibroblasts (HCFs) in vitro, through the regulation of the expression of 20α-hydroxysteroid dehydrogenases (aldo-keto reductase [AKR]1C1, AKR1C2, or AKR1C3), 5α-reductase type 1 (5α-RDT1), and/or 17β-hydroxysteroid dehyrogenases (17β-HSD) type 1 and 2. The expression of both progesterone receptor (PR) and estrogen receptor α (ERα) was also studied. Human cervical fibroblasts were found to express AKR1C1, C2, and C3, with AKR1C1 exhibiting the greatest expression. These cells also expressed 5α-RDT1 and 17β-HSD1 and 2, albeit to a lesser level compared to the aldo-keto reductases. The fibroblasts also expressed both PR and ERα. Interleukin 1β (IL-1β) significantly increased the expression of AKR1C1 and C2 but not C3 but did not alter 5α-RDT1 nor 17β-HSD1 or 2 expression. Interleukin 1β treatment significantly increased progesterone metabolism by these cells. Use of specific inhibitors for aldo-keto reductases or 5α reductases confirmed that the increased progesterone metabolism was a consequence of the increased expression and/or activity of AKR1C1/2. Our results indicate that a major proinflammatory cytokine, IL-1β, can facilitate local progesterone metabolism in a cell type critical for maintaining cervical structure via regulating expression of AKR1C1 and 2.
    Reproductive sciences (Thousand Oaks, Calif.) 11/2011; 19(3):271-81. · 2.31 Impact Factor
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    ABSTRACT: Basal plasma ACTH(1-39) concentrations are elevated in long-term hypoxic (LTH) fetal sheep. This study was designed to determine whether the expression of genes regulating cortisol biosynthesis was altered after LTH. Pregnant ewes were maintained at high altitude (3,820 m) from day 30 of gestation to near term, when the animals were transported to the laboratory. Reduced PO2 was maintained by nitrogen infusion through a maternal tracheal catheter. On days 137-141, fetal adrenal glands were collected from LTH and normoxic control fetuses. Real-time PCR was used to quantify mRNA for steroidogenic acute regulatory protein, 17alpha-hydroxylase (CYP17), 21-hydroxylase (CYP21), cholesterol side-chain cleavage (CYP11A1), 3beta-hydroxysteroid dehydrogenase type II (HSD3B2), and the ACTH receptor. We analyzed mRNA by slot-blot hybridization and also quantified mRNA for transcription factors necessary for adrenocortical development by quantitative real-time PCR: steroidogenic factor 1 and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome (DAX-1). Protein was quantified by Western blot analysis. Adrenal mRNAs for CYP17, CYP11A1, and the ACTH receptor were significantly reduced in LTH fetal sheep compared with levels shown in controls. Similarly, CYP11A1 protein and CYP17 protein were reduced in the LTH group. CYP21, steroidogenic acute regulatory protein, HSD3B2, steroidogenic factor 1, and DAX-1 expressions were not altered in response to LTH. We conclude that expression of two key steroidogenic enzymes (CYP17, CYP11A1) regulating cortisol biosynthesis and the ACTH receptor is lower in response to LTH. This likely represents an adaptive response to LTH, to prevent excessive cortisol production that would restrict fetal growth and potentially induce preterm delivery.
    AJP Regulatory Integrative and Comparative Physiology 01/2006; 289(6):R1707-14. · 3.28 Impact Factor
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    ABSTRACT: Secondary stressors in long-term hypoxic (LTH) fetal sheep lead to altered function of the hypothalamic-pituitary-adrenal axis. Although ACTH is considered the primary mediator of glucocorticoid production in fetal sheep, proopiomelanocortin (POMC) and 22-kDa pro-ACTH (22-kDa ACTH) have been implicated in the regulation of cortisol production in the ovine fetus. This study was designed to determine whether POMC expression and processing are altered after LTH. Pregnant ewes were maintained at high altitude (3,820 m) from day 30 of gestation to near term, when the animals were transported to the laboratory. Reduced Po2 was maintained by nitrogen infusion through a maternal tracheal catheter. On days 139-141, fetal anterior pituitaries were collected from normoxic control and LTH fetuses. We measured POMC and corticotrophin-releasing factor type 1 receptor (CRF1-R) mRNA using quantitative real-time PCR, and we used Western blot analysis for quantitation of ACTH, ACTH precursor, and CRF1-R proteins. We measured plasma ACTH1-39 using a two-site immunoradiometric assay specific for ACTH1-39. Plasma ACTH precursors were measured by ELISA. Anterior pituitary POMC mRNA levels were not different between groups, whereas CRF1-R levels were significantly higher in the LTH anterior pituitaries compared with control (P<0.05). In contrast, protein levels of POMC, CRF1-R, 22-kDa ACTH, and ACTH1-39 were significantly lower in the LTH group. Plasma concentrations of both ACTH precursors and ACTH1-39 were significantly elevated in LTH fetuses, whereas the ratio of plasma precursors to ACTH was significantly lower. We conclude that LTH results in enhanced POMC processing and/or release to ACTH and increased hypothalamic drive.
    AJP Regulatory Integrative and Comparative Physiology 06/2005; 288(5):R1178-84. · 3.28 Impact Factor