Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-25T18:12:34.229Z Has data issue: false hasContentIssue false
  • English
  • Français

A heretical view: rather than a solely placental protective function, placental 11β hydroxysteroid dehydrogenase 2 also provides substrate for fetal peripheral cortisol synthesis in obese pregnant ewes

Published online by Cambridge University Press:  10 March 2020

Adel B. Ghnenis Open the ORCID record for Adel B. Ghnenis [Opens in a new window] ,
John F. Odhiambo ,
Ashley M. Smith ,
Chris L. Pankey ,
Peter W. Nathanielsz  and
Stephen P. Ford
Adel B. Ghnenis*
Affiliation:
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY82071, USA Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX77807, USA
John F. Odhiambo
Affiliation:
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY82071, USA Division of Agricultural and Food Sciences, Florida A&M University, Tallahassee, FL32307, USA
Ashley M. Smith
Affiliation:
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY82071, USA
Chris L. Pankey
Affiliation:
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY82071, USA
Peter W. Nathanielsz*
Affiliation:
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY82071, USA
Stephen P. Ford
Affiliation:
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY82071, USA
*
Address for correspondence: Adel B. Ghnenis, Department of Animal Science, 1000 E. University Avenue, University of Wyoming, Laramie, WY82071, USA. Email: ghnenis@medicine.tamhsc.edu; Peter W. Nathanielsz, Department of Neuroscience & Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 8447 Riverside Parkway, Bryan, TX77807, USA. Email: peter.nathanielsz@uwyo.edu
Address for correspondence: Adel B. Ghnenis, Department of Animal Science, 1000 E. University Avenue, University of Wyoming, Laramie, WY82071, USA. Email: ghnenis@medicine.tamhsc.edu; Peter W. Nathanielsz, Department of Neuroscience & Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 8447 Riverside Parkway, Bryan, TX77807, USA. Email: peter.nathanielsz@uwyo.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11β hydroxysteroid dehydrogenase 2 (11β-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11β-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11β-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11β-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11β-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11β-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11β-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses.

Keywords

Glucocorticoids11β hydroxysteroid dehydrogenasematernal obesityplacentafetal cortisol
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 1 , February 2021 , pp. 94 - 100
Check for updates
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

†

These authors contributed equally to this work.

References

Ogden, CL, Carroll, MD, Kit, BK, Flegal, KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014; 311, 806–814.CrossRefGoogle ScholarPubMed
Leddy, MA, Power, ML, Schulkin, J. The impact of maternal obesity on maternal and fetal health. Rev Obstet Gynecol. 2008; 1, 170–178.Google ScholarPubMed
Li, M, Sloboda, DM, Vickers, MH. Maternal obesity and developmental programming of metabolic disorders in offspring: evidence from animal models. Exp Diabetes Res. 2011; 2011, 592408.10.1155/2011/592408CrossRefGoogle ScholarPubMed
Parsons, TJ, Power, C, Manor, O. Fetal and early life growth and body mass index from birth to early adulthood in 1958 British cohort: longitudinal study. BMJ. 2001; 323, 1331–1335.CrossRefGoogle ScholarPubMed
Lawlor, DA, Smith, GD, O’Callaghan, M, et al. Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the mater-university study of pregnancy and its outcomes. Am J Epidemiol. 2007; 165, 418–424.CrossRefGoogle ScholarPubMed
Vickers, MH, Breier, BH, Cutfield, WS, Hofman, PL, Gluckman, PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab. 2000; 279, E83–E87.CrossRefGoogle ScholarPubMed
Fletcher, AJ, Forhead, AJ, Fowden, AL, Ford, WR, Nathanielsz, PW, Giussani, DA. Effects of gestational age and cortisol treatment on ovine fetal heart function in a novel biventricular Langendorff preparation. J Physiol. 2005; 562, 493–505.CrossRefGoogle Scholar
Crudo, A, Suderman, M, Moisiadis, VG, et al. Glucocorticoid programming of the fetal male hippocampal epigenome. Endocrinology. 2013; 154, 1168–1180.10.1210/en.2012-1980CrossRefGoogle ScholarPubMed
Dunn, E, Kapoor, A, Leen, J, Matthews, SG. Prenatal synthetic glucocorticoid exposure alters hypothalamic-pituitary-adrenal regulation and pregnancy outcomes in mature female guinea pigs. J Physiol. 2010; 588, 887–899.CrossRefGoogle ScholarPubMed
Mallozzi, M, Bordi, G, Garo, C, Caserta, D. The effect of maternal exposure to endocrine disrupting chemicals on fetal and neonatal development: a review on the major concerns. Birth Defects Res C Embryo Today. 2016; 108, 224–242.CrossRefGoogle ScholarPubMed
Cottrell, EC, Seckl, JR. Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci. 2009; 3, 19.CrossRefGoogle ScholarPubMed
Fowden, AL, Forhead, AJ. Glucocorticoids as regulatory signals during intrauterine development. Exp Physiol. 2015; 100, 1477–1487.CrossRefGoogle ScholarPubMed
Chin, EH, Schmidt, KL, Martel, KM, et al. A maternal high-fat, high-sucrose diet has sex-specific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice. PLoS One. 2017; 12, e0174030.CrossRefGoogle ScholarPubMed
Hohwu, L, Henriksen, TB, Gronborg, TK, Hedegaard, M, Sorensen, TI, Obel, C. Maternal salivary cortisol levels during pregnancy are positively associated with overweight children. Psychoneuroendocrinology. 2015; 52, 143–152.CrossRefGoogle ScholarPubMed
Khorram, NM, Magee, TR, Wang, C, Desai, M, Ross, M, Khorram, O. Maternal undernutrition programs offspring adrenal expression of steroidogenic enzymes. Reprod Sci. 2011; 18, 931–940.CrossRefGoogle ScholarPubMed
Khorram, O, Ghazi, R, Chuang, TD, et al. Excess maternal glucocorticoids in response to in utero undernutrition inhibit offspring angiogenesis. Reprod Sci. 2014; 21, 601–611.Google ScholarPubMed
Moisiadis, VG, Constantinof, A, Kostaki, A, Szyf, M, Matthews, SG. Prenatal glucocorticoid exposure modifies endocrine function and behaviour for 3 generations following maternal and paternal transmission. Sci Rep. 2017; 7, 11814.CrossRefGoogle ScholarPubMed
Buckingham, JC. Glucocorticoids: exemplars of multi-tasking. Br J Pharmacol. 2006; 147 (Suppl 1), S258–S268.CrossRefGoogle ScholarPubMed
Fowden, AL, Li, J, Forhead, AJ. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc Nutr Soc. 1998; 57, 113–122.CrossRefGoogle ScholarPubMed
Jameison, K, Dinan, TG. Glucocorticoids and cognitive function: from physiology to pathophysiology. Hum Psychopharmacol. 2001; 16, 293–302.CrossRefGoogle ScholarPubMed
Wang, M. The role of glucocorticoid action in the pathophysiology of the metabolic syndrome. Nutr Metab (Lond). 2005; 2, 3.CrossRefGoogle ScholarPubMed
Zanchi, NE, Filho, MA, Felitti, V, Nicastro, H, Lorenzeti, FM, Lancha, AH Jr . Glucocorticoids: extensive physiological actions modulated through multiple mechanisms of gene regulation. J Cell Physiol. 2010; 224, 311–315.CrossRefGoogle ScholarPubMed
Guo, C, Li, C, Myatt, L, Nathanielsz, PW, Sun, K. Sexually dimorphic effects of maternal nutrient reduction on expression of genes regulating cortisol metabolism in fetal baboon adipose and liver tissues. Diabetes. 2013; 62, 1175–1185.CrossRefGoogle ScholarPubMed
Wang, Y, Liu, L, Du, H, et al. Transgenic overexpression of hexose-6-phosphate dehydrogenase in adipose tissue causes local glucocorticoid amplification and lipolysis in male mice. Am J Physiol Endocrinol Metab. 2014; 306, E543–E551.10.1152/ajpendo.00491.2013CrossRefGoogle ScholarPubMed
Edwards, CR, Benediktsson, R, Lindsay, RS, Seckl, JR. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet. 1993; 341, 355–357.CrossRefGoogle ScholarPubMed
Murphy, BE, Clark, SJ, Donald, IR, Pinsky, M, Vedady, D. Conversion of maternal cortisol to cortisone during placental transfer to the human fetus. Am J Obstet Gynecol. 1974; 118, 538–541.CrossRefGoogle ScholarPubMed
Seckl, JR, Holmes, MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal “programming” of adult pathophysiology. Nat Clin Pract Endocrinol Metab. 2007; 3, 479–488.Google ScholarPubMed
Krozowski, Z, MaGuire, JA, Stein-Oakley, AN, Dowling, J, Smith, RE, Andrews, RK. Immunohistochemical localization of the 11 beta-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta. J Clin Endocrinol Metab. 1995; 80, 2203–2209.Google ScholarPubMed
Yang, K. Placental 11 beta-hydroxysteroid dehydrogenase: barrier to maternal glucocorticoids. Rev Reprod. 1997; 2, 129–132.CrossRefGoogle ScholarPubMed
van Beek, JP, Guan, H, Julan, L, Yang, K. Glucocorticoids stimulate the expression of 11beta-hydroxysteroid dehydrogenase type 2 in cultured human placental trophoblast cells. J Clin Endocrinol Metab. 2004; 89, 5614–5621.CrossRefGoogle ScholarPubMed
Ford, SP, Zhang, L, Zhu, M, et al. Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences. Am J Physiol Regul Integr Comp Physiol. 2009; 297, R835–R843.CrossRefGoogle Scholar
Long, NM, Nathanielsz, PW, Ford, SP. The impact of maternal overnutrition and obesity on hypothalamic-pituitary-adrenal axis response of offspring to stress. Domest Anim Endocrinol. 2012; 42, 195–202.CrossRefGoogle ScholarPubMed
Pankey, CL, Walton, MW, Odhiambo, JF, et al. Intergenerational impact of maternal overnutrition and obesity throughout pregnancy in sheep on metabolic syndrome in grandsons and granddaughters. Domest Anim Endocrinol. 2017; 60, 67–74.CrossRefGoogle ScholarPubMed
Tuersunjiang, N, Odhiambo, JF, Long, NM, Shasa, DR, Nathanielsz, PW, Ford, SP. Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels. Am J Physiol Endocrinol Metab. 2013; 305, E868–E878.CrossRefGoogle ScholarPubMed
Nathanielsz, PW, Ford, SP, Long, NM, Vega, CC, Reyes-Castro, LA, Zambrano, E. Interventions to prevent adverse fetal programming due to maternal obesity during pregnancy. Nutr Rev. 2013; 71 (Suppl 1), S78–S87.CrossRefGoogle ScholarPubMed
National Research Council (U.S.). Subcommittee on Sheep Nutrition. Nutrient Requirements of Sheep, 1985. 6th rev. ed. Washington, D.C.: National Academy Press.Google Scholar
Dong, F, Ford, SP, Nijland, MJ, Nathanielsz, PW, Ren, J. Influence of maternal undernutrition and overfeeding on cardiac ciliary neurotrophic factor receptor and ventricular size in fetal sheep. J Nutr Biochem. 2008; 19, 409–414.CrossRefGoogle ScholarPubMed
Ma, Y, Zhu, MJ, Zhang, L, Hein, SM, Nathanielsz, PW, Ford, SP. Maternal obesity and overnutrition alter fetal growth rate and cotyledonary vascularity and angiogenic factor expression in the ewe. Am J Physiol Regul Integr Comp Physiol. 2010; 299, R249–R258.CrossRefGoogle ScholarPubMed
Seyed Jafari, SM, Hunger, RE. IHC optical density score: A New practical method for quantitative immunohistochemistry image analysis. Appl Immunohistochem Mol Morphol. 2017; 25, e12–e13.CrossRefGoogle ScholarPubMed
Albiston, AL, Obeyesekere, VR, Smith, RE, Krozowski, ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994; 105, R11–R17.CrossRefGoogle ScholarPubMed
Brown, RW, Chapman, KE, Kotelevtsev, Y, et al. Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2. Biochem J. 1996; 313 (Pt 3): 1007–1017.CrossRefGoogle ScholarPubMed
Jamieson, PM, Chapman, KE, Edwards, CR, Seckl, JR. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology. 1995; 136, 4754–4761.CrossRefGoogle ScholarPubMed
Ricketts, ML, Shoesmith, KJ, Hewison, M, Strain, A, Eggo, MC, Stewart, PM. Regulation of 11 beta-hydroxysteroid dehydrogenase type 1 in primary cultures of rat and human hepatocytes. J Endocrinol. 1998; 156, 159–168.CrossRefGoogle ScholarPubMed
Tomlinson, JW, Walker, EA, Bujalska, IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004; 25, 831–866.CrossRefGoogle ScholarPubMed
Lavery, GG, Walker, EA, Draper, N, et al. Hexose-6-phosphate dehydrogenase knock-out mice lack 11 beta-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. J Biol Chem. 2006; 281, 6546–6551.CrossRefGoogle ScholarPubMed
Paterson, JM, Morton, NM, Fievet, C, et al. Metabolic syndrome without obesity: Hepatic overexpression of 11 beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101, 7088–7093.Google Scholar
Kotelevtsev, Y, Holmes, MC, Burchell, A, et al. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A. 1997; 94, 14924–14929.CrossRefGoogle ScholarPubMed
Morton, NM, Holmes, MC, Fievet, C, et al. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem. 2001; 276, 41293–41300.CrossRefGoogle ScholarPubMed
Masuzaki, H, Paterson, J, Shinyama, H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001; 294, 2166–2170.CrossRefGoogle ScholarPubMed
Wyrwoll, CS, Holmes, MC, Seckl, JR. 11beta-hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol. 2011; 32, 265–286.CrossRefGoogle ScholarPubMed
Williams, LJ, Lyons, V, MacLeod, I, et al. C/EBP regulates hepatic transcription of 11beta -hydroxysteroid dehydrogenase type 1. A novel mechanism for cross-talk between the C/EBP and glucocorticoid signaling pathways. J Biol Chem. 2000; 275, 30232–30239.CrossRefGoogle Scholar
Yang, Z, Guo, C, Zhu, P, Li, W, Myatt, L, Sun, K. Role of glucocorticoid receptor and CCAAT/enhancer-binding protein alpha in the feed-forward induction of 11beta-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts. J Endocrinol. 2007; 195, 241–253.CrossRefGoogle ScholarPubMed
Ignatova, ID, Kostadinova, RM, Goldring, CE, Nawrocki, AR, Frey, FJ, Frey, BM. Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells. Am J Physiol Endocrinol Metab. 2009; 296, E367–E377.CrossRefGoogle ScholarPubMed
Yang, Z, Zhu, X, Guo, C, Sun, K. Stimulation of 11beta-HSD1 expression by IL-1beta via a C/EBP binding site in human fetal lung fibroblasts. Endocrine. 2009; 36, 404–411.CrossRefGoogle Scholar
Hayashi, R, Wada, H, Ito, K, Adcock, IM. Effects of glucocorticoids on gene transcription. Eur J Pharmacol. 2004; 500, 51–62.CrossRefGoogle ScholarPubMed
Smoak, KA, Cidlowski, JA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev. 2004; 125, 697–706.CrossRefGoogle ScholarPubMed
Zilberfarb, V, Siquier, K, Strosberg, AD, Issad, T. Effect of dexamethasone on adipocyte differentiation markers and tumour necrosis factor-alpha expression in human PAZ6 cells. Diabetologia. 2001; 44, 377–386.CrossRefGoogle ScholarPubMed
Hernandez, R, Teruel, T, Lorenzo, M. Insulin and dexamethasone induce GLUT4 gene expression in foetal brown adipocytes: synergistic effect through CCAAT/enhancer-binding protein alpha. Biochem J. 2003; 372, 617–624.CrossRefGoogle ScholarPubMed
Yang, H, Mammen, J, Wei, W, et al. Expression and activity of C/EBPbeta and delta are upregulated by dexamethasone in skeletal muscle. J Cell Physiol. 2005; 204, 219–226.CrossRefGoogle ScholarPubMed
Yang, H, Menconi, MJ, Wei, W, Petkova, V, Hasselgren, PO. Dexamethasone upregulates the expression of the nuclear cofactor p300 and its interaction with C/EBPbeta in cultured myotubes. J Cell Biochem. 2005; 94, 1058–1067.CrossRefGoogle Scholar
Roth, M, Johnson, PR, Borger, P, et al. Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004; 351, 560–574.CrossRefGoogle ScholarPubMed
Rudiger, JJ, Roth, M, Bihl, MP, et al. Interaction of C/EBPalpha and the glucocorticoid receptor in vivo and in nontransformed human cells. FASEB J. 2002; 16, 177–184.CrossRefGoogle ScholarPubMed
Gout, J, Tirard, J, Thevenon, C, Riou, JP, Begeot, M, Naville, D. CCAAT/enhancer-binding proteins (C/EBPs) regulate the basal and cAMP-induced transcription of the human 11beta-hydroxysteroid dehydrogenase encoding gene in adipose cells. Biochimie. 2006; 88, 1115–1124.CrossRefGoogle ScholarPubMed