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Horm Metab Res 2008; 40(7): 446-453
DOI: 10.1055/s-2008-1058101
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Epidermal Growth Factor and Parathyroid Hormone-related Peptide mRNA in the Mammary Gland and their Concentrations in Milk: Effects of Postpartum Hypoxia in Lactating Rats

E. D. Bruder 1 , J. Van Hoof 1 , 2 , J. B. Young 3 , H. Raff 1 , 2
  • 1Endocrine Research Laboratory, Aurora St. Luke's Medical Center, Milwaukee, Wisconsin, USA
  • 2Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  • 3Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Further Information

Publication History

received 06.06.2007

accepted 02.10.2007

Publication Date:
06 March 2008 (online)

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Abstract

The physiological adaptations of the neonatal rat to hypoxia from birth include changes in gastrointestinal function and intermediary metabolism. We hypothesized that the hypoxic lactating dam would exhibit alterations in mammary gland function leading to changes in the concentration of milk peptides that are important in neonatal gastrointestinal development. The present study assessed the effects of chronic hypoxia on peptides produced by the mammary glands and present in milk. Chronic hypoxia decreased the concentration of epidermal growth factor (EGF) in expressed milk and pup stomach contents and decreased maternal mammary gland Egf mRNA. The concentration of parathyroid hormone-related protein (PTHrp) was unchanged in milk and decreased in pup stomach contents; however, mammary Pthlh mRNA was increased by hypoxia. There was a significant increase in adiponectin concentrations in milk from hypoxic dams. Chronic hypoxia decreased maternal body weight, and pair feeding normoxic dams an amount of food equivalent to hypoxic dam food intake decreased body weight to an equivalent degree. Decreased food intake did not affect the expression of Egf, Pthlh, or Lep mRNA in mammary tissue. The results indicated that chronic hypoxia modulated mammary function independently of hypoxia-induced decreases in maternal food intake. Decreased EGF and increased adiponectin concentrations in milk from hypoxic dams likely affect the development of neonatal intestinal function.

Key words

lactation - leptin - adiponectin - stomach contents

References

  • 1 Butte NF, King JC. Energy requirements during pregnancy and lactation.  Public Health Nutr. 2005;  8 1010-1027
    CrossrefPubMedGoogle Scholar
  • 2 Dewey KG. Energy and protein requirements during lactation.  Annu Rev Nutr. 1997;  17 19-36
    CrossrefPubMedGoogle Scholar
  • 3 Picciano MF. Pregnancy and lactation: physiological adjustments, nutritional requirements and the role of dietary supplements.  J Nutr. 2003;  133 1997-2002
    CrossrefPubMedGoogle Scholar
  • 4 Flint DJ, Vernon RG. Effects of food restriction on the responses of the mammary gland and adipose tissue to prolactin and growth hormone in the lactating rat.  J Endocrinol. 1998;  156 299-305
    CrossrefPubMedGoogle Scholar
  • 5 Grosvenor CE, Picciano MF, Baumrucker CR. Hormones and growth factors in milk.  Endocr Rev. 1993;  14 710-728
    CrossrefPubMedGoogle Scholar
  • 6 Rasmussen KM. Effects of under- and overnutrition on lactation in laboratory rats.  J Nutr. 1998;  128 390-393
    CrossrefPubMedGoogle Scholar
  • 7 Bruder ED, Lee JJ, Widmaier EP, Raff H. Microarray and real-time PCR analysis of adrenal gland gene expression in the 7-day-old rat: effects of hypoxia from birth.  Physiol Genomics. 2007;  29 193-200
    CrossrefPubMedGoogle Scholar
  • 8 Chiodi H, Whitmore S. Lipid metabolism in suckling rats with fatty liver induced by hypoxia.  Experientia. 1974;  30 463-465
    CrossrefPubMedGoogle Scholar
  • 9 Harris RJ. Plasma nonesterified fatty acid and blood glucose levels in healthy and hypoxemic newborn infants.  J Pediatr. 1974;  84 578-584
    CrossrefPubMedGoogle Scholar
  • 10 Lee PC, Jelinek B, Struve M, Bruder ED, Raff H. Effect of neonatal hypoxia on the development of hepatic lipase in the rat.  Am J Physiol Regul Integr Comp Physiol. 2000;  279 1341-1347
    CrossrefPubMedGoogle Scholar
  • 11 White MM, MacCullough RE, Dyckes R, Robertson AD, Moore LG. Effects of pregnancy and chronic hypoxia on contractile responsiveness to alpha1-adrenergic stimulation.  J Appl Physiol. 1998;  85 2322-2329
    CrossrefPubMedGoogle Scholar
  • 12 Raff H, Sandri RB, Segerson TP. Renin, ACTH, and adrenocortical function during hypoxia and hemorrhage in conscious rats.  Am J Physiol. 1986;  250 240-244
    PubMedGoogle Scholar
  • 13 Raff H, Bruder ED. Adiponectin and resistin in the neonatal rat: effects of dexamethasone and hypoxia.  Endocrine. 2006;  29 341-344
    CrossrefPubMedGoogle Scholar
  • 14 Westerterp-Plantenga MS, Westerterp KR, Rubbens M, Verwegen CR, Richelet JP, Gardette B. Appetite at “high altitude” [Operation Everest III (Comex-‘97)]: a simulated ascent of Mount Everest.  J Appl Physiol. 1999;  87 391-399
    CrossrefPubMedGoogle Scholar
  • 15 Bruder ED, Lee PC, Raff H. Lipid and fatty acid profiles in the brain, liver, and stomach contents of neonatal rats: effects of hypoxia.  Am J Physiol Endocrinol Metab. 2005;  288 314-320
    CrossrefPubMedGoogle Scholar
  • 16 Raff H, Bruder ED, Jankowski BM, Goodfriend TL. Neonatal hypoxic hyperlipidemia in the rat: effects on aldosterone and corticosterone synthesis in vitro.  Am J Physiol Regul Integr Comp Physiol. 2000;  278 663-668
    CrossrefPubMedGoogle Scholar
  • 17 Seagroves TN, Hadsell D, MacManaman J, Palmer C, Liao D, MacNulty W, Welm B, Wagner KU, Neville M, Johnson RS. HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland.  Development. 2003;  130 1713-1724
    CrossrefPubMedGoogle Scholar
  • 18 Bruder ED, Lee PC, Raff H. Metabolic consequences of hypoxia from birth and dexamethasone treatment in the neonatal rat: comprehensive hepatic lipid and fatty acid profiling.  Endocrinology. 2004;  145 5364-5372
    CrossrefPubMedGoogle Scholar
  • 19 Moromisato DY, Moromisato MY, Brasel JA, Cooper DM. Effect of growth hormone therapy in mitigating hypoxia-induced and food restriction-induced growth retardation in the newborn rat.  Crit Care Med. 1999;  27 2234-2238
    CrossrefPubMedGoogle Scholar
  • 20 Raff H, Bruder ED, Jankowski BM, Colman RJ. Effect of neonatal hypoxia on leptin, insulin, growth hormone and body composition in the rat.  Horm Metab Res. 2001;  33 151-155
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Bowen RA, Clandinin MT. Dietary low linolenic acid compared with docosahexaenoic acid alter synaptic plasma membrane phospholipid fatty acid composition and sodium-potassium ATPase kinetics in developing rats.  J Neurochem. 2002;  83 764-774
    CrossrefPubMedGoogle Scholar
  • 22 Murphy KG, Dhillo WS, Bloom SR. Gut peptides in the regulation of food intake and energy homeostasis.  Endocr Rev. 2006;  27 719-727
    CrossrefPubMedGoogle Scholar
  • 23 Read LC, Francis GL, Wallace JC, Ballard FJ. Growth factor concentrations and growth-promoting activity in human milk following premature birth.  J Dev Physiol. 1985;  7 135-145
    PubMedGoogle Scholar
  • 24 Kang SG, Brown AL, Chung JH. Oxygen tension regulates the stability of insulin receptor substrate-1 (IRS-1) through caspase-mediated cleavage.  J Biol Chem. 2007;  282 6090-6097
    CrossrefPubMedGoogle Scholar
  • 25 Foltzer-Jourdainne C, Garaud JC, Nsi-Emvo E, Raul F. Epidermal growth factor and the maturation of intestinal sucrase in suckling rats.  Am J Physiol. 1993;  265 459-466
    PubMedGoogle Scholar
  • 26 Bruder ED, Lee PC, Raff H. Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids.  J Appl Physiol. 2005;  98 981-990
    CrossrefPubMedGoogle Scholar
  • 27 Strewler GJ. The physiology of parathyroid hormone-related protein.  N Engl J Med. 2000;  342 177-185
    CrossrefPubMedGoogle Scholar
  • 28 VanHouten J, Dann P, MacGeoch G, Brown EM, Krapcho K, Neville M, Wysolmerski JJ. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport.  J Clin Invest. 2004;  113 598-608
    CrossrefPubMedGoogle Scholar
  • 29 Dunger D, Ong K. Abundance of adiponectin in the newborn.  Clin Endocrinol. 2004;  61 416-417
    CrossrefPubMedGoogle Scholar
  • 30 Kotani Y, Yokota I, Kitamura S, Matsuda J, Naito E, Kuroda Y. Plasma adiponectin levels in newborns are higher than those in adults and positively correlated with birth weight.  Clin Endocrinol. 2004;  61 418-423
    CrossrefPubMedGoogle Scholar
  • 31 Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity.  Obes Rev. 2005;  6 13-21
    CrossrefPubMedGoogle Scholar
  • 32 Mistry AM, Swick A, Romsos DR. Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice.  Am J Physiol. 1999;  277 742-747
    PubMedGoogle Scholar
  • 33 Sanchez J, Oliver P, Miralles O, Ceresi E, Pico C, Palou A. Leptin orally supplied to neonate rats is directly uptaken by the immature stomach and may regulate short-term feeding.  Endocrinology. 2005;  146 2575-2582
    CrossrefPubMedGoogle Scholar
  • 34 Walker CD, Salzmann C, Long H, Otis M, Roberge C, Gallo-Payet N. Direct inhibitory effects of leptin on the neonatal adrenal and potential consequences for brain glucocorticoid feedback.  Endocr Res. 2004;  30 837-844
    CrossrefPubMedGoogle Scholar
  • 35 Lee PC, Struve M, Raff H. Effects of hypoxia on the development of intestinal enzymes in neonatal and juvenile rats.  Exp Biol Med. 2003;  228 717-723
    CrossrefPubMedGoogle Scholar
  • 36 Raff H, Jacobson L, Cullinan WE. Elevated corticosterone and inhibition of ACTH responses to CRH and ether in the neonatal rat: effect of hypoxia from birth.  Am J Physiol Regul Integr Comp Physiol. 2003;  285 1224-1230
    CrossrefPubMedGoogle Scholar
  • 37 Nagasawa H. A device for milk collection from mice.  Lab Anim Sci. 1979;  29 633-635
    PubMedGoogle Scholar
  • 38 Schaudies RP, Grimes J, Wray HL, Koldovsky O. Identification and partial characterization of multiple forms of biologically active EGF in rat milk.  Am J Physiol. 1990;  259 1056-1061
    PubMedGoogle Scholar
  • 39 Lee PC, Struve M, Lewis SM, Raff H. Neonatal hypoxia in the rat: effects on exocrine pancreatic development.  J Pediatr Gastroenterol Nutr. 2002;  34 542-547
    CrossrefPubMedGoogle Scholar
  • 40 Dembinski AB, Johnson LR. Effect of epidermal growth factor on the development of rat gastric mucosa.  Endocrinology. 1985;  116 90-94
    CrossrefPubMedGoogle Scholar
  • 41 Puccio F, Lehy T. Oral administration of epidermal growth factor in suckling rats stimulates cell DNA synthesis in fundic and antral gastric mucosae as well as in intestinal mucosa and pancreas.  Regul Pept. 1988;  20 53-64
    CrossrefPubMedGoogle Scholar
  • 42 Feng J, Besner GE. Heparin-binding epidermal growth factor-like growth factor promotes enterocyte migration and proliferation in neonatal rats with necrotizing enterocolitis.  J Pediatr Surg. 2007;  42 214-220
    CrossrefPubMedGoogle Scholar
  • 43 Caplan MS, Russell T, Xiao Y, Amer M, Kaup S, Jilling T. Effect of polyunsaturated fatty acid (PUFA) supplementation on intestinal inflammation and necrotizing enterocolitis (NEC) in a neonatal rat model.  Pediatr Res. 2001;  49 647-652
    CrossrefPubMedGoogle Scholar
  • 44 Pacha J. Development of intestinal transport function in mammals.  Physiol Rev. 2000;  80 1633-1667
    CrossrefPubMedGoogle Scholar
  • 45 Menard D, Arsenault P, Gallo-Payet N. Epidermal growth factor does not act as a primary cue for inducing developmental changes in suckling mouse jejunum.  J Pediatr Gastroenterol Nutr. 1986;  5 949-955
    CrossrefPubMedGoogle Scholar
  • 46 Morisset J. Regulation of growth and development of the gastrointestinal tract.  J Dairy Sci. 1993;  76 2080-2093
    CrossrefPubMedGoogle Scholar
  • 47 Blackshaw LA. Parathyroid hormone-related peptide: A jack of all trades that masters gastric responses to stress.  J Gastroenterol Hepatol. 2003;  18 1-3
    CrossrefPubMedGoogle Scholar
  • 48 Yamaji R, Sakamoto M, Miyatake K, Nakano Y. Hypoxia inhibits gastric emptying and gastric acid secretion in conscious rats.  J Nutr. 1996;  126 673-680
    CrossrefPubMedGoogle Scholar
  • 49 Yoshimoto M, Sasaki M, Naraki N, Mohri M, Miki K. Regulation of gastric motility at simulated high altitude in conscious rats.  J Appl Physiol. 2004;  97 599-604
    CrossrefPubMedGoogle Scholar
  • 50 Weyermann M, Beermann C, Brenner H, Rothenbacher D. Adiponectin and leptin in maternal serum, cord blood, and breast milk.  Clin Chem. 2006;  52 2095-2102
    CrossrefPubMedGoogle Scholar
  • 51 Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1.  J Biol Chem. 2002;  277 34601-34609
    CrossrefPubMedGoogle Scholar
  • 52 Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG, Carrasco N. The mammary gland iodide transporter is expressed during lactation and in breast cancer.  Nat Med. 2000;  6 871-878
    CrossrefPubMedGoogle Scholar
  • 53 Capuco AV, Kahl S, Jack LJ, Bishop JO, Wallace H. Prolactin and growth hormone stimulation of lactation in mice requires thyroid hormones.  Proc Soc Exp Biol Med. 1999;  221 345-351
    CrossrefPubMedGoogle Scholar
  • 54 Berg MN, Dharmarajan AM, Waddell BJ. Glucocorticoids and progesterone prevent apoptosis in the lactating rat mammary gland.  Endocrinology. 2002;  143 222-227
    CrossrefPubMedGoogle Scholar
  • 55 Draper N, Stewart PM. 11beta-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action.  J Endocrinol. 2005;  186 251-271
    CrossrefPubMedGoogle Scholar
  • 56 Burnol AF, Leturque A, Loizeau M, Postic C, Girard J. Glucose transporter expression in rat mammary gland.  Biochem J. 1990;  270 277-279
    CrossrefPubMedGoogle Scholar
  • 57 Shennan DB, Peaker M. Transport of milk constituents by the mammary gland.  Physiol Rev. 2000;  80 925-951
    CrossrefPubMedGoogle Scholar
  • 58 Ishiki M, Klip A. Mini-review: recent developments in the regulation of glucose transporter-4 traffic: new signals, locations, and partners.  Endocrinology. 2005;  146 5071-5078
    CrossrefPubMedGoogle Scholar
  • 59 Frankel L, Stevenson DK. Metabolic emergencies of the newborn: hypoxemia and hypoglycemia.  Compr Ther. 1987;  13 14-19
    PubMedGoogle Scholar
  • 60 Friedman AH, Fahey JT. The transition from fetal to neonatal circulation: normal responses and implications for infants with heart disease.  Semin Perinatol. 1993;  17 106-121
    PubMedGoogle Scholar

Correspondence

H. RaffPhD 

Endocrinology

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