Prenatal testosterone exposure leads to gonadal hormone-dependent hyperinsulinemia and gonadal hormone-independent glucose intolerance in adult male rat offspring

Biology of Reproduction

Volumn 94, Issue 1, 2016, Pages

  More, Amar S ^a   Mishra, Jay S ^a   Gopalakrishnan, Kathirvel ^a   Blesson, Chellakkan S ^b   Hankins, Gary D ^a   Sathishkumar, Kunju ^a  

^a University of Texas Medical Branch School of Medicine   (United States)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

Developmental programing; Glucose intolerance; Gonadectomy; Hyperinsulinemia; Insulin resistance; Pancreas

Indexed keywords

C PEPTIDE; GLUCOSE BLOOD LEVEL; INSULIN RECEPTOR; TESTOSTERONE; TESTOSTERONE PROPIONATE;

ANIMAL; BLOOD; BODY WEIGHT; DRUG EFFECTS; FEMALE; GLUCOSE BLOOD LEVEL; GLUCOSE INTOLERANCE; HYPERANDROGENISM; HYPERINSULINISM; MALE; METABOLISM; ORCHIECTOMY; PANCREAS; PANCREAS ISLET; PANCREAS ISLET BETA CELL; PATHOLOGY; PREGNANCY; PRENATAL EXPOSURE; RAT; SKELETAL MUSCLE; SPRAGUE DAWLEY RAT;

ANIMALS; BLOOD GLUCOSE; BODY WEIGHT; C-PEPTIDE; FEMALE; GLUCOSE INTOLERANCE; HYPERANDROGENISM; HYPERINSULINISM; INSULIN-SECRETING CELLS; ISLETS OF LANGERHANS; MALE; MUSCLE, SKELETAL; ORCHIECTOMY; PANCREAS; PREGNANCY; PRENATAL EXPOSURE DELAYED EFFECTS; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, INSULIN; TESTOSTERONE; TESTOSTERONE PROPIONATE;

EID: 84957899774     PISSN: 00063363     EISSN: 15297268     Source Type: Journal    
DOI: 10.1095/biolreprod.115.133157     Document Type: Article

References (83)

1. Centers for Disease Control and Prevention (CDC). National diabetes statistics report [Internet], 2014. Atlanta, GA: Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/pubs/statsreport14.htm. Accessed 17 February 2014.
2. Demissie M, Lazic M, Foecking EM, Aird F, Dunaif A, Levine JE. Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am J Physiol Endocrinol Metab 2008; 295:E262-E268.
3. Eisner JR, Dumesic DA, Kemnitz JW, Abbott DH. Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys. J Clin Endocrinol Metab 2000; 85:1206-1210.
4. Padmanabhan V, Veiga-Lopez A, Abbott DH, Recabarren SE, Herkimer C. Developmental programming: impact of prenatal testosterone excess and postnatal weight gain on insulin sensitivity index and transfer of traits to offspring of overweight females. Endocrinology 2010; 151:595-605.
5. Roland AV, Nunemaker CS, Keller SR, Moenter SM. Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol 2010; 207:213-223.
6. Veiga-Lopez A, Moeller J, Patel D, Ye W, Pease A, Kinns J, Padmanabhan V. Developmental programming: impact of prenatal testosterone excess on insulin sensitivity, adiposity, and free fatty acid profile in postpubertal female sheep. Endocrinology 2013; 154:1731-1742.
7. Alexander BT. Fetal programming of hypertension. Am J Physiol Regul Integr Comp Physiol 2006; 290:R1-R10.
8. Blesson CS, Sathishkumar K, Chinnathambi V, Yallampalli C. Gestational protein restriction impairs insulin-regulated glucose transport mechanisms in gastrocnemius muscles of adult male offspring. Endocrinology 2014; 155:3036-3046.
9. Ozaki T, Nishina H, Hanson MA, Poston L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol 2001; 530:141-152.
10. Stocker CJ, Arch JR, Cawthorne MA. Fetal origins of insulin resistance and obesity. Proc Nutr Soc 2005; 64:143-151.
11. Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG. Androgens in preeclampsia. Am J Obstet Gynecol 1999; 180:60-63.
12. Ghorashi V, Sheikhvatan M. The relationship between serum concentration of free testosterone and pre-eclampsia. Endokrynol Pol 2008; 59:390-392.
13. Salamalekis E, Bakas P, Vitoratos N, Eleptheriadis M, Creatsas G. Androgen levels in the third trimester of pregnancy in patients with preeclampsia. Eur J Obstet Gynecol Reprod Biol 2006; 126:16-19.
14. Codner E, Escobar-Morreale HF. Clinical review: hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus. J Clin Endocrinol Metab 2007; 92:1209-1216.
15. Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Perez-Bravo F, Recabarren SE. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod 2002; 17:2573-2579.
16. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 1983; 57:304-310.
17. Pasquali R, Casimirri F, Cantobelli S, Labate AM, Venturoli S, Paradisi R, Zannarini L. Insulin and androgen relationships with abdominal body fat distribution in women with and without hyperandrogenism. Horm Res 1993; 39:179-187.
18. Sarkar P, Bergman K, Fisk NM, O'Connor TG, Glover V. Amniotic fluid testosterone: relationship with cortisol and gestational age. Clin Endocrinol (Oxf) 2007; 67:743-747.
19. Sarkar P, Bergman K, O'Connor TG, Glover V. Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: possible implications for foetal programming. J Neuroendocrinol 2008; 20:489-496.
20. Kandel DB, Udry JR. Prenatal effects of maternal smoking on daughters' smoking: nicotine or testosterone exposure? Am J Public Health 1999; 89:1377-1383.
21. Ramlau-Hansen CH, Thulstrup AM, Olsen J, Ernst E, Andersen CY, Bonde JP. Maternal smoking in pregnancy and reproductive hormones in adult sons. Int J Androl 2008; 31:565-572.
22. Rizwan S, Manning JT, Brabin BJ. Maternal smoking during pregnancy and possible effects of in utero testosterone: evidence from the 2D:4D finger length ratio. Early Hum Dev 2007; 83:87-90.
23. Hall WD, Ferrario CM, Moore MA, Hall JE, Flack JM, Cooper W, Simmons JD, Egan BM, Lackland DT, Perry M Jr, Roccella EJ. Hypertension-related morbidity and mortality in the southeastern United States. Am J Med Sci 1997; 313:195-209.
24. Hoyert DL, Freedman MA, Strobino DM, Guyer B. Annual summary of vital statistics: 2000. Pediatrics 2001; 108:1241-1255.
25. Huisman HW, Schutte AE, Van Rooyen JM, Malan NT, Malan L, Schutte R, Kruger A. The influence of testosterone on blood pressure and risk factors for cardiovascular disease in a black South African population. Ethn Dis 2006; 16:693-698.
26. Clark LT, El-Atat F. Metabolic syndrome in African Americans:implications for preventing coronary heart disease. Clin Cardiol 2007; 30:161-164.
27. Jiang B, Kamat A, Mendelson CR. Hypoxia prevents induction of aromatase expression in human trophoblast cells in culture: potential inhibitory role of the hypoxia-inducible transcription factor Mash-2 (mammalian achaete-scute homologous protein-2). Mol Endocrinol 2000; 14:1661-1673.
28. Zhu SJ, Li Y, Li H, Wang YL, Xiao ZJ, Vihko P, Piao YS. Retinoic acids promote the action of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 on the biosynthesis of 17beta-estradiol in placental cells. J Endocrinol 2002; 172:31-43.
29. Diaz L, Noyola-Martinez N, Barrera D, Hernandez G, Avila E, Halhali A, Larrea F. Calcitriol inhibits TNF-a-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol 2009; 81:17-24.
30. Milczarek R, Sokolowska E, Hallmann A, Kaletha K, Klimek J. NADPHand iron-dependent lipid peroxidation inhibit aromatase activity in human placental microsomes. J Steroid Biochem Mol Biol 2008; 110:230-235.
31. Christensen A. Hormone and enzyme assays in pregnancy. I. Studies on the placental and the tissue cystine-aminopeptidase activity in peripheral plasma from non-pregnant and pregnant women, and in plasma from the umbilical cord. Acta Endocrinol (Copenh) 1974; 76:189-200.
32. Zhang C, Williams MA, Sanchez SE, King IB, Ware-Jauregui S, Larrabure G, Bazul V, Leisenring WM. Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women. Am J Epidemiol 2001; 153:572-580.
33. Williams MA, Woelk GB, King IB, Jenkins L, Mahomed K. Plasma carotenoids, retinol, tocopherols, and lipoproteins in preeclamptic and normotensive pregnant Zimbabwean women. Am J Hypertens 2003; 16:665-672.
34. Cackovic M, Buhimschi CS, Zhao G, Funai EF, Norwitz ER, Kuczynski E, Lockwood CJ, Buhimschi IA. Fractional excretion of tumor necrosis factor-a in women with severe preeclampsia. Obstet Gynecol 2008; 112:93-100.
35. Kaur G, Mishra S, Sehgal A, Prasad R. Alterations in lipid peroxidation and antioxidant status in pregnancy with preeclampsia. Mol Cell Biochem 2008; 313:37-44.
36. de Zegher F, Devlieger H, Eeckels R. Fetal growth: boys before girls. Horm Res 1999; 51:258-259.
37. Viger RS, Silversides DW, Tremblay JJ. New insights into the regulation of mammalian sex determination and male sex differentiation. Vitam Horm 2005; 70:387-413.
38. Hotchkiss AK, Lambright CS, Ostby JS, Parks-Saldutti L, Vandenbergh JG, Gray LE Jr. Prenatal testosterone exposure permanently masculinizes anogenital distance, nipple development, and reproductive tract morphology in female Sprague-Dawley rats. Toxicol Sci 2007; 96:335-345.
39. Carlsen SM, Jacobsen G, Romundstad P. Maternal testosterone levels during pregnancy are associated with offspring size at birth. Eur J Endocrinol 2006; 155:365-370.
40. Manikkam M, Crespi EJ, Doop DD, Herkimer C, Lee JS, Yu S, Brown MB, Foster DL, Padmanabhan V. Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology 2004; 145:790-798.
41. Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension 2000; 36:790-794.
42. Padmanabhan V, Manikkam M, Recabarren S, Foster D. Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female. Mol Cell Endocrinol 2006; 246:165-174.
43. Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord 2007; 8:127-141.
44. Wu XY, Li ZL, Wu CY, Liu YM, Lin H, Wang SH, Xiao WF. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J 2010; 57:201-209.
45. Chinnathambi V, Balakrishnan M, Yallampalli C, Sathishkumar K. Prenatal testosterone exposure leads to hypertension that is gonadal hormone-dependent in adult rat male and female offspring. Biol Reprod 2012. 86:137.
46. Kent SC, Gnatuk CL, Kunselman AR, Demers LM, Lee PA, Legro RS. Hyperandrogenism and hyperinsulinism in children of women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab 2008; 93:1662-1669.
47. Sir-Petermann T, Maliqueo M, Codner E, Echiburu B, Crisosto N, Perez V, Perez-Bravo F, Cassorla F. Early metabolic derangements in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:4637-4642.
48. King AJ, Olivier NB, Mohankumar PS, Lee JS, Padmanabhan V, Fink GD. Hypertension caused by prenatal testosterone excess in female sheep. Am J Physiol Endocrinol Metab 2007; 292:E1837-E1841.
49. Blesson CS, Chinnathambi V, Hankins GD, Yallampalli C, Sathishkumar K. Prenatal testosterone exposure induces hypertension in adult females via androgen receptor-dependent protein kinase Cd-mediated mechanism. Hypertension 2014; 65:683-690.
50. Alexanderson C, Eriksson E, Stener-Victorin E, Lystig T, Gabrielsson B, Lonn M, Holmang A. Postnatal testosterone exposure results in insulin resistance, enlarged mesenteric adipocytes, and an atherogenic lipid profile in adult female rats: comparisons with estradiol and dihydrotestosterone. Endocrinology 2007; 148:5369-5376.
51. Recabarren SE, Padmanabhan V, Codner E, Lobos A, Duran C, Vidal M, Foster DL, Sir-Petermann T. Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone. Am J Physiol Endocrinol Metab 2005; 289:E801-E806.
52. Eisner JR, Dumesic DA, Kemnitz JW, Colman RJ, Abbott DH. Increased adiposity in female rhesus monkeys exposed to androgen excess during early gestation. Obes Res 2003; 11:279-286.
53. Nilsson C, Niklasson M, Eriksson E, Bjorntorp P, Holmang A. Imprinting of female offspring with testosterone results in insulin resistance and changes in body fat distribution at adult age in rats. J Clin Invest 1998; 101:74-78.
54. Franco MC, Dantas AP, Akamine EH, Kawamoto EM, Fortes ZB, Scavone C, Tostes RC, Carvalho MH, Nigro D. Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. J Cardiovasc Pharmacol 2002; 40:501-509.
55. Woods LL, Ingelfinger JR, Rasch R. Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol 2005; 289:R1131-R1136.
56. Varlamov O, Bethea CL, Roberts CT Jr. Sex-specific differences in lipid and glucose metabolism. Front Endocrinol (Lausanne) 2014; 5:241.
57. Wolf CJ, Hotchkiss A, Ostby JS, LeBlanc GA, Gray LE Jr. Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study. Toxicol Sci 2002; 65:71-86.
58. Sathishkumar K, Elkins R, Yallampalli U, Yallampalli C. Protein restriction during pregnancy induces hypertension in adult female rat offspring: influence of estradiol. Br J Nutr 2012; 107:665-673.
59. Hsing AW, Gao YT, Chua S Jr, Deng J, Stanczyk FZ. Insulin resistance and prostate cancer risk. J Natl Cancer Inst 2003; 95:67-71.
60. Park JM, Bong HY, Jeong HI, Kim YK, Kim JY, Kwon O. Postprandial hypoglycemic effect of mulberry leaf in Goto-Kakizaki rats and counterpart control Wistar rats. Nutr Res Pract 2009; 3:272-278.
61. Zhong L, Georgia S, Tschen SI, Nakayama K, Nakayama K, Bhushan A. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic b cells. J Clin Invest 2007; 117:2869-2876.
62. Huang HH, Farmer K, Windscheffel J, Yost K, Power M, Wright DE, Stehno-Bittel L. Exercise increases insulin content and basal secretion in pancreatic islets in type 1 diabetic mice. Exp Diabetes Res 2011; 2011:481427.
63. Sathishkumar K, Elkins R, Chinnathambi V, Gao H, Hankins GD, Yallampalli C. Prenatal testosterone-induced fetal growth restriction is associated with down-regulation of rat placental amino acid transport. Reprod Biol Endocrinol 2011; 9:1-12.
64. Sathishkumar K, Elkins R, Yallampalli U, Balakrishnan M, Yallampalli C. Fetal programming of adult hypertension in female rat offspring exposed to androgens in utero. Early Hum Dev 2011; 87:407-414.
65. Tura A, Ludvik B, Nolan JJ, Pacini G, Thomaseth K. Insulin and Cpeptide secretion and kinetics in humans: direct and model-based measurements during OGTT. Am J Physiol Endocrinol Metab 2001; 281:E966-E974.
66. Chinnathambi V, Yallampalli C, Sathishkumar K. Prenatal testosterone induces sex-specific dysfunction in endothelium-dependent relaxation pathways in adult male and female rats. Biol Reprod 2013; 89:1.
67. Wolf CJ, LeBlanc GA, Gray LE Jr. Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. Toxicol Sci 2004; 78:135-143.
68. Beckett EM, Astapova O, Steckler TL, Veiga-Lopez A, Padmanabhan V. Developmental programing: impact of testosterone on placental differentiation. Reproduction 2014; 148:199-209.
69. Recabarren SE, Lobos A, Figueroa Y, Padmanabhan V, Foster DL, Sir-Petermann T. Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep. Biol Res 2007; 40:329-338.
70. Birch RA, Padmanabhan V, Foster DL, Unsworth WP, Robinson JE. Prenatal programming of reproductive neuroendocrine function: fetal androgen exposure produces progressive disruption of reproductive cycles in sheep. Endocrinology 2003; 144:1426-1434.
71. Parker L, Lai M, Wolk F, Lifrak E, Kim S, Epstein L, Hadley D, Miller J. Orchiectomy does not selectively increase adrenal androgen concentrations. J Clin Endocrinol Metab 1984; 59:547-550.
72. Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology 2009; 150:2109-2117.
73. German JP, Wisse BE, Thaler JP, Oh I, Sarruf DA, Ogimoto K, Kaiyala KJ, Fischer JD, Matsen ME, Taborsky GJ Jr, Schwartz MW, Morton GJ. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 2010; 59:1626-1634.
74. Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG, Kieffer TJ, Bamji SX, Clee SM, et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 2012; 16:723-737.
75. Costes S, Langen R, Gurlo T, Matveyenko AV, Butler PC. b-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 2013; 62:327-335.
76. Li RJ, Qiu SD, Wang HX, Tian H, Wang LR, Huo YW. Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus. Apoptosis 2008; 13:959-971.
77. Nicol LE, O'Brien TD, Dumesic DA, Grogan T, Tarantal AF, Abbott DH. Abnormal infant islet morphology precedes insulin resistance in PCOSlike monkeys. PLOS ONE 2014; 9:e106527.
78. Morimoto S, Fernandez-Mejia C, Romero-Navarro G, Morales-Peza N, Diaz-Sanchez V. Testosterone effect on insulin content, messenger ribonucleic acid levels, promoter activity, and secretion in the rat. Endocrinology 2001; 142:1442-1447.
79. Grillo ML, Jacobus AP, Scalco R, Amaral F, Rodrigues DO, Loss ES, Wassermann GF. Testosterone rapidly stimulates insulin release from isolated pancreatic islets through a non-genomic dependent mechanism. Horm Metab Res 2005; 37:662-665.
80. Rankin MM, Kushner JA. Adaptive b-cell proliferation is severely restricted with advanced age. Diabetes 2009; 58:1365-1372.
81. Tschen SI, Dhawan S, Gurlo T, Bhushan A. Age-dependent decline in bcell proliferation restricts the capacity of b-cell regeneration in mice. Diabetes 2009; 58:1312-1320.
82. Cnop M, Hughes SJ, Igoillo-Esteve M, Hoppa MB, Sayyed F, van de Laar L, Gunter JH, de Koning EJ, Walls GV, Gray DW, Johnson PR, Hansen BC, et al. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 2010; 53:321-330.
83. Fatani S, Abubakari AR, Itua I, Wong C, Thomas C, Naderali EK. Effects of diet-induced obesity on protein expression in insulin signaling pathways of skeletal muscle in male Wistar rats. Int J Gen Med 2012; 5:573-582.