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Adult male mice conceived by in vitro fertilization exhibit increased glucocorticoid receptor expression in fat tissue

  • R. K. Simbulan (a1), X. Liu (a1), S. K. Feuer (a1), E. Maltepe (a2), A. Donjacour (a1) (a3) and P. Rinaudo (a1)...

Prenatal development is highly plastic and readily influenced by the environment. Adverse conditions have been shown to alter organ development and predispose offspring to chronic diseases, including diabetes and hypertension. Notably, it appears that the changes in glucocorticoid hormones or glucocorticoid receptor (GR) levels in peripheral tissues could play a role in the development of chronic diseases. We have previously demonstrated that in vitro fertilization (IVF) and preimplantation embryo culture is associated with growth alterations and glucose intolerance in mice. However, it is unknown if GR signaling is affected in adult IVF offspring. Here we show that GR expression is increased in inbred (C57Bl6/J) and outbred (CF-1× B6D2F1/J) blastocysts following in vitro culture and elevated levels are also present in the adipose tissue of adult male mice. Importantly, genes involved in lipolysis and triglyceride synthesis and responsive to GR were also increased in adipose tissue, indicating that increased GR activates downstream gene pathways. The promoter region of GR, previously reported to be epigenetically modified by perinatal manipulation, showed no changes in DNA methylation status. Our findings demonstrate that IVF results in a long-term change in GR gene expression in a sex- and tissue-specific manner. These changes in adipose tissues may well contribute to the metabolic phenotype in mice conceived by IVF.

Corresponding author
*Address for correspondence: P. Rinaudo, Division of Reproductive Endocrinology and Infertility, 513 Parnassus Ave, HSW 1463E San Francisco, CA 94143, USA. (Email
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2. KM Godfrey , DJ Barker . Fetal programming and adult health. Public Health Nutr. 2001; 4, 611624.

6. DJ Barker . The developmental origins of insulin resistance. Horm Res. 2005; 64(Suppl. 3), 27.

7. AL Fowden , AJ Forhead . Endocrine mechanisms of intrauterine programming. Reproduction. 2004; 127, 515526.

9. MJ Nyirenda , RS Lindsay , CJ Kenyon , A Burchell , JR Seckl . Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest. 1998; 101, 21742181.

11. P Rinaudo , E Wang . Fetal programming and metabolic syndrome. Annu Rev Physiol. 2012; 74, 107130.

12. VW Jaddoe , JC Witteman . Hypotheses on the fetal origins of adult diseases: contributions of epidemiological studies. Eur J Epidemiol. 2006; 21, 91102.

13. D Liu , J Diorio , B Tannenbaum , et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997; 277, 16591662.

14. C Bertram , AR Trowern , N Copin , AA Jackson , CB Whorwood . The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology. 2001; 142, 28412853.

15. JD Turner , SR Alt , L Cao , et al. Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Biochem Pharmacol. 2010; 80, 18601868.

16. IC Weaver , N Cervoni , FA Champagne , et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7, 847854.

18. CB Whorwood , SJ Donovan , D Flanagan , DI Phillips , CD Byrne . Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes. 2002; 51, 10661075.

22. M Ceelen , MM van Weissenbruch , JP Vermeiden , FE van Leeuwen , HA Delemarre-van de Waal . Growth and development of children born after in vitro fertilization. Fertil Steril. 2008; 90, 16621673.

23. G Giritharan , S Talbi , A Donjacour , et al. Effect of in vitro fertilization on gene expression and development of mouse preimplantation embryos. Reproduction. 2007; 134, 6372.

24. PF Rinaudo , G Giritharan , S Talbi , AT Dobson , RM Schultz . Effects of oxygen tension on gene expression in preimplantation mouse embryos. Fertil Steril. 2006; 86(4 Suppl.), 12521265.

27. E Bloise , W Lin , X Liu , et al. Impaired placental nutrient transport in mice generated by in vitro fertilization. Endocrinology. 2012; 153, 34573467.

28. DJ Ecker , P Stein , Z Xu , et al. Long-term effects of culture of preimplantation mouse embryos on behavior. Proc Natl Acad Sci U S A. 2004; 101, 15951600.

29. A Donjacour , X Liu , W Lin , R Simbulan , PF Rinaudo . In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse model. Biol Reprod. 2014; 90, 80.

31. E Rexhaj , A Paoloni-Giacobino , SF Rimoldi , et al. Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span. J Clin Invest. 2013; 123, 50525060.

32. SK Feuer , A Donjacour , RK Simbulan , et al. Sexually dimorphic effect of in vitro fertilization (IVF) on adult mouse fat and liver metabolomes. Endocrinology. 2014; 155(11), 45544567.

33. CY Yu , O Mayba , JV Lee , et al. Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLoS One. 2010; 5, e15188.

34. P Rinaudo , RM Schultz . Effects of embryo culture on global pattern of gene expression in preimplantation mouse embryos. Reproduction. 2004; 128, 301311.

35. JD Baxter , GG Rousseau . Glucocorticoid hormone action: an overview. Monogr Endocrinol. 1979; 12, 124.

36. KL Burnstein , JA Cidlowski . The down side of glucocorticoid receptor regulation. Mol Cell Endocrinol. 1992; 83, C1C8.

37. Y Makino , N Yoshikawa , K Okamoto , et al. Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function. J Biol Chem. 1999; 274, 31823188.

39. FM Manejwala , RM Schultz . Blastocoel expansion in the preimplantation mouse embryo: stimulation of sodium uptake by cAMP and possible involvement of cAMP-dependent protein kinase. Dev Biol. 1989; 136, 560563.

40. Y Goto , Y Noda , T Mori , M Nakano . Increased generation of reactive oxygen species in embryos cultured in vitro. Free Radic Biol Med. 1993; 15, 6975.

41. F Svec . Glucocorticoid receptor regulation. Life Sci. 1985; 36, 23592366.

42. A Vegiopoulos , S Herzig . Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol. 2007; 275, 4361.

43. BR Walker . Cortisol--cause and cure for metabolic syndrome? Diabet Med. 2006; 23, 12811288.

44. M Weinstock . The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev. 2008; 32, 10731086.

45. VM Negron-Perez , FD Echevarria , SR Huffman , RM Rivera . Determination of allelic expression of h19 in pre- and peri-implantation mouse embryos. Biol Rep. 2013; 88, 97.

46. W Reik , W Dean , J Walter . Epigenetic reprogramming in mammalian development. Science. 2001; 293, 10891093.

48. AS Doherty , MR Mann , KD Tremblay , MS Bartolomei , RM Schultz . Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod. 2000; 62, 15261535.

49. RL Kember , EL Dempster , TH Lee , et al. Maternal separation is associated with strain-specific responses to stress and epigenetic alterations to Nr3c1, Avp, and Nr4a1 in mouse. Brain Behav. 2012; 2(4), 455467.

50. J Lesage , L Dufourny , C Laborie , et al. Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats. J Neuroendocrinol. 2002; 14, 135143.

51. M Leonhardt , J Lesage , L Dufourny , et al. Perinatal maternal food restriction induces alterations in hypothalamo-pituitary-adrenal axis activity and in plasma corticosterone-binding globulin capacity of weaning rat pups. Neuroendocrinology. 2002; 75, 4554.

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