Genomic Analysis of Sexual Dimorphism of Gene Expression in the Mouse Adrenal Gland

Abstract

A relevant gender difference exists in adrenal physiology and propensity to disease. In mice, a remarkable sexual dimorphism is present in several components of the hypothalamic-pituitary-adrenal axis, with females displaying higher adrenal weight, plasma ACTH, corticosterone, and aldosterone levels than males. The molecular bases of this sexual dimorphism are little known. We have compared global gene expression profiles in males vs. female mouse adrenal glands and also studied the effect that testosterone treatment and castration have on adrenal gene expression in female vs. male mice, respectively. Our study evidenced a set of 71 genes that are coordinately modulated according to sex and hormonal treatments and represent the core sexually dimorphic expression program in the mouse adrenal gland. Moreover, we show that some genes involved in steroid metabolism have a remarkable sexual dimorphic expression and identify new potential markers for the adrenal X-zone, a transitory cellular layer in the inner adrenal cortex, which spontaneously regresses at puberty in males and during the first pregnancy in females and has an uncertain physiological role. Finally, sexually dimorphic expression of the transcriptional regulators Nr5a1 and Nr0b1 may explain at least in part the differences in adrenal steroidogenesis between sexes.

Key words

gene expression - adrenal gland - genomics

^* These authors contributed equally to this work.

• References

• 1 Brown ES, Varghese FP, McEwen BS. Association of depression with medical illness-does cortisol play a role?. Biol Psychiatry 2004; 55: 1-9
• 2 Schwartz AR, Gerin W, Davidson KW, Pickering TG, Brosschot JF, Thayer JF, Christenfield N, Linden W. Towards a causal model of cardiovascular responses to stress and the development of cardiovascular disease. Psychosom Med 2003; 65: 22-35
• 3 Kreier F, Yilmaz A, Kalsbeek A, Romjin JA, Sauerwein HP, Fliers E, Buijs RM. Hypothesis: shifting the equilibrium from activity to food leads to autonomic unbalance and the metabolic syndrome. Diabetes 2003; 52: 2652-2656
• 4 McCabe PM, Sheridan JF, Weiss JM, Kaplan JP, Natelson BH, Pare WP. Animal models of disease. Physiol Behav 2000; 68: 501-507
• 5 Spinedi E, Suescun MO, Hadid R, Daneva T, Gaillard RC. Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological sexual dimorphism. Endocrinology 1992; 131: 2430-2436
• 6 Bielohuby M, Herbach N, Wanke R, Maser-Gluth C, Beuschlein F, Wolf E, Hoeflich A. Growth analysis of the mouse adrenal gland from weaning to adulthood: time- and gender-dependent alterations of cell size and number in the cortical compartment. Am J Physiol Endocrinol Metab 2007; 293: E139-E146
• 7 Howard-Miller E. A transitory zone in the adrenal cortex which shows age and sex relationships. Am J Anat 1927; 40: 251-293
• 8 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-159
• 9 El Wakil A, Bandulik S, Guy N, Bendahhou S, Zennaro M-C, Niehrs C, Mari B, Warth R, Barhanin J, Lalli E. Dkk3 is a component of the genetic circuitry regulating aldosterone biosynthesis in the adrenal cortex. Hum Mol Genet 2012; 21: 4922-4929
• 10 Bastida CM, Cremades A, Castells MT, López-Contreras AJ, López-García C, Sánchez-Mas J, Peñafiel R. Sexual dimorphism of ornithine decarboxylase in the mouse adrenal: influence of polyamine deprivation on catecholamine and corticoid levels. Am J Physiol Endocrinol Metab 2007; 292: E1010-E1017
• 11 Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, El Wakil A, Lalli E, Guy N, Mengual R, Reichold M, Tegtmeier I, Bendahhou S, Gomez-Sanchez CE, Aller MI, Wisden W, Weber A, Lesage F, Warth R, Barhanin J. Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO J 2008; 27: 179-187
• 12 Chen A, Zorrilla E, Smith S, Rousso D, Levy C, Vaughan J, Donaldson C, Roberts A, Lee KF, Vale W. Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior. J Neurosci 2006; 26: 5500-5510
• 13 DeGroot LJ, Jameson JL. (eds.). Endocrinology. Fourth Edition Philadephia: W. B. Saunders; 2001
• 14 Zubair M, Ishihara S, Oka S, Okumura K, Morohashi K. Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Mol Cell Biol 2006; 26: 4111-4121
• 15 Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y. Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology 2007; 148: 976-988
• 16 Pihlajoki M, Gretzinger E, Cochran R, Kyrönlahti A, Schrade A, Hiller T, Sullivan L, Shoykhet M, Schoeller EL, Brooks MD, Heikinheimo M, Wilson DB. Conditional mutagenesis of Gata6 in SF1-positive cells causes gonadal-like differentiation in the adrenal cortex of mice. Endocrinology 2013; 154: 1754-1767
• 17 Luu-The V, Pelletier G, Labrie F. Quantitative appreciation of steroidogenic gene expression in mouse tissues: new roles for type 2 5alpha-reductase, 20alpha-hydroxysteroid dehydrogenase and estrogen sulfotransferase. J Steroid Biochem Mol Biol 2005; 93: 269-276
• 18 Parker KL, Schimmer BP. Steroidogenic Factor 1: a key determinant of endocrine development and function. Endocrine Rev 1997; 18: 361-377
• 19 Lalli E, Sassone-Corsi P. DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation. Mol Endocrinol 2003; 17: 1445-1453
• 20 Mukai T, Kusaka M, Kawabe K, Goto K, Nawata H, Fujieda K, Morohashi K. Sexually dimorphic expression of Dax-1 in the adrenal cortex. Genes Cells 2002; 7: 717-729