aromatase; oestradiol; brain; sexual differentiation
Abstract :
[en] The present study was carried out to determine whether aromatase knockout (ArKO) mice are completely devoid of aromatase activity in their brain and gonads and to compare aromatase activity in wild-type and ArKO mice, as well as in heterozygous (HET) mice of both sexes that were previously shown to display a variety of reproductive behaviours; at levels intermediate between wild-type and ArKO mice. Aromatase activity was extremely low, and undetectable by the tritiated water assay, in homogenates of the preoptic area-hypothalamus of adult wild-type mice, but was induced following a 12-day treatment with testosterone. The induction of aromatase activity by testosterone was significantly larger in males than in females. Even after 12 days exposure to testosterone, no aromatase activity was detected in the brain of ArKO mice of either sex whereas HET mice showed intermediate levels of activity between ArKO and wild-type. Aromatase activity was also undetectable in the ovary of adult ArKO females but was very high in the wildtype ovary and intermediate in the HET ovary. In wild-type mice, a high level of aromatase activity was detected on the day of birth even without pretreatment with testosterone. This neonatal activity was higher in males than in females, but females nevertheless appear to display a substantial level of oestrogen production in their brain. Aromatase activity was undetectable in the brain of newborn ArKO males and females and was intermediate between wild-type and ArKO in HET mice. In conclusion, the present study confirms that ArKO mice are unable to synthesize any oestrogens, thereby validating the ArKO mouse as a valuable tool in the study of the physiological roles of oestradiol. In addition, it demonstrates that the intermediate behaviour of HET mice presumably reflects the effect of gene dosage on aromatase expression and activity, that aromatase activity is sexually differentiated in mice during the neonatal period as well as in adulthood and, finally, that the neonatal female brain produces substantial amounts of oestrogens that could play a significant role in the sexual differentiation of the female brain early in life.
Bakker, Julie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie de la différenciation sexuelle du cerveau
Baillien, M.
Honda, S.
Harada, N.
Balthazart, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie de la différenciation sexuelle du cerveau
Language :
English
Title :
Relationships between aromatase activity in the brain and gonads and behavioural deficits in homozygous and heterozygous aromatase knockout mice
MacLusky NJ, Naftolin F. Sexual differentiation of the central nervous system. Science 1981; 211: 1294-1302.
Naftolin F, Ryan KJ, Davies IJ, Reddy VV, Flores F, Petro Z, Kuhn M, White RJ, Takoaka Y, Wolin L. The formation of estrogens by central neuroendocrine tissues. Rec Prog Horm Res 1975; 31: 295-315.
Baum MJ. Differentiation of coital behavior in mammals: a comparative analysis. Neurosci Biobehav Rev 1979; 3: 265-284.
Bakker J, Brand T, van Ophemert J, Slob AK. Hormonal regulation of adult partner preference behavior in neonatally ATD-treated male rats. Behav Neurosci 1993; 107: 480-487.
Davidson JM. Effects of estrogen on the sexual behavior of male rats. Endocrinology 1969; 84: 1365-1372.
Baum MJ, Carroll RS, Cherry JA, Tobet SA. Steroidal control of behavioural, neuroendocrine, and brain sexual differentiation: studies in a carnivore, the ferret. J Neuroendocrinol 1990; 2: 401-418.
Balthazart J, Reid J, Absil P, Foidart A, Ball GF. Appetitive as well as consummatory aspects of male sexual behavior in quail are activated by androgens and estrogens. Behav Neurosci 1995; 109: 485-501.
Fisher CR, Graves KH, Parlow AF, Simpson ER. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the Cyp19 gene. Proc Natl Acad Sci USA 1998; 95: 6965-6970.
Honda S, Harada N, Ito S, Takagi Y, Maeda S. Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem Biophys Res Comms 1998; 252: 445-449.
Toda K, Okada T, Takeda K, Akira S, Saibara T, Shiraishi M, Onishi S, Shizuta Y. Oestrogen at the neonatal stage is critical for the reproductive ability of male mice as revealed by supplementation with 17β-oestradiol to aromatase gene (Cyp19) knockout mice. J Endocrinol 2001; 168: 455-463.
Bakker J, Honda S, Harada N, Balthazart J. Sexual partner preference requires a functional aromatase (Cyp19) gene in male mice. Horm Behav 2002; 42: 158-171.
Matsumoto T, Honda S, Harada N. Alteration in sex-specific behaviors in male mice lacking the aromatase gene. Neuroendocrinology 2003; 77: 416-424.
Bakker J, Honda S, Harada N, Balthazart J. Restoration of male sexual behavior by adult exogenous estrogens in male aromatase knockout mice. Horm Behav 2004; in press.
Bakker J, Honda S, Harada N, Balthazart J. The aromatase knockout mouse provides new evidence that estradiol is required during development in the female for the expression of socio-sexual behaviors in adulthood. J Neurosci 2002; 22: 9104-9112.
Raynaud P. Influence of rat estradiol binding plasma protein (EBP) on uterotrophic activity. Steroids 1971; 21: 249-258.
Tchoudakova A, Callard GV. Identification of multiple CYP19 genes encoding different cytochrome P450 aromatase isozymes in brain and ovary. Endocrinology 1998; 139: 2179-2189.
Chiang EF, Yan YL, Tong SK, Hsiao PH, Guiguen Y, Postlethwait J, Chung BC. Characterization of duplicated zebrafish cyp19 genes. J Exp Zool 2001; 290: 709-714.
Kwon JW, McAndrew BJ, Penman DJ. Cloning of brain aromatase gene and expression of brain and ovarian aromatase genes during sexual differentiation in genetic male and female Nile tilapia Oreochromis niloticus. Mol Reprod Dev 2001; 59: 359-370.
Valle LD, Ramina A, Vianello S, Belvedere P, Colombo L. Cloning of two mRNA variants of brain aromatase cytochrome P450 in rainbow trout (Oncorhynchus mykiss Walbaum). J Steroid Biochem Mol Biol 2002; 82: 19-32.
Choi I, Troyer DL, Cornwell DL, Kirby-Dobbels KR, Collante WR, Simmen FA. Closely related genes encode developmental and tissue isoforms of porcine cytochrome P450 aromatase. DNA Cell Biol 1997; 16: 769-777.
Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR, Simpson ER. Structural analysis of the gene encoding human aromatase cytochrome p-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 1989; 15: 19385-19391.
Harada N, Yamada K, Saito K, Kibe N, Dohmae S, Takagi Y. Structural characterization of the human estrogen synthetase (aromatase) gene. Biochem Biophys Res Comm 1990; 15: 365-372.
Toda K, Takeda K, Okada T, Akira S, Saibara T, Kaname T, Yamamura K, Onishi S, Shizuta Y. Targeted disruption of the aromatase P450 gene (Cyp 19) in mice and their ovarian and uterine responses to 17β-oestradiol. J Endocrinol 2001; 170: 99-111.
Roselli CE, Klosterman SA, Fanasi TA. Sex differences in androgen responsiveness in the rat brain: regional differences in the induction of aromatase activity. Neuroendocrinology 1996; 64: 139-145.
Roselli CE, Resko JA. Aromatase activity in the rat brain: hormonal regulation and sex differences. J Steroid Biochem Mol Biol 1993; 44: 499-508.
Baillien M, Balthazart J. A direct dopaminergic control of aromatase activity in the quail preoptic area. J Steroid Biochem Mol Biol 1997; 63: 99-113.
Wozniak A, Hutchison RE, Hutchison JB. Localisation of aromatase activity in androgen target areas of the mouse brain. Neurosci Lett 1992; 146: 191-194.
Foidart A, Silverin B, Baillien M, Harada N, Balthazart J. Neuro-anatomical distribution and variations across the reproductive cycle of aromatase activity and aromatase-immunoreactive cells in the pied flycatcher (Ficedula hyoleuca). Horm Behav 1998; 33: 180-196.
Sinchak K, Roselli CE, Clemens LG. Levels of serum steroids, aromatase activity, and estrogen receptors in preoptic area, hypothalamus, and amygdala of B6D2F1 male house mice that differ in the display of copulatory behavior after castration. Behav Neurosci 1996; 110: 593-602.
Harada N, Yamada K, Foidart T, Balthazart J. Regulation of aromatase cytochrome P-450 (estrogen synthetase) transcriptsin the quail brain by testosterone. Brain Res Mol Brain Res 1992; 15: 19-26.
Harada N, Abe-Dohmai S, Loeffen R, Foidart A, Balthazart J. Synergism between androgens and estrogens in the induction of aromatase and its messenger RNA in the brain. Brain Res 1993; 17: 243-256.
Gilmore DP. Sexual dimorphism in the central nervous system of marsupials. Int Rev Cytol 2002; 214: 193-224.
Balthazart J, Baillien M, Charlier TD, Cornil CA, Ball GF. Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level. J Steroid Biochem Mol Biol 2003; 86: 367-379.
Roselli CE, Klosterman SA. Sexual differentiation of aromatase activity in the rat brain: effects of perinatal steroid exposure. Endocrinology 1998; 139: 3193-3201.
Beyer C, Wozniak A, Hutchison JB. Sex-specific aromatization of testosterone in mouse hypothalamic neurons. Neuroendocrinology 1993; 58: 673-681.
Hutchison JB, Beyer C, Green S, Wozniak A. Brain formation of oestrogen in the mouse: sex dimorphism in aromatase development. J Steroid Biochem Mol Biol 1994; 49: 407-415.
Hutchison JB, Beyer C, Hutchison RE, Wozniak A. Sexual dimorphism in the developmental regulation of brain aromatase. J Steroid Biochem Mol Biol 1995; 53: 307-313.
Tobet SA, Baum MJ, Tang HB, Shim JH, Canick JA. Aromatase activity in the perinatal rat forebrain: effects of age, sex and intrauterine position. Brain Res 1985; 355: 171-178.
Weniger JP. Estrogen production by fetal rat gonads. J Steroid Biochem Mol Biol 1993; 44: 459-462.
Weniger JP, Zeis A, Chouraqui J. Estrogen production by fetal and infantile rat ovaries. Reprod Nutr Dev 1993; 33: 129-136.
Lieberburg I, McEwen BS. Estradiol-17β: a metabolite of testosterone recovered in cell nuclei from limbic areas of neonatal rat brains. Brain Res 1975; 85: 165-170.
McEwen BS, Plapinger L, Chapal C, Gerlach J, Wallach G. The role of fetoneonatal estrogen binding proteins in the association of estrogen with neonatal brain cell nuclear receptors. Brain Res 1975; 96: 400-407.
Döhler KD, Hancke JL, Srivastava SS, Hofman C, Shrine JE, Gorski RA. Participation of estrogens in female sexual differentiation of the brain: neuroanatomical, neuroendocrine, and behavioral evidence. In. De Vries GJ, De Bruin JPC, Uylings HBM, Corner MA, eds. Progress in Brain Research, vol. 61 Sex Differences in the Brain: the Relation Between Structure and Function. Amsterdam, The Netherlands: Elsevier Science Publishers, 1984: 99-117.
Liere P, Akwa YI, Weill-Engerer S, Eychenne B, Pianos A, Robel P, Sjovall J, Schumacher M, Baulieu EE. Validation of an analytical procedure to measure trace amounts of neurosteroids in brain tissue by gas chromatography-mass spectometry. J Chromatogr B 2000; 739: 301-312.
Pointis G, Latreille MT, Cedard L. Gonado-pituitary relationships in the fetal mouse at various times during sexual differentiation. J Endocrinol 1980; 86: 483-488.
Pang SF, Tang F. Sex differences in the serum concentrations of testosterone in mice and hamsters during their critical periods of neural sexual differentiation. J Endocrinol 1984; 100: 7-11.
Vreeburg JTM, Groeneveld JO, Post PE, Ooms MP. Concentrations of testosterone and androsterone in peripheral and umbilical venous plasma of fetal rats. J Reprod Fert 1983; 68: 171-175.
Baum MJ, Woutersen PJA, Slob AK. Sex difference in whole-body androgen content in rats on fetal days 18 and 19 without evidence that androgen passes from males to females. Biol Reprod 1991; 44: 747-751.
Vom Saal FS, Bronson FH. Sexual characteristics of adult female mice are correlated with their blood testosterone levels during prenatal development. Science 1980; 108: 597-599.
Gibori G, Sridaran R. Sites of androgen and estradiol production in the second half of pregnancy in the rat. Biol Reprod 1981; 24: 249-256.
Zahniser NR, Simosky JK, Mayfield RD, Negri CA, Hanania T, Larson GA, Kelly MA, Grandy DK, Rubinstein M, Low MJ, Fredholm BB. Functional uncoupling of adenosine A (2A) receptors and reduced response to caffeine in mice lacking dopamine D2 receptors. J Neurosci 2000; 20: 5949-5957.
Fowler SC, Zarcone TJ, Vorontsova E, Chen R. Motor and associative deficits in D2 dopamine receptor knockout mice. Int J Dev Neurosci 2002; 20: 309-321.
Li S, Yamauchi A, Marchal CC, Molitoris JK, Quilliam LA, Dinauer MC. Chemoattractant-stimulated Rac activation in wild-type and Rac2-deficient murine neutrophils: preferential activation of Rac2 and Rac2 gene dosage effect on neutrophil functions. J Immunol 2002; 169: 5043-5051.
Van den Buuse M, Simpson ER, Jones ME. Prepulse inhibition of acoustic startle in aromatase knock-out mice: effects of age and gender. Genes Brain Behav 2003; 2: 93-102.
Tzortzaki EG, Yang M, Glass D, Deng L, Evan AP, Bledsoe SB, Stambrook PJ, Sahota A, Tischfield JA. Impaired expression of an organic cation transporter, IMPT1, in a knockout mouse model for kidney stone disease. Urol Res 2003; 31: 257-261.
