Disease relevance of Cyp19a1

• By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney [1].
• Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired [2].
• Breast tumors, however, secrete soluble factors that stimulate aromatase expression through an alternative proximal promoter, promoter II [3].
• We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia [4].
• We have reported that aromatase-knockout (ArKO) mice showed bone loss by increased bone resorption not only in female but also in male mice, suggesting essential roles of estrogen in bone metabolism in both sexes [5].

Psychiatry related information on Cyp19a1

• The results indicate that despite the pronounced redistribution of sleep and motor activity in oestrogen deficient mice, the basic homeostatic mechanisms of sleep regulation in ArKO mice remain intact [6].
• Attraction thresholds and sex discrimination of urinary odorants in male and female aromatase knockout (ArKO) mice [7].
• Overall, we found that aromatase activity and P(4) levels change in association with an important life history transition, and may provide a mechanistic basis for plasticity in paternal behavior [8].

High impact information on Cyp19a1

• The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated [9].
• To test the functional capacity of a fission yeast chromosome in mouse cells, a strain of the fission yeast Schizosaccharomyces pombe, ED628 Int5, was constructed [10].
• This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action [11].
• Our findings indicate that Sm-C/IGF-I synergizes with FSH in the induction of rat granulosa cell aromatase activity at nanomolar concentrations compatible with its granulosa cell receptor binding affinity (thus far studied only in porcine cells [12].
• However, when estrogen production was blocked by embryonic treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione, the feminine phenotype of these mice was rescued [13].

Chemical compound and disease context of Cyp19a1

• We have addressed this question using aromatase-knockout (ArKO) mice that are estrogen-deficient during their lifespan but have elevated androgen levels and develop prostate enlargement and hyperplasia (McPherson SJ, Wang H, Jones ME, Pedersen J, Iismaa TP, Wreford N, Simpson ER, Risbridger GP: Endocrinology 2001, 142:2458-2467) [14].
• Because both wild-type and ArKO mice developed epithelial hyperplasia and inflammation following neonatal diethylstilbestrol treatment, this validates that estrogens directly cause prostatic inflammation and epithelial hyperplasia [14].
• Aromatase overexpression transgenic mice model: cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology [15].
• The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis [16].
• Effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on serum hormones and bone characteristics in a preclinical tumor model for breast cancer [17].

Biological context of Cyp19a1

• We observed significant downregulation of Cyp19a1 and upregulation of Star and Cyp11a1 mRNA expression in both COCs and MGCs after in vivo administration of hCG or in vitro treatment with gonadotropins or 8-Br-cAMP [18].
• The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotrophins or androgens [2].
• We show here that in both genders, ArKO(-/-) mice are vulnerable to beta-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin [19].
• Interestingly, administration of an aromatase inhibitor partly reduced T action on periosteal bone formation in orchidectomized WT mice (-34% versus orchidectomized WT mice on T), but not in ARKO mice [20].
• The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis [4].

Anatomical context of Cyp19a1

• Other down-regulated genes included: Cyp19a1, Fshr, Inhb, and the oocyte factors Zp1-3 and Gja4 [21].
• Female ArKO mice at 9 weeks of age displayed underdeveloped external genitalia and uteri [22].
• Our findings indicate that local expression of aromatase is essential for spermatogenesis and provide evidence for a direct action of estrogen on male germ cell development and thus fertility [2].
• When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice [1].
• Despite the demonstration of the aromatase enzyme, which converts androgens to estrogens, and estrogen receptors within the rodent seminiferous epithelium, the role of aromatase and estrogen in germ cell development is unknown [2].

Associations of Cyp19a1 with chemical compounds

• One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse [1].
• Circulating testosterone and dihydrotestosterone levels were significantly decreased by neonatal diethylstilbestrol treatment, remained suppressed in adult wild-type mice, but rapidly returned to control levels in ArKO animals [14].
• However, adult prostate weight and luminal size were reduced in both wild-type and ArKO animals [14].
• Nonaromatizable (dihydrotestosterone [DHT]) and aromatizable (testosterone [T]) androgens and T plus an aromatase inhibitor (anastrazole) were administered to orchidectomized ARKO and WT mice [20].
• In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets [4].

Physical interactions of Cyp19a1

• A steroidogenic factor-1-binding site and cyclic adenosine 3',5'-monophosphate response element-like elements are required for the activity of the rat aromatase promoter in rat Leydig tumor cell lines [23].
• This inhibition may explain some of the effects observed in AMG treatment which cannot be ascribed to its direct effect on the cytochrome P450scc complex or aromatase [24].

Regulatory relationships of Cyp19a1

• Even though ERbeta is expressed in aromatase/ERKO mice, lack of ERalpha leads to impaired mammary growth in these mice [25].
• We genetically engineered an aromatase-deficient mouse (Ar(-/-) mouse) to express an enhanced green fluorescent protein (EGFP) gene in the uterus, ovary, adrenal and pituitary glands in a 17beta-estradiol (E2)-inducible manner [26].
• This conclusion is supported by colocalization studies which reveal a high number of fetal hypothalamic aromatase neurones co-expressing androgen receptor [27].

Other interactions of Cyp19a1

• To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ERalpha (alphaERKO) respectively [19].
• Upon treatment of ArKO mice with the ERbeta agonist 2,3-bis(4-hydroxyphenyl)propionitrile, GLUT4 expression was reduced [28].
• As a result, betaERKO ovaries were unable to fully respond to an ovulatory bolus of gonadotropin, leading to a reduced rate of follicle rupture; insufficient induction of prostaglandin-synthase 2 and progesterone receptor; an aberrant increase in aromatase activity and plasma estradiol; and incomplete expansion of the cumulus-oocyte complex [29].
• Cyp19 encodes the key enzyme of estrogen biosynthesis, aromatase cytochrome P450 [30].
• In contrast, Cyp17 and Cyp19 expression were elevated in alphaERKO but normal in betaERKO and alphabetaERKO [31].

Analytical, diagnostic and therapeutic context of Cyp19a1

• Furthermore, data showed activation of the Stat5 (signal transducer and activator of transcription 5) signaling pathway in the AROM+ male mammary gland [32].
• When males were treated with fadrozole (an aromatase inhibitor), aggressive behavior was reduced, although castration did not reduce aggression [33].
• Using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis, we found that aromatase as well as estrogen receptors (alpha/beta) are already expressed prenatally in the hippocampus of both sexes [34].
• These results suggest that the ArKO mouse is an animal model suitable for studying effects of estrogenic chemicals as well as estrogen in vivo [35].
• Electron microscopy revealed the presence of well-developed smooth endoplasmic reticulum, few lipid droplets and mitochondria with less organized tubular structures in the ArKO luteinized interstitial cells [36].

References