Analysis Tools
reproductive system
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• hemorrhages in ovaries observed at 8 months of age
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• increased apoptotic DNA fragmentation and expression of pro-apoptotic genes in mutant ovaries relative to wild-type, not suppressed by 17beta-estradiol supplementation
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• at 9 weeks of age, male homozygotes show increased seminal vesicle weight relative to wild-type males
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• at 8 weeks of age, ovarian follicles are present at various maturational stages including primary to large antral follicles but corpora lutea are absent
• at 8 weeks, only a few lipid droplets and well-developed smooth endoplasmic reticulum are noted in mutant ovarian luteinized interstitial cells, and mitochondria show less organized tubular structures atypical of steroid-producing cells
• ultrastructural interstitial cell anomalies are reversed by 17beta-estradiol supplementation (15 microg/mouse every fourth day from 4 weeks of age for 1 month), although corpus luteum remains undetectable
• at 8 months of age, mutant ovaries display depletion of follicles, large hemorrhages, occasional macrophage-like cells in the follicular antrum, and increased frequence of mast cells relative to wild-type ovaries
• transcripts of pro-apoptotic genes (Trp53 and Bax) are significantly increased in mutant ovaries relative to wild-type; however, 17beta-estradiol supplementation fails to suppress their elevated expression
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• both at 8 weeks and at 8 months of age
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• depletion of ovarian follicles at 8 months of age
• folliculogenesis is promoted by supplemental 17beta-estradiol
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ovary cyst
(
J:70359
)
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• hemorrhagic ovarian cysts at 8 months of age
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• at 14 weeks of age, the seminiferous epithelial layers of mutant testes (stage VII of spermatogenesis) are thinner than those of wild-type testes
• however, no gross differences in thickness are observed at other stages of spermatogenesis at 14 weeks, or in testicular and epididymal weight or sperm number at 9-16 weeks and at 10 months, and mutant sperm are capable of fertilization in vitro at all test ages
• 17beta-estradiol supplementation (7.5 ug/mouse) begun within 7 days after birth results in increased thickness of mutant seminiferous epithelial cell layers
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• decreased endometrial thickness at 8 weeks of age
• treatment with 17beta-estradiol (15 microg/mouse every fourth day from 4 weeks of age for 1 month) increases proliferation of cells in the endometrium
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• decreased myometrial thickness at 8 weeks of age
• treatment with 17beta-estradiol (15 microg/mouse every fourth day from 4 weeks of age for 1 month) increases proliferation of cells in the myometrium
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small uterus
(
J:70359
)
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• at 8 weeks and 8 months of age, mutant uterine size is significantly reduced relative to wild-type size
• treatment with 17beta-estradiol (15 microg/mouse every fourth day from 4 weeks of age for 1 month) restores uterine size to wild-type levels and increases uterine expression of estrogen-regulated (lactoferrin and progesterone receptor) genes
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• at 8 weeks of age, the wet weight of mutant uterus is 6.7-fold less than that of wild-type weight
(J:70359)
• although homozygotes display a normal growth rate after birth, uterine weight is significantly reduced at 9 weeks, indicating estrogen deficiency
(J:114305)
• treatment of female homozygotes with 17beta-estradiol restores uterine weight to wild-type levels
(J:114305)
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anovulation
(
J:70359
)
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• at 8 weeks of age, absence of corpus luteum and a reduction in the number of luteinized interstitial cells indicate anovulation
• treatment with 17beta-estradiol (15 microg/mouse every fourth day from 4 weeks of age for 1 month) supports follicular development but fails to promote ovulation
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• unlike in wild-type females, treatment with PMSG followed by hCG injection at 5 weeks of age fails to induce ovulation in mutant females
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• at 8 weeks of age, fewer luteinized interstitial cells are observed in the mutant ovary consistent with anovulation
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• homozygous mutant females are totally infertile
(J:68190)
(J:70359)
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• at 10-18 weeks of age, 85% of homozygous mutant males are unable to sire offspring
• reduced male fertility is, at least in part, due to decreased mounting behavior
• normal male reproductive function is restored with 17beta-estradiol supplementation begun at birth and at 7 days, but not at 15 days, of age and is dose-dependent
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homeostasis/metabolism
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• at 24 and 36 weeks of age, male homozygotes show significantly higher fasting blood glucose levels than age-matched wild-type littermates (133.8+/-9.3 mg/dl vs 87.8+/-9.1 mg/dl and 157.8+/-12.1 mg/dl vs 73.2+/-5.3 mg/dl, respectively)
• however, no significant differences are noted in fasting blood glucose levels at 12 and 18 weeks of age
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• at 16-20 weeks of age, serum testosterone levels are significantly increased in both sexes, esp. in female homozygotes, where they are ~10-fold higher than in wild-type females
(J:70359)
• at 24 and 36 weeks of age, mean serum testosterone levels of male homozygotes are ~3.3-fold and 2-fold higher than in wild-type controls, respectively
(J:82070)
• treatment of male homozygotes with bezafibrate at a dose corresponding to 500 mg/kb body weight/day, began at 20 weeks and continued for a month, reduces serum testosterone levels at 24 weeks by 87.4%
(J:82070)
• oral administration of pioglitazone at 10 mg/kb body weight/day for 10 days prior to the age of 36 weeks, reduces serum testosterone levels at 36 weeks by 78.4%
(J:82070)
• at 9 weeks of age, serum testosterone levels are significantly increased in both female and male homozygous mutants relative to wild-type controls
(J:114305)
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• at 16-20 weeks of age, serum 17beta-estradiol levels are below the detection limit (>10 pg/ml) in both female and male homozygous mutants
(J:70359)
• at 9 weeks of age, serum 17beta-estradiol levels are undetectable in both female and male homozygous mutants
(J:114305)
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• at >2 months of age, constitutive mRNA expression of mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD) and of three peroxisome-associated enzymes, namely very long fatty acyl-CoA synthetase (VLACS), peroxisomal acyl-CoA oxidase (AOX) and catalase, are significantly lower in estrogen-free homozygotes relative to wild-type controls and estrogen-supplemented homozygotes
• in contrast, mRNA expression of microsomal CYP4A1 is significantly higher in estrogen-free homozygotes
• no significant differences are observed in the binding activities of hepatic nuclear extracts to a peroxisome proliferator response element, indicating that expression of peroxisome proliferator activated receptor alpha (PPARA) is not impaired
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• at 18 weeks and thereafter (i.e. at 24 and 36 weeks), male homozygotes show an impaired glucose tolerance relative to wild-type males during the course of an i.p. glucose tolerance test
• treatment of male homozygotes with 17beta-estradiol began at birth or at 24 weeks of age for a 12-wk period ameliorates the glucose response to a similar degree, as measured by an i.p. glucose tolerance test at 36 weeks
• treatment with bezafibrate at 24 weeks of age causes a significant reduction of blood glucose levels during an i.p. glucose tolerance test relative to untreated male homozygotes
• similarly, treatment with pioglitazone at 36 weeks of age leads to reduced blood glucose levels during an i.p. glucose tolerance test relative to untreated male homozygotes, although the response of treated mutants is still abnormal
• no significant differences in glucose tolerance are noted between mutant and wild-type males at 12 weeks of age
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• at 12 weeks of age, male homozygotes showed a small but significant reduction in blood glucose levels after i.p. insulin injection relative to wild-type controls, suggesting improved insulin tolerance at this age
• however, at 18 weeks and thereafter, males homozygotes displayed a rebound increase in glucose levels 30 min after i.p. insulin injection (0.75 mU insulin/g) during an insulin tolerance test, whereas wild-type males showed a continuous decline in blood glucose levels over the next 60 min
• insulin resistance in untreated mutant males appears to be related to high serum testosterone levels and undetectable estrogen levels
• treatment of male homozygotes with 17beta-estradiol began at birth or at 24 weeks of age for a 12-wk period ameliorates insulin sensitivity to a similar degree as measured by an i.p. insulin tolerance test at 36 weeks
• treatment with pioglitazone at 36 weeks of age leads to an ameliorated glucose response during an i.p. insulin tolerance test relative to untreated male homozygotes
• although fasting serum insulin levels of male homozygotes tend to be higher than those of wild-type males at 18, 24, and 36 weeks of age, these differences fail to reach statistical significance
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• at >2 months of age, homozygotes display a significantly increased hepatic lipid content relative to wild-type controls and estrogen-supplemented homozygotes
• relative ratio of lipid content in wild-type mice vs estrogen-free mutant mice varies from 5.5 to 14.0 in liver and from 0.75 to 3.5 in plasma
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• after a meal, total serum cholesterol levels in male homozygotes both with and without bezafibrate treatment are significantly higher than in wild-type controls at 24 weeks of age
• after a meal, male homozygotes display significantly higher total serum cholesterol levels than wild-type males at 36 weeks of age
• treatment with pioglitazone causes a significant reduction of postprandial total serum cholesterol levels in mutant males at 36 weeks of age
• no differences in fasting total serum cholesterol levels are noted between mutant and wild-type males at 13 or 25 weeks of age
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• after a meal, serum triglyceride levels are significantly increased in male homozygotes relative to wild-type controls at 36 weeks of age
• treatment with pioglitazone causes a significant reduction of postprandial serum triglyceride levels in mutant males at 36 weeks of age
• no differences in fasting serum triglycerides levels are noted between mutant and wild-type males at 13 or 25 weeks of age
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skeleton
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• at 9 weeks of age, the number of TRAP-positive multinucleated osteoclasts is significantly increased in trabecular bone from the distal femoral metaphysis of both female and male homozygotes relative to wild-type controls
• treatment with 17beta-estradiol restores osteoclast cell number to the respective wild-type numbers in both sexes
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• at 9 weeks (but not at 4 weeks), both female and male homozygotes show a significant and comparable decrease in femoral BMD relative to wild-type controls
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• at 32 weeks, female homozygotes show a much more severe loss of femoral cortical bone than age-matched male homozygotes
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• at 9 weeks of age, both female and male homozygotes show a significant loss of mineralized cancellous bone, esp. in the distal metaphysis of the femur
• by 32 weeks, female homozygotes show complete loss of femoral cancellous bone whereas age-matched male homozygotes retain some volume of cancellous bone relative to wild-type controls
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• at 9 weeks, the typical plate-like architecture of trabecular bone is destroyed and many of the connecting rods are absent
• at 9 weeks, trabecular separation is increased in female, but not in male, mutant mice
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• treatment with 17beta-estradiol completely prevents loss of femoral BMD in both sexes
• at 32 weeks, female homozygotes display a much more severe loss of femoral cancellous and cortical bone than age-matched male homozygotes, indicating that progression of bone loss is age- and sex-dependent
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• at 9 weeks of age, both female and male homozygotes show increased osteoclastic bone resorption relative to wild-type controls
• increased bone resorption is confirmed by increased serum levels of pyridinolin at 9 and 32 weeks in both sexes
• treatment with 17beta-estradiol restores bone resorption to wild-type levels in both sexes
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liver/biliary system
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• at >2 months of age, estrogen-free hepatic cells in the centrilobular and intermediate zones of mutant liver lobules show spontaneous microvesicular steatosis in the absence of necroinflammatory lesions
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• starting at 2 months of age, estrogen-free homozygotes exhibit spontaneous microvesicular hepatic steatosis of liver cells in zones 3 and 2 (centrilobular and intermediate zones in the lobules) while liver cells in zone 1 (periportal) remain intact
(J:79603)
• mutant liver cells with microvesicular steatosis are devoid of large fat droplets; however, the cytoplasm of some liver cells filled with numerous fat droplets contain both small and large fat droplets
(J:79603)
• administration of 17beta-estradiol rescues homozygotes from massive hepatic steatosis
(J:79603)
• starting at 10 weeks of age, male homozygotes display hepatic steatosis, although no differences in liver weight are noted at 12 weeks
(J:82070)
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• at >2 months of age, the livers of estrogen-free homozygotes show impaired peroxisomal and mitochondrial fatty acid beta-oxidation activity, as shown by reduced mRNA expression of VLACS, AOX, and MCAD
• in vitro assays of fatty acid beta-oxidation activity using very long (C24:0), long (C16:0), or medium (C12:0) chain fatty acids as substrates confirmed the reduction of corresponding enzyme activities
• gene expression and enzyme activities of fatty acid beta-oxidation in liver are restored to wild-type levels following treatment with 17beta-estradiol
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endocrine/exocrine glands
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• hemorrhages in ovaries observed at 8 months of age
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• increased apoptotic DNA fragmentation and expression of pro-apoptotic genes in mutant ovaries relative to wild-type, not suppressed by 17beta-estradiol supplementation
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• at 9 weeks of age, male homozygotes show increased seminal vesicle weight relative to wild-type males
|
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• at 8 weeks of age, ovarian follicles are present at various maturational stages including primary to large antral follicles but corpora lutea are absent
• at 8 weeks, only a few lipid droplets and well-developed smooth endoplasmic reticulum are noted in mutant ovarian luteinized interstitial cells, and mitochondria show less organized tubular structures atypical of steroid-producing cells
• ultrastructural interstitial cell anomalies are reversed by 17beta-estradiol supplementation (15 microg/mouse every fourth day from 4 weeks of age for 1 month), although corpus luteum remains undetectable
• at 8 months of age, mutant ovaries display depletion of follicles, large hemorrhages, occasional macrophage-like cells in the follicular antrum, and increased frequence of mast cells relative to wild-type ovaries
• transcripts of pro-apoptotic genes (Trp53 and Bax) are significantly increased in mutant ovaries relative to wild-type; however, 17beta-estradiol supplementation fails to suppress their elevated expression
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• both at 8 weeks and at 8 months of age
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• depletion of ovarian follicles at 8 months of age
• folliculogenesis is promoted by supplemental 17beta-estradiol
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ovary cyst
(
J:70359
)
|
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• hemorrhagic ovarian cysts at 8 months of age
|
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• at 14 weeks of age, the seminiferous epithelial layers of mutant testes (stage VII of spermatogenesis) are thinner than those of wild-type testes
• however, no gross differences in thickness are observed at other stages of spermatogenesis at 14 weeks, or in testicular and epididymal weight or sperm number at 9-16 weeks and at 10 months, and mutant sperm are capable of fertilization in vitro at all test ages
• 17beta-estradiol supplementation (7.5 ug/mouse) begun within 7 days after birth results in increased thickness of mutant seminiferous epithelial cell layers
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adipose tissue
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• at 22 weeks of age, male homozygotes show increased gonadal fat pad weights relative to wild-type controls
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• at 22 weeks of age, male homozygotes show increased perirenal fat pad weights relative to wild-type controls
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• starting at 2 months of age, homozygotes gradually accumulate abdominal fat in an estrogen-free condition
(J:79603)
• starting at 10 weeks, male homozygotes exhibit a gradual increase in visceral fat deposits relative to age-matched wild-type controls
(J:82070)
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cardiovascular system
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• hemorrhages in ovaries observed at 8 months of age
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behavior/neurological
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• at 16-24 weeks of age, only 10% of male homozygotes show mounting behavior against ovariectomized females during a 30-min test period vs >90% of wild-type males
• latency to first mount in male homozygotes is increased by ~190 sec relative to wild-type
• extending the test time to 60 min fails to increase the number of mounts or signs of intromission
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hematopoietic system
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• at 9 weeks of age, the number of TRAP-positive multinucleated osteoclasts is significantly increased in trabecular bone from the distal femoral metaphysis of both female and male homozygotes relative to wild-type controls
• treatment with 17beta-estradiol restores osteoclast cell number to the respective wild-type numbers in both sexes
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immune system
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• at 9 weeks of age, the number of TRAP-positive multinucleated osteoclasts is significantly increased in trabecular bone from the distal femoral metaphysis of both female and male homozygotes relative to wild-type controls
• treatment with 17beta-estradiol restores osteoclast cell number to the respective wild-type numbers in both sexes
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cellular
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• increased apoptotic DNA fragmentation and expression of pro-apoptotic genes in mutant ovaries relative to wild-type, not suppressed by 17beta-estradiol supplementation
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growth/size/body
ovary cyst
(
J:70359
)
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• hemorrhagic ovarian cysts at 8 months of age
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• although mean body weights of male homozygotes are similar to those of wild-type males at 10 weeks, male homozygotes weigh significantly more than wild-type controls by 12 weeks of age
• increased body weight is associated with increased gonadal and perirenal fat pad weight
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• starting at 10 to 12 weeks of age, male homozygotes begin to develop obesity
• however, no significant differences in food intake per day are noted from 8 to 19 weeks of age relative to wild-type controls
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• male homozygotes show a significant increase in weight gain relative to wild-type males from 6 to 48 weeks of age
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