Analysis Tools
mortality/aging
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• female heterozygotes exhibit premature biological aging
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• female heterozygotes fail to reproduce after 8-9 months of age ("retired breeders") due to an accelerated loss of ovarian function/oocytes
(J:81460)
• female heterozygotes (dubbed "menopausal" mice) exhibit premature reproductive senescence mimicking reproductive failure in postmenopausal women
(J:89713)
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reproductive system
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• aging female heterozygotes sometimes display uterine bleeding as the first sign of uterine pathology
• in areas of hemorrhage, hemosiderin, a golden-yellow to brown granular pigment, is phagocytized by macrophages
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• at 20 months of age, heterozygous ovaries are atrophic and contain no follicles or corpora lutea but only cysts
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• at 20 months of age
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• total exhaustion of ovarian follicles at 20 months of age
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ovary atrophy
(
J:89713
)
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• at 20 months of age
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• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side
(J:81460)
• at 20 months of age
(J:89713)
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• female heterozygotes fail to reproduce after 8-9 months of age ("retired breeders") due to an accelerated loss of ovarian function/oocytes
(J:81460)
• female heterozygotes (dubbed "menopausal" mice) exhibit premature reproductive senescence mimicking reproductive failure in postmenopausal women
(J:89713)
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• at 12 months of age, heterozygous females display an abnormally enlarged uterus with hyperplastic and disorganized luminal epithelium and numerous blood vessels in the uterine stroma suggesting acceleration of angiogenesis
• up to 25% of virgin heterozygous females develop a variable uterine pathology, including cyst-like structures and enlarged lumen, abundant small vessels in the endometrium, adenomyosis, dilated endometrial vessels without thrombosis but associated with hemosiderin containing macrophages, and (in some cases) large uterine masses that resemble organized thrombi composed of red blood cells and fibrin along with increased angiogenesis in the stroma next to the thrombus
• most retired breeders develop larger unilateral uterine masses with varying degrees of thrombi in the outer myometrium of the affected (right) horn, regions of calcification localized in vessels near the myometrium, giant multinucleated cells similar to syncytiotrophoblasts and mononuclear cells resembling cytotrophoblasts, and increased uterine angiogenesis
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• at 12 months of age, endometrial glands are enlarged and the epithelia are hypertrophied
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uterus cyst
(
J:81460
)
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• at 12 months of age, uterine transverse sections reveal the presence of cyst-like structures
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• by 12 months of age, 23% of virgin heterozygous females and 82% of retired heterozygous female breeders display a large nodular structure (mass) in one uterine horn
• unilateral uterine masses occur predominantly in the right horn (67% of cases), while the left horn remains relatively unaffected
• among different female heterozygotes, the weight of the uterine nodular structure alone ranges from 205 mg to >4000 mg (~8% of the body weight) in extreme cases
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• at 12 months of age
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• by 1 yr of age, heterozygous females with no visible tumors show a 77% increase in uterine weight relative to wild-type females
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• some older virgin heterozygous females have endometrial glands and stroma present within the myometrium with no connection to the endometrial cavity
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• by 12 months of age, most female heterozygotes exhibit highly irregular or absent estrous cycles
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• at 8-10 months of age, the % of resorbed pups per pregnancy is significantly increased relative to wild-type controls (12% vs 7% at 10 dpc and 90% vs 18% at 18 dpc, respectively)
• at 10-13 months of age, the % of resorbed pups is further increased, with a fetal resorption rate of 92% at 14 dpc and >92% at 18 dpc vs only ~40% in wild-type controls
• overall, female heterozygotes show a significantly higher rate of pregnancy failure relative to wild-type females
• interestingly, structures resembling fetal tissue persist (or reappear) several months after a failed pregnancy
• pregnancy failure and induction of uterine pathology are associated with an imbalance of progesterone receptor isoforms A and B and an increase in LH receptors in the uterus along with increased angiogenesis, vascular abnormalities, and adenomyosis occuring in the uterine horn bearing the pathological mass
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• as early as 3 months of age, female heterozygotes display reduced fertility relative to wild-type females
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• at 3 months of age, female heterozygotes produce ~40% fewer pups than wild-type females (average 5.6 vs 9.8 pups, respectively)
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behavior/neurological
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• female heterozygotes display a progressive, age-related increase in anxiety in the open field test
• at 20 months of age, female heterozygotes show a 2-fold increase in latency (time required to move from the center of the box to the wall) in an open field, relative to wild-type controls
• no significant differences in latency are observed at 1 month of age, and both heterozygous and wild-type aged mice show increased locomotor activity at 20 months
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• at 20 months of age, female heterozygotes show increased thigmotaxis relative to wild-type controls
• however, no significant differences in thigmotaxis are observed between genotypes at 1 month of age
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nervous system
astrocytosis
(
J:89713
)
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• at both 3 and 20 months of age, astroglial cells in the dentate gyrus of female heterozygotes show hypertrophic, swollen pericaria and thick processes relative to wild-type controls
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• in female heterozygotes, neurons in the dentate gyrus show signs of progressive degenerative changes, hypertrophy and gliosis, with subsequent cell shrinkage and death
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• aging female heterozygotes show degenerative changes in the CNS; the region most affected is the hippocampus
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• aging female heterozygotes show altered estrogen receptor expression and significant reductions in choline acetyltransferase enzymatic activity and synapsin immunoreactivity in the hippocampus at 20 months
• early degenerative changes are evident in the hippocampus (dentate gyrus) at 1 month and progress to cell shrinkage and loss at the age of 20 months
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homeostasis/metabolism
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• in heterozygous females, plasma testosterone levels are significantly higher than wild-type levels at 12 months, but not at 3 months of age
(J:81460)
• female heterozygotes display higher plasma testosterone levels relative to wild-type controls, which become pronounced at 12 and 20 months of age
(J:89713)
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• in heterozygous females, plasma E2 levels are moderately reduced at proestrus at 3 months of age, and significantly reduced by 12 months of age relative to wild-type levels
(J:81460)
• at 1 and 3 months of age, female heterozygotes show a moderate reduction in plasma estradiol-17beta (E2) levels relative to wild-type controls; by 7 months of age, plasma E2 levels are virtually undetectable
(J:89713)
• notably, expression of nuclear estrogen receptor alpha in the amygdala of aging heterozygotes is increased, whereas expression of estrogen receptor beta in the medial amygdala is markedly reduced, possibly contributing to increased anxiogenic-like behavior
(J:89713)
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• in heterozygous females, plasma FSH levels are increased by 77% relative to wild-type levels at 12 months, with no significant differences at 3 months of age
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• in heterozygous females, plasma LH levels are increased by 33% relative to wild-type levels at 12 months, with no significant differences at 3 months of age
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• in heterozygous females, plasma progesterone levels are significantly reduced at both 3 and 12 months of age relative to wild-type levels
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• many older virgin and retired heterozygous female breeders display dilated uterine vessels with varying degrees of thrombosis in the outer myometrium of the affected uterine horn bearing the pathological mass
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• at 20 months of age, choline acetyltransferase (ChAT) enzymatic activity is reduced by 30% in the hippocampi of female heterozygotes relative to wild-type controls
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endocrine/exocrine glands
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• at 12 months of age, endometrial glands are enlarged and the epithelia are hypertrophied
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• at 20 months of age, heterozygous ovaries are atrophic and contain no follicles or corpora lutea but only cysts
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• at 20 months of age
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• total exhaustion of ovarian follicles at 20 months of age
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ovary atrophy
(
J:89713
)
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• at 20 months of age
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• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side
(J:81460)
• at 20 months of age
(J:89713)
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neoplasm
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• by 12 months of age, 23% of virgin heterozygous females and 82% of retired heterozygous female breeders display a large nodular structure (mass) in one uterine horn
• unilateral uterine masses occur predominantly in the right horn (67% of cases), while the left horn remains relatively unaffected
• among different female heterozygotes, the weight of the uterine nodular structure alone ranges from 205 mg to >4000 mg (~8% of the body weight) in extreme cases
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cardiovascular system
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• aging female heterozygotes sometimes display uterine bleeding as the first sign of uterine pathology
• in areas of hemorrhage, hemosiderin, a golden-yellow to brown granular pigment, is phagocytized by macrophages
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growth/size/body
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• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side
(J:81460)
• at 20 months of age
(J:89713)
|
uterus cyst
(
J:81460
)
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• at 12 months of age, uterine transverse sections reveal the presence of cyst-like structures
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cellular
astrocytosis
(
J:89713
)
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• at both 3 and 20 months of age, astroglial cells in the dentate gyrus of female heterozygotes show hypertrophic, swollen pericaria and thick processes relative to wild-type controls
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