Phenotypes associated with this allele

• Allele Symbol: Cyp19a1^tm1Esi
• Allele Name: targeted mutation 1, Evan R Simpson
• Allele ID: MGI:2154536
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cyp19a1^tm1Esi/Cyp19a1^tm1Esi	involves: 129S6/SvEvTac	MGI:2662434
hm2	Cyp19a1^tm1Esi/Cyp19a1^tm1Esi	involves: 129S6/SvEvTac * C57BL/6	MGI:2450128
hm3	Cyp19a1^tm1Esi/Cyp19a1^tm1Esi	involves: 129S6/SvEvTac * C57BL/6J	MGI:3814613
cx4	Apoe^tm1Unc/Apoe^tm1Unc Cyp19a1^tm1Esi/Cyp19a1^tm1Esi	involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6	MGI:5428435

Genotype
MGI:2662434

hm1

• Allelic Composition: Cyp19a1^tm1Esi/Cyp19a1^tm1Esi
• Genetic Background: involves: 129S6/SvEvTac

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

Cyp19a1^tm1Esi/Cyp19a1^tm1Esi livers are larger, pale and accumulate lipid droplets

cellular

oligozoospermia ( J:83254 )

♂ • reduced sperm concentration at 1 year of age

♂ • normal sperm concentration at 15 weeks of age

asthenozoospermia ( J:83254 )

♂ • decreased sperm motility evident at 15 weeks of age and more severe at 1 year of age

♂ • fertilization was possible in vitro at 15 weeks of age, but not at 1 year of age

growth/size/body

ovary cyst ( J:78634 )

♀ • increase in incidence of hemorrhagic cysts when fed a soy-free diet

decreased lean body mass ( J:65805 )

• the increase in fat mass is accompanied by a decrease in lean mass

increased body weight ( J:65805 )

• females are heavier starting at 3 months of age, while males show an increase in weight beginning at 1 year of age

enlarged liver ( J:65805 )

• at 1 year of age

adipose tissue

increased total body fat amount ( J:65805 )

• progressively accumulate more intraabdominal adipose tissue than wild-type

• increased adiposity is not due to hyperphagia or reduced resting energy expenditure

increased fat cell size ( J:65805 )

• increase in adipocyte volume and size in gonadal fat pads over time

increased gonadal fat pad weight ( J:65805 )

• both males and females have significantly larger gonadal fat pads from 3-4 months of age onward

increased renal fat pad weight ( J:65805 )

• both males and females have significantly larger infrarenal fat pads from 3-4 months of age onward

• administration of exogenous 17beta-estradiol to females for 21 days restores the fat deposits to masses comparable to wild-type

homeostasis/metabolism

increased circulating leptin level ( J:65805 )

• seen in mutants at 3-4 months and 1 year of age

increased circulating cholesterol level ( J:65805 )

• seen in mutants at 1 year of age, but not at 3-4 moths of age

increased circulating HDL cholesterol level ( J:65805 )

• seen in mutants at 1 year of age, but not at 3-4 moths of age

increased circulating triglyceride level ( J:65805 )

• circulating triglyceride levels are elevated in 1 year old males but not in females

abnormal glucose homeostasis ( J:65805 )

• glucose oxidation rates are 59% lower than in wild-type, however resting energy expenditure and fat oxidation rates are normal

increased circulating insulin level ( J:65805 )

• seen in male mutants at 1 year of age, but not at 3-4 moths of age

liver/biliary system

enlarged liver ( J:65805 )

• at 1 year of age

hepatic steatosis ( J:65805 )

• accumulation of lipid droplets in the livers at 3 months and 1 year of age

pale liver ( J:65805 )

• at 1 year of age

behavior/neurological

bradykinesia ( J:65805 )

• older females exhibit reduced spontaneous physical activity

abnormal mating frequency ( J:83254 )

• reduced mounting behavior exhibited by males at 12 to 14 weeks of age and at 1 year of age

reduced male mating frequency ( J:83254 )

♂ • males at 12 to 14 weeks of age and at 1 year of age demonstrated impaired mounting behavior

reproductive system

ovary hemorrhage ( J:78634 )

♀ • increase in incidence of hemorrhagic cysts when fed a soy-free diet

asthenozoospermia ( J:83254 )

♂ • decreased sperm motility evident at 15 weeks of age and more severe at 1 year of age

♂ • fertilization was possible in vitro at 15 weeks of age, but not at 1 year of age

abnormal ovary morphology ( J:78634 )

♀ • the ovaries of mice on a soy free diet exhibit seminiferous tubule-like structures throughout 80% of ovaries, hemorrhagic cysts, and age dependent increase in collagen deposition

♀ • in constrast, animals fed a soy diet do not display Sertoli-like cells in follicles

absent corpus luteum ( J:78634 )

♀ • ovaries lack corpora lutea when mice are fed a soy-free diet

abnormal mature ovarian follicle morphology ( J:78634 )

♀ • on a soy-free diet, mature follicles appear atretic; uneven granulose cell layers and cellular debris within antral compartments

impaired ovarian folliculogenesis ( J:78634 )

♀ • ovaries of 16-18 week old mice on a soy-free diet show a near-complete block in folliculogenesis at the primordial or primary stage

♀ • normal follicular morphology is partly restored by estradiol treatment

abnormal tertiary ovarian follicle morphology ( J:78634 )

♀ • absence of healthy antral follicles when fed a soy-free diet

ovary cyst ( J:78634 )

♀ • increase in incidence of hemorrhagic cysts when fed a soy-free diet

abnormal spermatogenesis ( J:83254 )

♂ • decreased number of round spermatids and/or spermatocytes at 3.5 months of age

oligozoospermia ( J:83254 )

♂ • reduced sperm concentration at 1 year of age

♂ • normal sperm concentration at 15 weeks of age

abnormal primary sex determination ( J:78634 )

• on a soy free diet, the ovaries develop cells that possess structural and functional characteristics of testicular interstitial (Leydig) cells and of seminiferous tubule-like structures lined with Sertoli cells

• the development of testicular tissue is postponed and reduced with estrogen replacement

reduced male fertility ( J:83254 )

♂ • at 3.5 months of age, males sired fewer litters than wild-type, with 50% siring no litters at all

hearing/vestibular/ear

abnormal auditory brainstem response ( J:135833 )

• following accoustic trauma, mice exhibit a greater shift in brainstem auditory evoked potential compared with similarly treated wild-type mice

cardiovascular system

ovary hemorrhage ( J:78634 )

♀ • increase in incidence of hemorrhagic cysts when fed a soy-free diet

endocrine/exocrine glands

ovary hemorrhage ( J:78634 )

♀ • increase in incidence of hemorrhagic cysts when fed a soy-free diet

abnormal ovary morphology ( J:78634 )

♀ • the ovaries of mice on a soy free diet exhibit seminiferous tubule-like structures throughout 80% of ovaries, hemorrhagic cysts, and age dependent increase in collagen deposition

♀ • in constrast, animals fed a soy diet do not display Sertoli-like cells in follicles

absent corpus luteum ( J:78634 )

♀ • ovaries lack corpora lutea when mice are fed a soy-free diet

abnormal mature ovarian follicle morphology ( J:78634 )

♀ • on a soy-free diet, mature follicles appear atretic; uneven granulose cell layers and cellular debris within antral compartments

impaired ovarian folliculogenesis ( J:78634 )

♀ • ovaries of 16-18 week old mice on a soy-free diet show a near-complete block in folliculogenesis at the primordial or primary stage

♀ • normal follicular morphology is partly restored by estradiol treatment

abnormal tertiary ovarian follicle morphology ( J:78634 )

♀ • absence of healthy antral follicles when fed a soy-free diet

ovary cyst ( J:78634 )

♀ • increase in incidence of hemorrhagic cysts when fed a soy-free diet

Genotype
MGI:2450128

hm2

• Allelic Composition: Cyp19a1^tm1Esi/Cyp19a1^tm1Esi
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

Absence of corpora lutea in Cyp19a1^tm1Esi/Cyp19a1^tm1Esi ovaries

pigmentation

abnormal coat/hair pigmentation ( J:48086 )

• at 3 weeks of age, both male and female homozygotes exhibit a dull coat

adipose tissue

increased gonadal fat pad weight ( J:48086 )

• males and females exhibited a 50% and 50% to 80% increase in gonadal fat pad weight, respectively

increased mammary fat pad weight ( J:48086 )

• females exhibited a 50% to 80% increase in mammary fat pad weight

endocrine/exocrine glands

ovary hemorrhage ( J:63458 )

♀ • by 21-23 weeks of age

increased granulosa cell apoptosis ( J:63458 )

♀ • marked apoptosis in granulosa cells of larger, antral size follicles at 10-12 weeks of age

♀ • by 1 yr of age, granulosa cell apoptosis is widespread throughout the ovary, as indicated by TUNEL analysis

abnormal salivary gland morphology ( J:92438 )

• massive leukocytic infiltration with destruction of acinar cells in the salivary glands of mice fed a phytoestrogen-free diet

enlarged salivary gland ( J:92438 )

• enlarged salivary glands in mice fed a phytoestrogen-free diet, although it is unclear if salivary gland/body weight ratio is normal or increased

salivary gland inflammation ( J:92438 )

• massive leukocytic infiltration with destruction of acinar cells in the salivary glands of mice fed a phytoestrogen-free diet

• mice raised on a phytoestrogen-free diet develop Sjogren-like syndrome by 12-17 months of age, showing presence of massive infiltration of B220+ B lymphocytes, presence of an alpha-fodrin fragment (120 kDa) in the salivary gland, and higher levels of serum anti-fodrin antibody than wild-type mice fed this diet

increased prostate gland anterior lobe weight ( J:70204 )

♂ • anterior prostate weights are increased by 40%, 21%, and 25% at 8-14, 16-26, and 48-56 weeks, respectively, relative to wild-type controls

prostate gland anterior lobe hyperplasia ( J:70204 )

♂ • in the anterior lobes, hyperplasia is observed at 16-26 weeks in the absence of increased infolding of the glandular epithelium

increased prostate gland dorsolateral lobe weight ( J:70204 )

♂ • dorsolateral prostate weights are increased by 54%, 55%, and 46% at 8-14, 16-26, and 48-56 weeks of age, respectively, relative to wild-type controls

prostate gland dorsolateral lobe hyperplasia ( J:70204 )

♂ • in the dorsolateral lobes, hyperplasia is observed at 16-26 weeks in the absence of increased infolding of the glandular epithelium

increased prostate gland ventral lobe weight ( J:70204 )

♂ • wet weights of ventral prostates are increased by 60%, 46%, and 57% at 8-14, 16-26, and 48-56 weeks of age, respectively, relative to wild-type controls

enlarged prostate gland ( J:70204 )

♂ • at 16-26 weeks of age, male mutants display significant enlargement of the ventral, anterior and dorsolateral prostatic lobes

♂ • increase in absolute volume of individual tissue compartments is attributed to increased volume of the entire prostate organ

♂ • no increase in the diameter of individual ducts or localized dysplastic growth are observed in one individual cell type or tissue compartment

increased prostate gland weight ( J:48086 , J:70204 )

♂ • increase in combined prostate/urinary bladder weight (J:48086)

♂ • wet weights of the ventral, anterior and dorsolateral prostate lobes are increased at 8-14 weeks of age and maintained up to 56 weeks of age (J:70204)

♂ • diet (regular vs soy-free) had no significant effect on the weight or volume of prostate from animals of the same genotype (J:70204)

♂ • no significant differences in body weights are noted between age-matched mutant and wild-type males at all ages examined (J:70204)

prostate gland hyperplasia ( J:70204 )

♂ • male mutants exhibit a hyperplasia of the entire prostate gland, which is induced at 8-14 weeks and maintained up to 56 weeks of age

♂ • observed changes are unaffected by maintaining mice on regular or soy-free diets

♂ • no signs of aberrant growth or enhanced malignancy are observed even at 56 weeks of age

♂ • short-term exposure to DES resulted in comparable regression of the prostate lobes and induction of squamous metaplasia in the anterior prostate of both wild-type and mutant males

prostate gland ventral lobe hyperplasia ( J:70204 )

♂ • in the ventral prostatic lobe, hyperplasia characterized by increased infolding of the prostatic epithelium is first noted at 8-14 weeks and becomes prominent at 48-56 weeks, in the absence of epithelial dysplasia

increased seminal vesicle weight ( J:48086 )

♂ • increased weight of seminal vescicles, putatively due to an increased volume of secretions rather than due to structural changes

abnormal ovary morphology ( J:48086 , J:63458 )

♀ (J:48086)

♀ • at 10-12 weeks of age, the mutant ovary displays follicles of all types (primordial, primary secondary, and antral), but no corpora lutea (J:63458)

♀ • at 10-12 weeks, aberrant and non-uniform layers of granulosa cells and numerous pyknotic nuclei are detected, with marked apoptosis in granulosa cells of larger, antral size follicles (J:63458)

♀ • at 21-23 weeks of age, follicles at all stages are still observed but many follicles are atretic; preantral follicles are randomly scattered and many antral follicles appear cystic and hemorrhagic (J:63458)

♀ • by 1 yr of age, no secondary or antral follicles are identified; remnants of large follicles, many of which are cystic and hemorrhagic, are present while primary follicles consist of oddly shaped and mostly pyknotic granulosa cells (J:63458)

absent corpus luteum ( J:48086 , J:63458 )

♀ (J:48086)

♀ • at 10-12 and 21-23 weeks and 1 yr of age (J:63458)

impaired ovarian folliculogenesis ( J:48086 , J:63458 )

♀ • though ovaries contained numerous follicles with abundant granulosa cells, antrum formation was arrested before ovulation (J:48086)

♀ • no corpora leutea (J:48086)

♀ (J:63458)

ovarian follicular cyst ( J:63458 )

♀ • hemorrhagic cystic follicles are observed by 21-23 weeks of age

abnormal seminiferous tubule morphology ( J:56358 )

♂ • at 4.5 months of age, 4 of 5 male homozygotes showed normal testicular morphology, but one animal displayed grossly dysmorphic seminiferous tubules and disrupted spermatogenesis

abnormal seminiferous tubule epithelium morphology ( J:56358 )

♂ • at 1 yr of age, male homozygotes show a significant decrease in the volume of seminiferous epithelium

♂ • however, no dilated lumens or other changes in the seminiferous tubule luminal volume are observed

increased Leydig cell number ( J:56358 )

♂ • at 1 yr of age, all male homozygotes show evidence of Leydig cell hyperplasia/hypertrophy, as evidenced by an increase in the absolute volume of Leydig cells per testis

decreased testis weight ( J:56358 )

♂ • by 1 yr of age, all male homozygotes show a reduction in testis weight

abnormal prostate gland physiology ( J:70204 )

♂ • at 16 weeks of age, tissue levels of 5alpha-dihydrotestosterone are significantly increased in the anterior prostate of mutant males relative to wild-type males

♂ • in contrast, tissue testosterone levels in the anterior prostate remain unchanged

homeostasis/metabolism

increased circulating dihydrotestosterone level ( J:70204 )

• at 16 weeks of age, serum 5alpha-dihydrotestosterone levels in mutant males are 2-fold higher than those in wild-type males

increased circulating testosterone level ( J:48086 , J:56358 , J:70204 )

• female testosterone level was increased to ~10 times the level in wild-type females (J:48086)

• male testosterone levels varied though they were in general increased relative to those of control males (J:48086)

• at 4.5 months and 1 yr of age, male serum testosterone levels are variable, with no significant increase or decrease, although levels are initially elevated at 12-14 weeks of age (J:56358)

• at 16 weeks of age, serum testosterone levels in mutant males are ~10-fold higher than those in wild-type males (J:70204)

increased circulating follicle stimulating hormone level ( J:48086 , J:56358 , J:63458 )

• female FSH levels were elevated 3- to 4-fold relative to wild-type females (J:48086)

• at 4.5 months and 1 yr of age, male serum FSH levels are unchanged relative to age-matched wild-type males (J:56358)

• female serum FSH levels are significantly higher than wild-type and heterozygous levels at 10-12 and 21-23 weeks and 1 yr of age (J:63458)

• at 1 yr of age, female serum FSH levels are 3-fold higher than wild-type levels (J:63458)

increased circulating luteinizing hormone level ( J:48086 , J:56358 , J:63458 )

• female LH levels were elevated 2- to 10-fold relative to wild-type females (J:48086)

• LH levels were also increased in male mice (J:48086)

• at 4.5 months and 1 yr of age, male homozygotes show elevated serum LH levels, similar to those initially reported at 12-14 weeks of age (J:56358)

• by 1 yr of age, serum LH levels of homozygous mutant mice are ~3-fold higher than wild-type and heterozygous levels (J:63458)

increased circulating prolactin level ( J:70204 )

• at 16 weeks of age, serum prolactin levels in mutant males are 3-fold higher than those in wild-type males

abnormal enzyme/coenzyme level ( J:105620 )

• at 10-14 weeks of age, 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme levels remain unchanged in most tissues of female homozygotes, except in the kidney, where they are reduced to only 10% of wild-type levels

• estradiol administered to mutant females restores renal 11betaHSD2 to wild-type levels, but does not further increase levels in wild-type mice

increased urine protein level ( J:92438 )

• in mice fed a phytoestrogen-free diet

reproductive system

abnormal male germ cell morphology ( J:56358 )

♂

decreased male germ cell number ( J:56358 )

♂ • at 1 yr of age, no significant decreases are observed in Sertoli cell numbers or in spermatogonia and spermatocyte populations; however, significantly less round and elongated spermatids are present in the mutant epithelium relative to wild-type controls

♂ • at 4.5 months of age, the numbers of Sertoli cells, spermatogonia, spermatocytes, round spermatids, and elongated spermatids are comparable to those of wild-type males

multinucleated giant male germ cells ( J:56358 )

♂

abnormal ovary morphology ( J:48086 , J:63458 )

♀ (J:48086)

♀ • at 10-12 weeks of age, the mutant ovary displays follicles of all types (primordial, primary secondary, and antral), but no corpora lutea (J:63458)

♀ • at 10-12 weeks, aberrant and non-uniform layers of granulosa cells and numerous pyknotic nuclei are detected, with marked apoptosis in granulosa cells of larger, antral size follicles (J:63458)

♀ • at 21-23 weeks of age, follicles at all stages are still observed but many follicles are atretic; preantral follicles are randomly scattered and many antral follicles appear cystic and hemorrhagic (J:63458)

♀ • by 1 yr of age, no secondary or antral follicles are identified; remnants of large follicles, many of which are cystic and hemorrhagic, are present while primary follicles consist of oddly shaped and mostly pyknotic granulosa cells (J:63458)

absent corpus luteum ( J:48086 , J:63458 )

♀ (J:48086)

♀ • at 10-12 and 21-23 weeks and 1 yr of age (J:63458)

impaired ovarian folliculogenesis ( J:48086 , J:63458 )

♀ • though ovaries contained numerous follicles with abundant granulosa cells, antrum formation was arrested before ovulation (J:48086)

♀ • no corpora leutea (J:48086)

♀ (J:63458)

ovarian follicular cyst ( J:63458 )

♀ • hemorrhagic cystic follicles are observed by 21-23 weeks of age

enlarged clitoris ( J:48086 )

♀ • 3-fold enlargement of the clitoral gland relative to that of wild-type

abnormal labium morphology ( J:48086 )

♀ • labial folds do not develop

abnormal uterus development ( J:63458 )

♀

decreased uterus weight ( J:63458 )

♀ • unlike in wild-type mice, mean uterine weights fail to increase significantly with age in mutant mice

♀ • by 1 yr of age, uterine weights of homozygous mutants are only 30% of wild-type and heterozygous weights

uterus hypoplasia ( J:48086 )

♀ • underdeveloped uterus observed at 12 to 14 weeks of age

abnormal spermatogenesis ( J:56358 )

♂ • male homozygotes develop spermatogenic disruptions between 4.5 months and 1 yr of age, despite no significant reductions in gonadotrophins or androgens

abnormal spermatid morphology ( J:56358 )

♂ • at 1 yr of age, male homozygotes show a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells relative to wild-type males

abnormal spermiogenesis ( J:56358 )

♂ • male homozygotes show a specific defect in the development of spermatids during spermiogenesis

abnormal acrosome assembly ( J:56358 )

♂ • at 1 yr of age, tubules with early spermiogenic arrest exhibit defects in early acrosomal development

♂ • multiple acrosomal vesicles are observed and, in some cases, acrosomes fail to uniformly spread over the spermatid nuclei

arrest of spermiogenesis ( J:56358 )

♂ • at 1 yr of age, the site of spermatogenic disruption appears to be early spermiogenesis with symplasts and degenerating round spermatids frequently observed

♂ • most mutants also display some tubules with normal morphology adjacent to tubules with spermiogenic arrest, suggesting a heterogeneous disruption

abnormal male reproductive system morphology ( J:48086 )

♂

increased prostate gland anterior lobe weight ( J:70204 )

♂ • anterior prostate weights are increased by 40%, 21%, and 25% at 8-14, 16-26, and 48-56 weeks, respectively, relative to wild-type controls

prostate gland anterior lobe hyperplasia ( J:70204 )

♂ • in the anterior lobes, hyperplasia is observed at 16-26 weeks in the absence of increased infolding of the glandular epithelium

increased prostate gland dorsolateral lobe weight ( J:70204 )

♂ • dorsolateral prostate weights are increased by 54%, 55%, and 46% at 8-14, 16-26, and 48-56 weeks of age, respectively, relative to wild-type controls

prostate gland dorsolateral lobe hyperplasia ( J:70204 )

♂ • in the dorsolateral lobes, hyperplasia is observed at 16-26 weeks in the absence of increased infolding of the glandular epithelium

increased prostate gland ventral lobe weight ( J:70204 )

♂ • wet weights of ventral prostates are increased by 60%, 46%, and 57% at 8-14, 16-26, and 48-56 weeks of age, respectively, relative to wild-type controls

enlarged prostate gland ( J:70204 )

♂ • at 16-26 weeks of age, male mutants display significant enlargement of the ventral, anterior and dorsolateral prostatic lobes

♂ • increase in absolute volume of individual tissue compartments is attributed to increased volume of the entire prostate organ

♂ • no increase in the diameter of individual ducts or localized dysplastic growth are observed in one individual cell type or tissue compartment

increased prostate gland weight ( J:48086 , J:70204 )

♂ • increase in combined prostate/urinary bladder weight (J:48086)

♂ • wet weights of the ventral, anterior and dorsolateral prostate lobes are increased at 8-14 weeks of age and maintained up to 56 weeks of age (J:70204)

♂ • diet (regular vs soy-free) had no significant effect on the weight or volume of prostate from animals of the same genotype (J:70204)

♂ • no significant differences in body weights are noted between age-matched mutant and wild-type males at all ages examined (J:70204)

prostate gland hyperplasia ( J:70204 )

♂ • male mutants exhibit a hyperplasia of the entire prostate gland, which is induced at 8-14 weeks and maintained up to 56 weeks of age

♂ • observed changes are unaffected by maintaining mice on regular or soy-free diets

♂ • no signs of aberrant growth or enhanced malignancy are observed even at 56 weeks of age

♂ • short-term exposure to DES resulted in comparable regression of the prostate lobes and induction of squamous metaplasia in the anterior prostate of both wild-type and mutant males

prostate gland ventral lobe hyperplasia ( J:70204 )

♂ • in the ventral prostatic lobe, hyperplasia characterized by increased infolding of the prostatic epithelium is first noted at 8-14 weeks and becomes prominent at 48-56 weeks, in the absence of epithelial dysplasia

increased seminal vesicle weight ( J:48086 )

♂ • increased weight of seminal vescicles, putatively due to an increased volume of secretions rather than due to structural changes

abnormal seminiferous tubule morphology ( J:56358 )

♂ • at 4.5 months of age, 4 of 5 male homozygotes showed normal testicular morphology, but one animal displayed grossly dysmorphic seminiferous tubules and disrupted spermatogenesis

abnormal seminiferous tubule epithelium morphology ( J:56358 )

♂ • at 1 yr of age, male homozygotes show a significant decrease in the volume of seminiferous epithelium

♂ • however, no dilated lumens or other changes in the seminiferous tubule luminal volume are observed

increased Leydig cell number ( J:56358 )

♂ • at 1 yr of age, all male homozygotes show evidence of Leydig cell hyperplasia/hypertrophy, as evidenced by an increase in the absolute volume of Leydig cells per testis

decreased testis weight ( J:56358 )

♂ • by 1 yr of age, all male homozygotes show a reduction in testis weight

abnormal epididymis morphology ( J:56358 )

♂ • at 1 yr of age, mutant epididymes show reduced or complete absence of sperm

abnormal reproductive system physiology ( J:48086 )

ovary hemorrhage ( J:63458 )

♀ • by 21-23 weeks of age

increased male germ cell apoptosis ( J:56358 )

♂ • at 1 yr of age, decline in round spermatid number is due to increased cell death in the adluminal compartment of the seminiferous epithelium

increased granulosa cell apoptosis ( J:63458 )

♀ • marked apoptosis in granulosa cells of larger, antral size follicles at 10-12 weeks of age

♀ • by 1 yr of age, granulosa cell apoptosis is widespread throughout the ovary, as indicated by TUNEL analysis

abnormal prostate gland physiology ( J:70204 )

♂ • at 16 weeks of age, tissue levels of 5alpha-dihydrotestosterone are significantly increased in the anterior prostate of mutant males relative to wild-type males

♂ • in contrast, tissue testosterone levels in the anterior prostate remain unchanged

anovulation ( J:63458 )

♀ • female homozygotes fail to ovulate

female infertility ( J:48086 , J:63458 )

♀ (J:48086)

♀ (J:63458)

male infertility ( J:56358 )

♂ • male homozygotes are initially fertile with normal testis morphology at 12-14 weeks, but develop progressive infertility between 4.5 months and 1 yr of age

♂ • mutant males mated at 7 months of age for an average of 6 months fail to sire litters

cardiovascular system

ovary hemorrhage ( J:63458 )

♀ • by 21-23 weeks of age

increased cardiac muscle contractility ( J:105620 )

• at 6 months of age, the maximum rate of change in blood pressure (dP/dT) occuring during systole is 40% higher in conscious female homozygotes relative to wild-type controls (1427 9 vs 1019 14 mm Hg/sec, respectively)

decreased heart rate variability ( J:105620 )

• at 6 months of age, HR variability is lower in conscious female homozygotes relative to wild-type controls over all frequency ranges

• total HR variability is only 43% of the value in wild-type female mice

increased heart rate ( J:105620 )

• at 6 months of age, conscious female homozygotes exhibit a ~7% increase in heart rate relative to wild-type females (514 5 vs 481 5 beats/min, respectively)

• however, no significant differences in respiratory rate are observed

abnormal systemic arterial blood pressure ( J:105620 )

• at 6 months of age, conscious female homozygotes show a significnat increase in BP variability within specific frequency ranges, namely the mid and high frequency bands

• specifically, the mid frequency power (0.3-0.5 Hz) corresponding to the autonomic range is 1.7 times greater while the high frequency region (0.5-1 Hz) is 2.4 times greater in female homozygotes relative to wild-type controls

• however, the overall BP variability (0-1 Hz) is not statistically different between mutant and wild-type females

decreased mean systemic arterial blood pressure ( J:105620 )

• at 6 months of age, conscious female homozygotes show a 4.5 2.0 mm Hg reduction in MAP relative to wild-type females

decreased systemic arterial diastolic blood pressure ( J:105620 )

• at 6 months of age, conscious female homozygotes show a lower diastolic arterial pressure than wild-type females (86.5 0.4 vs 92.6 0.5 mm Hg, respectively)

• however, no significant differences in the systolic blood pressure are observed

cellular

abnormal male germ cell morphology ( J:56358 )

♂

abnormal acrosome assembly ( J:56358 )

♂ • at 1 yr of age, tubules with early spermiogenic arrest exhibit defects in early acrosomal development

♂ • multiple acrosomal vesicles are observed and, in some cases, acrosomes fail to uniformly spread over the spermatid nuclei

abnormal spermatid morphology ( J:56358 )

♂ • at 1 yr of age, male homozygotes show a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells relative to wild-type males

decreased male germ cell number ( J:56358 )

♂ • at 1 yr of age, no significant decreases are observed in Sertoli cell numbers or in spermatogonia and spermatocyte populations; however, significantly less round and elongated spermatids are present in the mutant epithelium relative to wild-type controls

♂ • at 4.5 months of age, the numbers of Sertoli cells, spermatogonia, spermatocytes, round spermatids, and elongated spermatids are comparable to those of wild-type males

multinucleated giant male germ cells ( J:56358 )

♂

increased male germ cell apoptosis ( J:56358 )

♂ • at 1 yr of age, decline in round spermatid number is due to increased cell death in the adluminal compartment of the seminiferous epithelium

increased granulosa cell apoptosis ( J:63458 )

♀ • marked apoptosis in granulosa cells of larger, antral size follicles at 10-12 weeks of age

♀ • by 1 yr of age, granulosa cell apoptosis is widespread throughout the ovary, as indicated by TUNEL analysis

nervous system

abnormal baroreceptor physiology ( J:105620 )

• at 6 months of age, the baroreflex sensitivity (BRS) in female conscious homozygotes is 46% of the value observed in wild-type females

muscle

increased cardiac muscle contractility ( J:105620 )

• at 6 months of age, the maximum rate of change in blood pressure (dP/dT) occuring during systole is 40% higher in conscious female homozygotes relative to wild-type controls (1427 9 vs 1019 14 mm Hg/sec, respectively)

integument

abnormal coat/hair pigmentation ( J:48086 )

• at 3 weeks of age, both male and female homozygotes exhibit a dull coat

digestive/alimentary system

abnormal salivary gland morphology ( J:92438 )

• massive leukocytic infiltration with destruction of acinar cells in the salivary glands of mice fed a phytoestrogen-free diet

enlarged salivary gland ( J:92438 )

• enlarged salivary glands in mice fed a phytoestrogen-free diet, although it is unclear if salivary gland/body weight ratio is normal or increased

salivary gland inflammation ( J:92438 )

• massive leukocytic infiltration with destruction of acinar cells in the salivary glands of mice fed a phytoestrogen-free diet

• mice raised on a phytoestrogen-free diet develop Sjogren-like syndrome by 12-17 months of age, showing presence of massive infiltration of B220+ B lymphocytes, presence of an alpha-fodrin fragment (120 kDa) in the salivary gland, and higher levels of serum anti-fodrin antibody than wild-type mice fed this diet

growth/size/body

ovarian follicular cyst ( J:63458 )

♀ • hemorrhagic cystic follicles are observed by 21-23 weeks of age

obese ( J:92438 )

• mice become obese with age when fed a phytoestrogen-free diet

enlarged spleen ( J:92438 )

• all mice over 1 year of age develop mild splenomegaly when fed a phytoestrogen-free diet

spleen hyperplasia ( J:92438 )

• splenic cellularity is increased by 2- to 4-fold in mice fed a phytoestrogen-free diet

hematopoietic system

enlarged spleen ( J:92438 )

• all mice over 1 year of age develop mild splenomegaly when fed a phytoestrogen-free diet

spleen hyperplasia ( J:92438 )

• splenic cellularity is increased by 2- to 4-fold in mice fed a phytoestrogen-free diet

increased bone marrow cell number ( J:92438 )

• progressive bone marrow hyperplasia with over production of mature granulocytes and B cells in mice fed a phytoestrogen-free diet

increased leukocyte cell number ( J:92438 )

• number of leukocytes, particularly lymphocytes, in peripheral blood is increased by 1.5- to 2-fold in aged mice fed a phytoestrogen-free diet

• absolute number of leukocytes in the bone marrow of mice fed a phytoestrogen-free diet is more than 3-fold that in wild-type mice at 12-16 month of age

increased granulocyte number ( J:92438 )

• 2-fold increase in the percentage of granulocytes in the bone marrow of 12- to 16-month old mice fed a phytoestrogen-free diet

increased lymphocyte cell number ( J:92438 )

• in aged mice fed a phytoestrogen-free diet

increased B cell number ( J:92438 )

• increase in the population of B220+ B lymphocytes in the blood of aged mice fed a phytoestrogen-free diet

• 2-fold increase in B220+ B lymphocytes in the bone marrow of 12- to 16-month old mice fed a phytoestrogen-free diet

increased mature B cell number ( J:92438 )

• the mature B cell compartment (IgM+/B220+) is increased, while the proportion of IgM+/B220- B cells is decreased in the spleen of mice fed a phytoestrogen-free diet

abnormal spleen germinal center morphology ( J:92438 )

• germinal center formation is seen in the spleen of mice fed a phytoestrogen-free diet, indicating immunological activation

increased IgG level ( J:92438 )

• aged mice fed a phytoestrogen-free diet show mild depositions of IgG in renal glomeruli, but no depositions of IgM or IgA are detected

immune system

salivary gland inflammation ( J:92438 )

• massive leukocytic infiltration with destruction of acinar cells in the salivary glands of mice fed a phytoestrogen-free diet

• mice raised on a phytoestrogen-free diet develop Sjogren-like syndrome by 12-17 months of age, showing presence of massive infiltration of B220+ B lymphocytes, presence of an alpha-fodrin fragment (120 kDa) in the salivary gland, and higher levels of serum anti-fodrin antibody than wild-type mice fed this diet

enlarged spleen ( J:92438 )

• all mice over 1 year of age develop mild splenomegaly when fed a phytoestrogen-free diet

spleen hyperplasia ( J:92438 )

• splenic cellularity is increased by 2- to 4-fold in mice fed a phytoestrogen-free diet

increased leukocyte cell number ( J:92438 )

• number of leukocytes, particularly lymphocytes, in peripheral blood is increased by 1.5- to 2-fold in aged mice fed a phytoestrogen-free diet

• absolute number of leukocytes in the bone marrow of mice fed a phytoestrogen-free diet is more than 3-fold that in wild-type mice at 12-16 month of age

increased granulocyte number ( J:92438 )

• 2-fold increase in the percentage of granulocytes in the bone marrow of 12- to 16-month old mice fed a phytoestrogen-free diet

increased lymphocyte cell number ( J:92438 )

• in aged mice fed a phytoestrogen-free diet

increased B cell number ( J:92438 )

• increase in the population of B220+ B lymphocytes in the blood of aged mice fed a phytoestrogen-free diet

• 2-fold increase in B220+ B lymphocytes in the bone marrow of 12- to 16-month old mice fed a phytoestrogen-free diet

increased mature B cell number ( J:92438 )

• the mature B cell compartment (IgM+/B220+) is increased, while the proportion of IgM+/B220- B cells is decreased in the spleen of mice fed a phytoestrogen-free diet

abnormal spleen germinal center morphology ( J:92438 )

• germinal center formation is seen in the spleen of mice fed a phytoestrogen-free diet, indicating immunological activation

increased IgG level ( J:92438 )

• aged mice fed a phytoestrogen-free diet show mild depositions of IgG in renal glomeruli, but no depositions of IgM or IgA are detected

enlarged mesenteric lymph nodes ( J:92438 )

• all mice over 1 year of age develop lymphoadenopathy when fed a phytoestrogen-free diet

increased autoantibody level ( J:92438 )

• mice fed a phytoestrogen-free diet have autoantibodies against filamentous cytoskeletal proteins

kidney inflammation ( J:92438 )

• kidneys of mice fed a phytoestrogen-free diet show massive infiltration of B lymphocytes, many of which are plasma cells

• however, glomerulonephritis is not seen in aged mice

renal/urinary system

increased urine protein level ( J:92438 )

• in mice fed a phytoestrogen-free diet

kidney inflammation ( J:92438 )

• kidneys of mice fed a phytoestrogen-free diet show massive infiltration of B lymphocytes, many of which are plasma cells

• however, glomerulonephritis is not seen in aged mice

renal glomerular immunoglobulin deposits ( J:92438 )

• aged mice fed a phytoestrogen-free diet show mild depositions of IgG in renal glomeruli

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Sjogren's syndrome		DOID:12894	OMIM:270150	J:92438

Genotype
MGI:3814613

hm3

• Allelic Composition: Cyp19a1^tm1Esi/Cyp19a1^tm1Esi
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6J

behavior/neurological

abnormal short-term spatial reference memory ( J:89632 )

• at ~3 months of age, both male and female homozygotes show a significant reduction in the total time spent in the novel arm of the Y-maze recognition task relative to wild-type controls

• both male and female mutants spent an equal time exploring all three arms of the Y-maze, suggesting a failure to recognize the novel arm

• gonadectomy reduces Y-maze responses in male and female wild-type controls, but has no effect in mutant mice

• after gonadectomy, there is no significant difference in the percentage time spent in the novel arm between mutant mice and wild-type controls

• notably, male and female mutants are NOT found to display increased anxiety-induced freezing or reduced explorative behavior in the elevated plus maze task

abnormal emotion/affect behavior ( J:129528 )

• at 6 months of age, male (but not female) homozygotes develop compulsive behaviors including excessive barbering, grooming and wheel running

• male-specific excessive wheel running and grooming activities are accompanied by a significant decrease in catechol-O-methyltransferase (COMT1) protein expression in the hypothalamus and can be reversed by 3 weeks of 17beta-estradiol treatment

abnormal barbering behavior ( J:129528 )

• at 6 months of age, male homozygotes display extreme barbering with a significant increase in facial hair loss relative to wild-type controls

• no significant differences are observed in barbering activity between female homozygotes and wild-type control females

increased grooming behavior ( J:129528 )

• at 6 months of age, male homozygotes show a significant increase in grooming activity, both in terms of frequency of initiation and duration of grooming, as analyzed during a 20-min period immediately after a water-mist spray

• male-specific excessive grooming activities are accompanied by a significant decrease in COMT1 protein expression in the hypothalamus and can be reversed by 3 weeks of 17beta-estradiol treatment

• no significant differences in grooming activity are observed between female homozygotes and wild-type control females

abnormal locomotor activation ( J:129528 )

• at 6 months of age, male homozygotes display a significant increase in wheel running activity relative to wild-type controls; excessive wheel running is male-specific and can be suppressed upon 17beta-stradiol replacement

• in contrast, male homozygotes display a significantly reduced general ambulatory activity, indicating a specific increase in wheel running as opposed to a general hyperactivity

• no significant differences are observed in either wheel running or ambulatory activity between female homozygotes and wild-type control females

• no stereotypic behaviors such as barmouthing, jumping, somersaulting or route-tracing are observed in male homozygotes housed in an "enriched environment"

Genotype
MGI:5428435

cx4

• Allelic Composition: Apoe^tm1Unc/Apoe^tm1Unc; Cyp19a1^tm1Esi/Cyp19a1^tm1Esi
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6

growth/size/body

increased body weight ( J:184647 )

• increased body weight at 3, 6, and 12 months of age

increased liver weight ( J:184647 )

• increase in liver weight at 3 and 6 months of age

cardiovascular system

abnormal aorta bulb morphology ( J:184647 )

• 3 month old mutants exhibit small aortic root lesions that are extensive at 6 months of age

• double mutants tend to have slightly larger lesion sizes than single Apoe mutants

atherosclerotic lesions ( J:184647 )

• mutants develop large atherosclerotic lesions in the aortic root by 12 months of age; lesions are advanced in development and show a clear fibrous component

• however there is little evidence of atherosclerotic plaque formation within the thoracic aorta with only small lesion development seen in the thoracic aorta at 12 months of age

increased systemic arterial blood pressure ( J:184647 )

• mutants have moderately increased mean arterial blood pressure at 3 months of age

hypertension ( J:184647 )

• mutants develop hypertension by 6 months of age which is sustained in older animals

adipose tissue

increased fat cell size ( J:184647 )

• mutants exhibit an increase in adipocyte size with a larger mean diameter compared to wild-type adipocytes, however no difference in the number of individual adipocytes

abnormal gonadal fat pad morphology ( J:184647 )

• increase in gonadal adipose

homeostasis/metabolism

increased circulating glucose level ( J:184647 )

• 3 month old mutants show a small elevation in baseline blood glucose concentration after an overnight fast

decreased circulating insulin level ( J:184647 )

• mutants of all ages show reduced plasma insulin levels

decreased circulating HDL cholesterol level ( J:184647 )

increased circulating cholesterol level ( J:184647 )

• random-fed non-fasting mutants show an increase in serum cholesterol levels

increased circulating LDL cholesterol level ( J:184647 )

increased circulating VLDL cholesterol level ( J:184647 )

increased circulating triglyceride level ( J:184647 )

increased circulating C-reactive protein level ( J:184647 )

• plasma levels of C-reactive protrein (CRP) are increased in 12 month old mutants

increased circulating interleukin-6 level ( J:184647 )

• plasma levels of IL-6 are increased in 12 month old mutants

increased circulating tumor necrosis factor level ( J:184647 )

• plasma levels of TNF-alpha are increased in 12 month old mutants

impaired glucose tolerance ( J:184647 )

• mutants administered a bolus of glucose show elevated plasma glucose

insulin resistance ( J:184647 )

• 3 month old mutants show a blunted plasma glucose response in response to exogenous insulin administration; this blunted response becomes more pronounced with age

immune system

increased circulating C-reactive protein level ( J:184647 )

• plasma levels of C-reactive protrein (CRP) are increased in 12 month old mutants

increased circulating interleukin-6 level ( J:184647 )

• plasma levels of IL-6 are increased in 12 month old mutants

increased circulating tumor necrosis factor level ( J:184647 )

• plasma levels of TNF-alpha are increased in 12 month old mutants

liver/biliary system

abnormal liver morphology ( J:184647 )

• from 6 months of age, livers begin to show yellow coloration

increased liver weight ( J:184647 )

• increase in liver weight at 3 and 6 months of age

increased susceptibility to age-related hepatic steatosis ( J:184647 )

• 3 month old mutants start to show small lipid droplets forming within livers which become more pronounced at 6 and 12 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
abdominal obesity-metabolic syndrome		DOID:0060611	OMIM:PS605552	J:184647